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Copy Review Submission Cover Sheet

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Item Number:

02A12002 4/17/2012 Rx for Safety Update to JPI Website

Copy Review Submission Cover Sheet for Websites, Micro Sites & Portals

Submitted On: Project Name: Category: Brand:

Anti-Infectives

Your Item Number is Available. Please Complete the Copy Review Submission Cover Sheet.
Instructions Copy Review Submission for Websites Instructions Detailed Instructions Submission Information DATES CRC Mtg. Target: Estimated 1st Use: 4/30/2012 5/12/2012 Name: Phone: (NEW) PROJECT OWNER Willliam Foster 908.704-4404 IT CONTACT Name: Phone: Antoine Bryan 609.730.7985 Agency: Contact: Phone: e-Mail: Agency Job # AGENCY [ Internal ] ----wfoster@its.jnj.com

Link and Password (to Website, Micro Site or Portal, if theres no password indicate NA) http://devjanssenpharmaceuticalsinc.jnj.com/ourproducts/rx-for-safety

Link:

Password:

NA

PRC Quality Submission Checklist Current approved product labeling Correct Indication(s) Current Important Safety Information All references supporting promotional claims and other data points have been included, e.g., reference sources noted Reference numbers cited are correctly linked to the appropriate reference articles and the relevant text or graphs in the reference materials have been highlighted to facilitate review. References from website sources should include the complete URL and the date the site was accessed. NOTE: Previously approved pieces cannot be used as a reference. Any previously PRC - approved material that may assist in the review should be included as "back-up"

i j k l m n Yes n N/A j k l m
i j k l m n Yes n N/A j k l m

i j k l m n Yes n N/A j k l m
j k l m n Yes n N/A i j k l m

j k l m n Yes n N/A i j k l m

j k l m n Yes n N/A i j k l m

https://ireviewext.janssen.com/form.asp?formid=23&wfdirect=&debug=&con_wfid=0&co... 4/18/2012

Copy Review Submission Cover Sheet

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Privacy statement, training disclaimers, etc. (if applicable) Directional statement for Prescribing Information and additional Important Safety Information and Boxed Warning (if applicable) Trademarks are acknowledged - proper use of J & J company trademarks and trademark attributions Company logo, copyright line, date and correct item number All fields completed on the Copy Submission Cover Sheet including: objective and description, intended use and audience; Copy Submission Cover Sheet attached to submission Revisions to PRC - approved pieces include original PRC approved copy PDF as backup and all revisions from the prior version are highlighted

i j k l m n Yes n N/A j k l m
i j k l m n Yes n N/A j k l m

i j k l m n Yes n N/A j k l m i j k l m n Yes n N/A j k l m i j k l m n Yes n N/A j k l m

j k l m n Yes n N/A i j k l m

Copy

References

Review Code Selection Audience Consumer

Promotional Review Filtering Guidance Document Category Interactive Digital Item - NEW Review Code RLMPC

Website / Micro Site / Portal Information Who is hosting this website or portal?

i j k l m n A J&J company (including ITS formerly NCS)


j k l m n Other

If a company other than ITS (formerly NCS) or J&J is hosting the website, have they gone through a Vendor Risk Assessment? Does this website or portal contain links to other websites? Comments

j k l m n Yes n No j k l m

i j k l m n Yes n No j k l m
Submitting this update to the Rx for Safety section, which currently exists on the JPI web site, on behalf of Tina Estabrook of the Established Products Group.

Intended Audience:

b c d e f g Healthcare Professionals b c d e f g Consumers b c d e f g Pharmacists b c d e f g Managed Care b c d e f g Patients b c d e f g Long-Term Care c d e f g Other:

Does this item contain alternative sampling? .g. coupon, rebate, voucher, debit card,

https://ireviewext.janssen.com/form.asp?formid=23&wfdirect=&debug=&con_wfid=0&co... 4/18/2012

Copy Review Submission Cover Sheet

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check hat functions as a coupon, e-sampling, e-detailing w/sampling, direct mail with BRC offering samples, loyalty card, etc. Does this item use or request personal info such as name, date of birth, etc? CRC Privacy Form

j k l m n Yes n No i j k l m

If yes, you must complete the CRC Privacy Form.

j k l m n Yes n No i j k l m
CRC Privacy Form

If yes, you must complete the CRC Privacy Form. Click on the link to the left to complete the Privacy Form. This will open a new browser window. Complete that form, then press the submit button below to complete this submission.

c d e f g I do not want to submit this yet; I want to save it for later.


Comps are still required for all submissions.

https://ireviewext.janssen.com/form.asp?formid=23&wfdirect=&debug=&con_wfid=0&co... 4/18/2012

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Prescription for Safety


Learn about safety tips and resources to help get the full benefit of medication while avoiding problems. For Patients For Physicians For Pharmacists Medication Guides Glossary

Product List Rx for Safety


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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Product List Rx for Safety


For Patients
Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

Prescription medicines have many benefits, yet it is important to understand that they are not risk free. By becoming well-informed about your medications and how to use them properly, you can help to ensure that you: Get a medications full benefits

Avoid potential problems such as side effects

is it not possible to avoid all side effects- can we rephrase?

Doctors, pharmacists and other healthcare professionals can help you better understand the benefits and risks associated with the medicines you take. In addition to seeking advice and information from healthcare professionals, doing your own homework on your medications is a great way to become a more informed patient.

For Physicians For Pharmacists Medication Guides Glossary

your

This section is designed to help you have productive and informative conversations with doctor, pharmacist and other healthcare professionals, and provide you with valuable information to help you use your medications safely and effectively. Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Becoming a More Informed Patient most of what is Product List Medication errors can happen in a variety of settings, but discussed has Rx for Safety nothing to do with most occur in a doctors office, pharmacy, hospital, or at a For Patients home. Although some medication errors result in Becoming a More medication error- inconvenience or discomfort and may go undetected, in the Informed Patient Tips for Avoiding delete this whole worst cases, medication errors can cause serious health Medication Errors problems or even death. paragraph Patient Resources
Reading a Package Insert

Being better informed about your prescription medications will help you get the most benefit from them and will help prevent medication errors.

For Physicians For Pharmacists Medication Guides Glossary

Getting Started: Know Your Medical History


A good place to start on the road to being an informed patient is to become familiar with your own medical history

including prescription medications, over the counter medications, vitamins and supplements, and herbal treatments

and the highlights of your familys medical history. Create a list of the medicines you take as well as information about surgeries, vaccinations, and allergies, and share this with any healthcare professional you visit so that he or she can develop the best possible treatment plan for you. Also, document important information from your familys medical history. Include information about close relatives who have or had conditions such as cardiovascular disease, diabetes, cancer, addictions, or intolerances. Using a personal medical log book can help keep all of this important information in one place.

Talk to Your Doctor and Other Healthcare Professionals


Tell your doctor and other healthcare professionals about any changes in your daily life, including an increase/decrease in sleep, a special diet, or changes in schedule. You should also inform your healthcare professionals of the following: Any allergies to medications, or if you suspect you have previously experienced an adverse or allergic reaction to a particular medicine If you are currently pregnant, have plans to become pregnant, or if you are nursing a baby Illnesses or problems for which another doctor or healthcare professional is currently treating or has recently treated you

Ask About Side Effects

than others?

A side effect or adverse reaction is an unwanted effect of a medication or therapy that occurs in addition to its intended effect. Some side effects are more predictable. Known and common side effects are listed in the printed information that comes with every drug. Some adverse reactions occur unexpectedly, some may be serious and some cannot be predicted. Serious adverse reactions are generally rare. The causes of adverse reactions include medication errors, such as overdose, interactions between drugs, or interactions between drugs and certain foods. Call your doctor, pharmacist or other healthcare professional immediately if you think you have experienced an adverse reaction to a medication. Your doctor, pharmacist or other healthcare professional can help you anticipate, understand and deal with side effects. Ask them any questions or discuss any concerns you have about your medications.

allergy to the medication, or direct action of the medication

Follow Prescription Directions


Always take medications as instructed by your doctor, pharmacist or other healthcare professional, and do not change the way you take them unless instructed by them to do so. With certain medications, some precautions are especially important. For example, if a

add a new section: Read the Medication Guide or other materials provided to you by your doctor or pharmacist

medication can cause drowsiness, you should not drive a car or operate heavy machinery while taking it. Other medications may require you to avoid certain foods or ingredients, such as alcohol or caffeine. If you are going to travel, find out if your medication can be used in different climates and if any adjustments are needed for changing time zones. If you are a caregiver for a child or another adult, you may have to remind him or her to take a medication, or you may need to administer it yourself. If your child goes to school, contact the school nurse for help in making sure your child's medicine is taken on time and safely.

Monitor Your Reactions


Side effects of prescription medicines can be due to many possible causes. If you experience unusual symptoms that begin after you start taking a new medication, contact your doctor, pharmacist or other healthcare professional immediately. It is important to determine if a symptom was drug-related and whether or not you should continue taking the medicine. In addition, for each medication, you should learn to recognize the signs of overdose and whether you should call a poison control center or another emergency number in the event that you or a family member experiences an overdose. Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

Using Your Medications Tips for Avoiding Medication Errors Correctly


caused by: Incomplete information provided by a patient to their doctor

Avoiding medication errors is key to getting the full benefit of any medication, and to help minimize the risk of side effects and other unwanted results. Medication errors are commonly

Incomplete information about a medication, such as warnings or side effects Poor communication regarding a prescription, such as illegible handwriting, confusion between similar drug names, misuse of zeroes or decimal points, or inappropriate abbreviations Lack of appropriate labeling on the drug container or pharmacy shelf

For Physicians For Pharmacists Medication Guides Glossary

Listed below are tips to help you avoid medication errors in a variety of settings.

At the Doctor's Office:


Before your appointment, make a complete list of all medications you take, including prescription, and non-prescription or over-the-counter medicines and nutritional or herbal supplements. Whenever your medications change, be sure to update your list Take your medications list with you to every doctors appointment Ask your doctor to explain your prescription, including the drug name, how you should take it, what the purpose of the medication is, and when you should call your doctor while taking the medication At least once a year, bring all of your medicines with you to your doctors appointment this way you can talk about all aspects of your medications and your doctor can make certain your records are up to date As you age, some drugs may affect your body differently, so ask your doctor periodically if it may be time to adjust dosages of medications you have been taking for a long time

At the Pharmacy

ensuring you take your medications safely

Pharmacists play a major role in preventing medication errors. Using one pharmacy will help your pharmacist keep a complete record of all your prescription medicines and cross-check for potential drug interactions. If you get an emergency or mail-order prescription filled elsewhere, bring the container to your usual pharmacist, so the information can be entered into your file. When picking up a prescription, be sure your pharmacist gives you printed information about your medication and you have clear answers to the following questions: What are the brand and generic names of the medication? What should the medication my doctor prescribed look like? Why am I taking it? How much should I take and how often? Is there a best time to take it? How long will I need to take it? Are there potential side effects, and what should I do if they happen? What should I do if I miss a dose? Does this medication interact with my other medications or with any foods? Does this medication replace anything else I have been taking? Where and how should I store it? How soon should I start to feel better? When should I report back to my healthcare professional? Should I avoid any liquids, foods, other substances or activities while using this medicine? Could I become tolerant, dependent or addicted to this medicine? If so, how can I avoid this? Where can I get more information about this medicine? Will it affect my pregnancy/nursing? If the directions say to take the medication every three or four hours, ask if that means throughout the night as well as during the day Is this medication available in a child-resistant container? What is this medications expiration date? When you buy over-the-counter medications, read the labels carefully they may contain ingredients you do not want or should not take. Ask your pharmacist for help if you have difficulty selecting the right product.

In the Hospital
Take your medications and your list of medications with you when you go to the hospital. The healthcare professionals there will need to know what youre taking Ask your doctor the name of each medication he or she prescribes for you and the reason you are taking it. If someone tells you anything different, you will know to ask questions, which may prevent errors Look at every medicine before you take it. If it does not look like what you usually take, ask why Do not let anyone give you medications without them checking your hospital identification bracelet each time. This helps prevent you from getting someone elses medications Before any test or procedure, ask if it will require any dyes or medicines to avoid allergic reactions When youre ready to go home, have the doctor, nurse or pharmacist discuss each medication with you and a family member. Update your medications list if any prescriptions change or if new medications are added

At Home
Keep medications in their original, labeled containers. This can help you identify each pill and to follow the proper directions After opening a container of medicine, take out the cotton plug, which may draw moisture into the container Do not store medications in the bathroom medicine cabinet or in direct sunlight, because humidity, heat, and light can affect a medications potency and safety Do not store medicines in the refrigerator unless instructed to do so, and keep liquid medicines from freezing Store medications where children cannot see or reach them for example, in a locked box or cabinet. Teach children that medications can be dangerous if misused Keep medications for people separate from pet medications or household chemicals Do not keep tubes of ointments or creams next to a tube of toothpaste. They may feel similar when you grab quickly Do not chew, crush or break capsules or tablets unless instructed to do so With liquid medication, use only the measuring device that came with it. Many household teaspoons and tablespoons are not accurate Keep phone numbers for your doctors and pharmacist in a convenient location, along with the numbers of your local EMS and poison control centers. Know the locations of pharmacies that are open 24 hours a day in case of an emergency Do not take medications in the dark although you may think you know exactly what the bottle on your nightstand contains, turn on a light to be sure Never take another person's prescription medication or share yours with anyone, even if the other person appears to have the same medical condition as you This information above was compiled from the following sources: Institute for Safe Medication Practices; U.S. Food & Drug Administration; Agency for Healthcare Research and Quality; and American Society of Health-System Pharmacists. If you think you have experienced a serious adverse reaction or other problem such as suspected counterfeiting or contamination with your medication, contact your doctor and report it on the FDAs Web site, MedWatch. Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

Drug companies prepare a product label, also referred to as a package insert, product dispense prescription medicines. The PI is a valuable resource for learning about your medication.

The PI is for HCPsdelete this sentence

information or prescribing information (PI), for healthcare professionals who prescribe or

Another medication guide resource for learning about a medication is a Patient Package Insert or Medication prescription does not include a Patient Package Insert, ask your doctor, pharmacist, or healthcare professional for this information.

For Physicians For Pharmacists Medication Guides Glossary

Guide. One of these may be included with some, but not all, prescription medications. If your

not all web sites have accurate information, The Internet offers a wealth of medical information; however, Web sites cannot cover all of a in medication's possible uses, actions, precautions, side effects, and interactions or provide addition,
Internet Resources
information specifically for you. Discussing your questions or concerns with your doctor, into your own treatment plan. If you do wish to locate more information about medications and medication errors, the following associations can be of help: American Pharmacists Association (APhA) 2215 Constitution Avenue, NW Washington, DC 20037-2985 Phone: (202) 628-4410 E-mail: No general e-mail address, but the site provides many addresses, depending on specific needs. Web site: www.aphanet.org Patient safety site: www.pharmacyandyou.org APhA is a professional association of U.S. pharmacists, providing information, education and advocacy to help its members improve medication use and advance patient care. American Society of Health-System Pharmacists (ASHP) 7272 Wisconsin Avenue Bethesda, Maryland 20814 Phone: (301) 657-3000 Web site: www.ashp.com Medication safety site: www.safemedication.com ASHP is the professional association representing pharmacists who practice in hospitals, health maintenance organizations, long-term care facilities, home care and other components of healthcare systems. Medication safety is a primary focus of ASHPs efforts. National Council on Patient Information and Education (NCPIE) 4915 Saint Elmo Ave., Suite 505 Bethesda, Maryland 20814-6082 Phone: (301) 340-3940 Web site: www.talkaboutrx.org NCPIE is a non-profit coalition of more than 125 organizations whose mission is to stimulate and improve communication of information on the appropriate use of medicines to patients and healthcare professionals. NCPIE develops programs, provides educational resources, and offers services to advance the common mission of its members. U.S. Food and Drug Administration (FDA) 5600 Fishers Lane Rockville, Maryland 20857-0001 Phone: 1-888-INFO-FDA (1-888-463-6332) E-mail: E-mail the Center for Drug Evaluation and Research directly from the site Web site: www.fda.gov Patient safety site: http://www.fda.gov/drugs/drugsafety/medicationerrors/default.htm (Center for Drug Evaluation and Research) Patient education: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM111085 The patient safety site includes medication error reports, a list of specific drugs associated with errors, directions for reporting a medication error, and federal guidelines. Downloadable resources related to medication safety are available on the patient education page. For information on individual drugs, visit the Consumer Drug Information page. Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert pharmacist, or other healthcare professional is the best way to find out how any medicine fits

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Reading a Package Insert


The Package Insert, also referred to as a "PI," "Prescribing Information" or "Labeling" is prepared by a medication's manufacturer for healthcare professionals who prescribe or dispense prescription medicines. Your pharmacy should have a current Package Insert for any drug that it dispenses. Reading the package insert cannot substitute for a discussion with your doctor, pharmacist or other healthcare professional about any medication you are about to take. The U.S. Food and Drug Administration (FDA) requires prescription drug labeling to contain specific information. Package Insert styles vary from company to company, but generally they must include information under the following section headings and in the order listed.

Product List Rx for Safety


For Patients
Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

For Physicians For Pharmacists Medication Guides Glossary

Description
This section of a PI contains the following general information: The generic name (sometimes referred to as the scientific or chemical name) and the brand name of the drug Dosage form (for example, capsules, tablets, liquid) and the way it is administered (for example, pill, shot, cream) Pharmacological or therapeutic class (for example, antibiotic, pain reliever, antidepressant) Chemical name and structural formula of the drug Other important chemical or physical information, if appropriate

Clinical Pharmacology
Clinical pharmacology refers to the properties and actions of the drug or how it works in the body. If the drug's method of action is unknown or if certain information is unavailable, the labeling will contain a statement to that effect.

Indications and Usage


This section contains information about the treatment of the particular diagnosis or diagnoses for which the FDA has approved the drug. However, drugs can sometimes be prescribed for reasons other than the FDA-approved indications based on currently available clinical data. Ask your doctor, pharmacist or other healthcare professional if you have questions about why a particular drug has been prescribed for you.

Contraindications
The contraindications section describes situations in which the drug should not be used because the risk of using it clearly outweighs the benefit. If no contraindications are known, this section of the labeling will state "None known."

Warnings
This section describes serious adverse reactions and potential safety hazards, the limitations they impose on use of the drug, and steps that should be taken if they occur. The FDA may require that notification of any special problems associated with the drug be placed in a prominently displayed box called a "black box."

Precautions
This section of the PI includes precautions for most individuals taking the drug, as well as for specific groups, such as pregnant women, nursing mothers or children. In this section, you will find recommendations for patients to ensure safe and effective use of the drug. For example, there may be precautions about driving when taking the medication or using substances such as other drugs, food or alcohol that may have harmful effects if taken while using the medication. The Precautions section also provides information about lab tests needed to track responses or to identify adverse reactions to the drug or about known interactions with other drugs, foods or ingredients.

Adverse Reactions
An adverse reaction is an undesirable effect that may be associated with use of a drug. Causes of adverse reactions can include medication errors, such as overdosage, or interactions between different drugs or between drugs and certain foods. This section of the PI lists the adverse reactions that occur with the drug and with other similar or related drugs, if applicable.

Drug Abuse and Dependence


Here you will find information if the drug is considered to have potential for abuse, dependence or withdrawal. Examples of drugs that may fall into this category are amphetamines and certain pain relievers.

Overdosage
This section describes the signs, symptoms and laboratory findings associated with an overdosage of the drug, as well as complications that can occur with it.

Dosage and Administration


This section states the usual recommended dose, the usual dosage range and, if appropriate, an upper limit beyond which safety and effectiveness have not been established. Also included in this section is information about the recommended timing between doses, the usual duration of treatment and any modification of dosage needed for special patient populations such as children or people with particular diseases.

How Supplied
The How Supplied section has information on the dosage forms in which the medication is available. This information generally includes: Strength of the dosage forms, such as 10-milligram tablets Units in which the dosage form is usually available for prescribers (for example, bottles of 100) Information such as shape and color to help identify the dosage forms Special handling and storage conditions

Additional Sections
The labeling may also contain these additional section headings if appropriate and in compliance with federal regulations: Animal pharmacology. In most cases, the labeling does not need to include this section. Significant animal data necessary for safe and effective use of the drug in humans will usually be included in one or more of the other sections of the labeling. Clinical studies or references. A reference to an important clinical study may appear in any section of the label.

Becoming a More Informed Patient Tips for Avoiding Medication Errors Patient Resources Reading a Package Insert

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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For Patients For Physicians
Healthcare Professional Resources Example of Medical Errors

Reducing Medication Errors Information for Healthcare Professionals


With the ever-increasing number of available prescription medications, opportunities for errors related to drug names, packaging, indications and adverse events are also increasing. Healthcare professionals must play a key role in preventing errors from occurring and in helping protect patients from harm when errors do occur. This section, intended for professional use, suggests measures that healthcare professionals can take to enhance medication safety and provides links to additional professional resources.

For Pharmacists Medication Guides Glossary

Defining medication error


The National Coordinating Council for Medication Error and Prevention (NCCMERP), a national coalition of 20 organizations focused on prevention of medication errors, has approved this working definition of medication error: "Any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the healthcare professional, patient, or patient. Such events may be related to professional practice, healthcare products, procedures, and systems including: prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use." Medication use is a complex process that includes a series of stepsmedication prescribing, order processing, dispensing, administration and effects monitoringany one of which could lead to medication error. Several national organizations whose missions are focused on enhancing the safe use of prescription medicines have developed practical guidelines and tips for healthcare professionals. The following represents some of their key recommendations.

Tips for healthcare professionals to reduce medication errors


Miscommunication between physicians, pharmacists and nurses is a common cause of medication errors. To minimize medication errors caused by miscommunication, it is important to verify drug information and eliminate communication barriers. Prescribers should avoid using abbreviations, including those for drug names because they can be misunderstood. Some examples of risky abbreviations include: g (microgram)can be mistaken for "mg" when handwritten and should be written as mcg q.d. or QD (every day)can be mistaken as q.i.d., especially if the period after the "q" or the tail of the "q" is misread as an "i"; "daily" or "every day" preferred IU (international unit)can be misread as IV; "units" preferred No zero before decimal point in dosage, for example, .5 mg (for 0.5 mg)can be misread as 5 mg. Obtaining the patient's pertinent demographic and clinical information will help practitioners select the appropriate medications, doses and routes of administration. Having complete patient information at the time of prescribing will result in a significant decrease in preventable adverse drug events (ADEs). Write prescriptions legibly and clearly, printing in block letters rather than writing in cursive. More than 15 percent of the prescription errors in the USP Medication Error Reporting database resulted from poor handwriting and misinterpretation of medication orders. Educate patients by using brochures when speaking to them. "Your Medicine: Play It Safe" is available through the National Council on Patient Information and Education and the Agency for Healthcare Policy and Research by calling (301) 340-3940 or by visiting www.talkaboutrx.org Take an inventory of a patient's medications. Have patients bring in all of their medications, including over-the-counter drugs and those prescribed by other physicians. Designate a special place for a detailed medication history in charts. Providing accurate and usable drug information to all healthcare professionals involved in the medication use process reduces the number of preventable ADEs. Not only should drug information be readily accessible from various sources such as drug references, formulary, protocols, dosing scales, but also the drug information must be up-to-date and accurate. Staff education should focus on priority topics, such as: new medications being used in the hospital, high-alert medications, medication errors that are known to have occurred both internally and externally, protocols and policies and procedures related to medication use. The FDA encourages healthcare professionals to report any actual or potential medication errors to the agency's MedWatch Adverse Reporting System online at www.fda.gov/medwatch, by phone at (800) 332-1088 or by fax at (800) 332-0178. Caller identification is kept confidential and is protected from disclosure by the Freedom of Information Act. For tips provided to pharmacists on how they can reduce medication errors, visit the Pharmacist Education section.

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Healthcare Professional Resources


American Medical Association (AMA)
515 N. State Street Chicago, Illinois 60610 Phone: (800) 621-8335 E-mail: Can e-mail the AMA directly through the site Web site: www.ama-assn.org The AMA's envisioned future is to be an essential part of the professional life of every physician and an essential force for progress in improving the nation's health. AMA offers a Quality of Care Campaign with activities that fall under four primary categories: Safety, Advocacy, Measurement and Education. Through awareness programs, confidential error-reporting systems and patient education efforts, AMA is working to promote a culture of patient safety.

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For Pharmacists Medication Guides Glossary

Institute of Medicine (IOM)


500 Fifth Street NW Washington DC 20001 Phone: (202) 334-2352 E-mail: iomwww@nas.ed Web site: www.iom.edu The IOM provides unbiased, evidence-based, and authoritative information and advice concerning health and science policy to policy-makers, professionals, leaders in every sector of society, and the public at large. IOM's "To Err is Human: Building A Safer Health System" report lays out a comprehensive strategy by which government, healthcare professionals, industry, and patients can reduce preventable medical errors.

Institute for Safe Medication Practices (ISMP)


200 Laneside Drive, Suite 200 Horsham, PA 19044 Phone: (215) 947-7797 Fax: (215) 914-1492 Web site: www.ismp.org ISMP is a non-profit agency of pharmacists, nurses and physicians with the mission of learning about medication errors, understanding their system-based causes and disseminating recommendations on error prevention. It is not a regulatory, licensing, inspecting or accrediting agency. Products and services include: professional and patient newsletters; educational programs on medication safety; posters, videos, patient brochures, books and other drug safety tools; and on-site risk assessments of medication safety in healthcare facilities.

National Coordinating Center for Medication Error Reporting and Prevention (NCCMERP)
One Renaissance Blvd. Oakbrook Terrace, IL 60181 Phone: (301) 816-8216 Fax: (301) 816-8532 E-mail: No general e-mail address, but the site provides contact information for the group's officers. Web site: www.nccmerp.org NCCMERP, a coalition of 20 national organizations, offers general information on medication error, as well as a detailed classification of medication errors. The Web site also offers a variety of formal recommendations and information on how to report medication errors.

U.S. Food and Drug Administration (FDA)


10903 New Hampshire Avenue Silver Spring, MD 20993 Phone: 1-888-INFO-FDA (1-888-463-6332) E-mail: E-mail the Center for Drug Evaluation and Research directly from the site Web site: www.fda.gov Patient safety site: http://www.fda.gov/Drugs/DrugSafety/MedicationErrors/default.htm (Center for Drug Evaluation and Research) Patient education: http://www.fda.gov/ForConsumers/default.htm The patient safety site includes medication error reports, a list of specific drugs associated with errors, directions for reporting a medication error and federal guidelines. Downloadable resources are available on the patient education page. For information on individual drugs, visit the Consumer Drug Information page.

United States Pharmacopeia Convention (USP)


12601 Twinbrook Parkway Rockville, Maryland 20852-1790 Phone: 800-227-8772 E-mail: No general e-mail address, but the site provides many addresses, depending on specific needs. Web site: www.usp.org USP is the official public standards-setting authority for all prescription and OTC medicines, dietary supplements and other healthcare products manufactured and sold in the United States. USP disseminates its standards to pharmaceutical manufacturers, pharmacists and other users through its publication, United States Pharmacopeia-National Formulary (USP-NF), other publications, official USP Reference Standards materials and educational courses. In addition, the Medication Errors Reporting Program allows healthcare professionals to directly report medication errors to USP, while MEDMARX, an Internet-based medication error and adverse drug reaction reporting program, is designed for use in hospitals and health systems.

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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September 2005: Healthcare Professionals Alerted to Reported Medication Errors Between TOPAMAX (topiramate) Tablets and TOPROL-XL (metroprolol succinate) extended-release tablets
For healthcare professionals, Janssen Pharmaceuticals, Inc., offers these suggestions to help reduce the potential for future errors: Be alert to the possibility of medication errors in patients taking TOPAMAX or TOPROL-XL. Be aware the possibility of medication errors in patients presenting with unexpected signs or symptoms while on TOPAMAX or TOPROL-XL. Confirm the brand and generic names and dosage prescribed on both written and oral prescriptions. Write full and legible prescriptions for these products and communicate oral prescriptions clearly. Counsel patients about the brand name, indication and proper use of each medication.

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Enhancing the Accuracy of Dispensing Prescription Medications: Guidelines for Pharmacists


With the ever-increasing number of available prescription medications, opportunities for errors related to drug names, packaging, indications and adverse events are also increasing. Pharmacists must play a key role in preventing errors from occurring and in helping protect patients from harm when errors do occur. This section, intended for professional use, suggests measures that pharmacists can take to enhance medication safety and provides links to additional professional resources.

Defining medication error


The National Coordinating Council for Medication Error and Prevention (NCCMERP), a national coalition of 20 organizations focused on prevention of medication errors, has approved this working definition of medication error: "Any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems including: prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use." Medication use is a complex process that includes a series of steps-medication prescribing, order processing, dispensing, administration and effects monitoring-any one of which could lead to medication error. Several national organizations whose missions are focused on enhancing the safe use of prescription medicines have developed practice guidelines and tips for pharmacists. The following represents some of their key recommendations. Tips for pharmacists to reduce medication errors A pharmacist should always review prescriptions and medication orders before dispensing. Orders that do not contain all the required information, that are written illegibly or that pose any other concern should be clarified. Obtaining the patient's pertinent demographic and clinical information will help practitioners select the appropriate medications, doses and routes of administration. Having complete patient information at the time of prescribing and dispensing will result in a significant decrease in preventable adverse drug events (ADEs). The medication dispensing area should be designed to prevent errors by: Addressing fatigue-related environmental conditions (adequate lighting, airconditioning, noise reduction, ergonomic fixtures) Minimizing distractions (telephone and personnel interruptions, clutter, unrelated tasks) Providing staffing and other resources appropriate to the workload. Product inventory should be arranged to help differentiate medications from one another. This may include the use of visual discriminators such as signs or markers. This is particularly important when there is confusion between strengths, similar-looking labels and names that sound or look similar. Checks should be established to assess the accuracy of the dispensing process before providing the medication to the patient. For example, whenever possible, a second individual should perform an independent check. Other methods of checking include automation (such as bar-coding systems), computer systems and patient profiles. Labels should be read at least three times: When selecting the product When packaging the product When returning the product to the shelf. Pharmacy staff should triple-check the replenishing of regular medication stock or automated dispensing machines or cabinets to ensure that each product is stored in the correct place: When selecting the product Before the product leaves the pharmacy Before placing the product in the automated dispensing machine/cabinet. Pharmacists should counsel patients at the time of dispensing and should regard counseling as an opportunity to verify both that the correct medication is being dispensed and that the patient understands its proper use. Counseling should include: Indications for use of the medication, as well as precautions and warnings Expected outcome of the medication Potential adverse reactions and interactions with food or other medications Actions to take when adverse reactions or interactions occur Storage requirements of the medication. For continuous quality improvement purposes, pharmacies should collect and analyze data regarding actual and potential errors-for example, by providing feedback to local prescribers or providing error information to national reporting programs and databases. Pharmacies should conduct both initial and ongoing staff training on the standards of practice regarding accurate dispensing processes. Each pharmacy should establish policies and procedures for the medication dispensing process. This will ensure that all personnel-pharmacists, support staff and relief staff-are informed of dispensing-process expectations. Providing accurate and usable drug information to all healthcare professionals involved in the medication use process reduces the number of preventable adverse drug events. Not only should drug information be readily accessible to staff from a variety of sources (drug references, formulary, protocols, and dosing scales) but also the drug information must be up-to-date and accurate. Staff education should focus on priority topics, such as: new medications being used in the hospital, high-alert medications, medication errors that are known to have occurred both internally and externally, protocols and policies and procedures related to medication use.

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Additional Considerations
Risky abbreviations
Prescribers should avoid the use of abbreviations, including those for drug names, because they can frequently be misunderstood. Some examples of risky abbreviations compiled by the Institute for Safe Medication Practices (ISMP) include: g (microgram)-can be mistaken for "mg" when handwritten and should be written as mcg q.d. or QD (every day)-can be mistaken as q.i.d., especially if the period after the "q" or the tail of the "q" is misread as an "i"; "daily" or "every day" preferred IU (international unit)-can be misread as IV; "units" preferred No zero before decimal point in dosage, for example, .5 mg (for 0.5 mg)-can be misread as 5 mg The following examples of drug names that have been misinterpreted illustrate the importance of spelling out a medication's complete name: AZT (zidovudine) can be misinterpreted as "azathioprine" CPZ (Compazine) can be misinterpreted as "chlorpromazine" DPT (diphtheria-pertussis-tetanus) can be misinterpreted as "Demerol-PhenerganThorazine" HCT (hydrocortisone) can be misinterpreted as "hydrochlorothiazide" HCTZ (hydrochlorothiazide) can be misinterpreted as "hydrocortisone" MgSO 4 (magnesium sulfate) can be misinterpreted as "morphine sulfate" MSO 4 (morphine sulfate) can be misinterpreted as "magnesium sulfate" TAC (triamcinolone) can be misinterpreted as "tetracaine, adrenalin, cocaine" 5-ASA (5-aminosalicylic acid) can be misinterpreted as "five tablets of aspirin"

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Medication Guides Glossary

"High-alert" medications
While most medications have a large safety margin, a small number have a high risk of causing injury when misused. The term "high-alert medication" is intended to draw attention to this characteristic so that everyone involved in using high-alert medications will treat them with the necessary care. Although errors may or may not be more common with these drugs than with others, the consequences when errors do occur may be serious. For a complete listing of highalert medications, go to http://www.ismp.org/faq.asp.

Confirmation bias
Confirmation bias refers to a type of selective thinking in which a person selects for what is familiar or expected, rather than what is actually there. Many errors occur when a practitioner, being familiar with so many products, expects to see a particular product and, because of that expectation, in fact selects one with a similar name.

Independent double-checks
While technologies like computerized prescriber order entry and bar-coding systems have great potential to detect human error, manual redundancies (like independent double-checks) still play an important role in error detection. Studies show that manual redundancies detect about 95 percent of errors. Independent double-checks serve two purposes: to prevent errors from reaching a patient and to draw attention to the systems that allow human error to be

this should be referenced. Delete otherwise

introduced. Independent double-checks should be done on error-prone processes such as the use of high-alert medications.

Patient education

performed

Patients must receive ongoing education from physicians, pharmacists and nurses about the brand and generic names of medications they are receiving, their indications, usual and actual doses, expected and possible adverse events, drug or food interactions and how to protect themselves from errors. Patients can play a vital role in preventing medication errors if pharmacists encourage them to ask questions about their medications before they are dispensed.

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Reducing Errors Associated with Verbal Orders


Medication orders that are communicated verbally offer unique opportunities for errors to occur. Verbal orders are defined as prescriptions or medication orders that are communicated as oral, spoken communications between senders and receivers-face to face, by telephone or by other auditory device. The National Coordinating Council for Medication Error and Prevention has developed a set of recommendations specifically intended to address the risks of verbal orders: Verbal communication of prescriptions or medication orders should be limited to urgent situations where immediate written or electronic communication is not feasible. Healthcare organizations should establish policies and procedures that: Describe limitations or prohibitions on use of verbal orders Provide a mechanism to ensure the prescriber's validity or authenticity List the elements that must be included in a complete verbal order Describe situations in which verbal orders may be used List and define the individuals who may send and receive verbal orders Provide guidelines for clear and effective communication of verbal orders. Pharmacists should encourage staff to question prescribers when there are any concerns or disagreements about verbal orders. Questions about verbal orders should be resolved before preparing, dispensing or administering the medication. A verbal order should include: Patient's name Patient's age and weight, when appropriate Drug name Dosage form (for example, tablets, capsules, inhalants) Exact strength or concentration Dose, frequency and route of administration Quantity and/or duration of treatment Purpose or indication (unless the prescriber considers disclosure inappropriate) Specific instructions for use Prescriber's name and telephone number when appropriate Name of individual transmitting the order, if different from the prescriber. The name of the drug should be confirmed by any of the following: Spelling Providing both the brand and the generic names of the medication Providing the indication for use. To avoid confusion with spoken numbers, a dose such as 50 mg should be dictated as "fifty milligrams...five zero milligrams" to distinguish from "fifteen milligrams...one five milligrams." Instructions for use should avoid abbreviations. For example, "1tab tid" should be communicated as "Take/give one tablet three times daily." The entire verbal order should be repeated back to the prescriber or the individual transmitting the order, using the principles outlined in these recommendations. All verbal orders should be written down immediately and signed by the individual receiving the order. Verbal orders should be documented in the patient's medical record, then reviewed and countersigned by the prescriber as soon as possible. Additional Considerations Reducing Errors Associated with Verbal Orders Pharmacist Resources Recent Medication Errors

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Pharmacist Resources
American College of Clinical Pharmacy (ACCP)
13000 W. 87 th Street Parkway Lenexa, MS 66215-4530 Phone: (913) 492-3311 Fax: (913) 492-0088 Web site: www.accp.com ACCP is a professional association of practitioners, scientists, educators, administrators, students, residents, fellows and others providing education, advocacy and resources for its members. Services include an online bookstore, meetings and the journal, Pharmacotherapy.

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Medication Guides Glossary

American Pharmacists Association (APhA)


2215 Constitution Avenue, NW Washington, DC 20037-2985 Fax: (202) 783-2351 E-mail: No general e-mail address, but the site provides many addresses, depending on specific needs Web site: www.aphanet.org Patient safety site: www.pharmacyandyou.org APhA is the professional association of U.S. pharmacists, providing information, education and advocacy to help its members improve medication use and advance patient care. In addition to educational activities, APhA engages in government relations and community activities, provides a career center and special-interest groups.

American Society of Health-System Pharmacists (ASHP)


7272 Wisconsin Avenue Bethesda, Maryland 20814 Phone: (301) 657-3000 Web site: www.ashp.com Medication safety site: www.safemedication.com ASHP is the professional association representing pharmacists who practice in hospitals, health maintenance organizations, long-term care facilities, home care and other components of healthcare systems. ASHP has extensive publishing and educational programs to help members improve their professional practice and is the national accrediting organization for pharmacy residency and pharmacy-technician training programs. Medication safety is a primary focus of ASHP's efforts.

Institute for Safe Medication Practices (ISMP)


200 Laneside Drive, Suite 200 Horsham, PA 19044 Phone: (215) 947-7797 Fax: (215) 914-1492 Web site: www.ismp.org ISMP is a non-profit agency of pharmacists, nurses and physicians with the mission of learning about medication errors, understanding their system-based causes and disseminating recommendations on error prevention. It is not a regulatory, licensing, inspecting or accrediting agency. Products and services include: professional and patient newsletters; educational programs on medication safety; posters, videos, patient brochures, books and other drug safety tools; on-site risk assessments of medication safety in healthcare facilities.

National Coordinating Center for Medication Error Reporting and Prevention (NCCMERP)
One Renaissance Blvd. Oakbrook Terrace, IL 60181 Phone: (301) 816-8216 Fax: (301) 816-8532 E-mail: No general e-mail address, but the site provides contact information for the group's officers Web site: www.nccmerp.org NCCMERP, a coalition of 20 national organizations, offers general information on medication error, as well as a detailed classification of medication errors. The Web site also offers a variety of formal recommendations and information on how to report medication errors.

U.S. Food and Drug Administration (FDA)


10903 New Hampshire Avenue Silver Spring, MD 20993 Phone: 1-888-INFO-FDA (1-888-463-6332) E-mail: E-mail the Center for Drug Evaluation and Research directly from the site Web site: www.fda.gov Patient safety site: http://www.fda.gov/Drugs/DrugSafety/MedicationErrors/default.htm (Center for Drug Evaluation and Research) Patient education: http://www.fda.gov/ForConsumers/default.htm The patient safety site includes medication error reports, a list of specific drugs associated with errors, directions for reporting a medication error and federal guidelines. Downloadable resources related to medication safety are available on the patient education page. For information on individual drugs, visit the Consumer Drug Information page.

United States Pharmacopeia Convention (USP)


12601 Twinbrook Parkway Rockville, Maryland 20852-1790 Phone: 800-227-8772 E-mail: No general e-mail address, but the site provides many addresses, depending on specific needs Web site: www.usp.org USP is the official public standards-setting authority for all prescription and OTC medicines, dietary supplements and other healthcare products manufactured and sold in the United States. USP disseminates its standards to pharmaceutical manufacturers, pharmacists and other users through its publication, United States Pharmacopeia-National Formulary (USP-NF), other publications, official USP Reference Standards materials and educational courses. In addition, the Medication Errors Reporting Program allows healthcare professionals to directly report medication errors to USP, while MEDMARX, an Internet-based medication error and adverse drug reaction reporting program, is designed for use in hospitals and health systems.

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Healthcare Professionals Alerted to Reported Medication Errors Between TOPAMAX (topiramate) Tablets and TOPROL-XL (metroprolol succinate) extended-release tablets
For pharmacists, Janssen Pharmaceuticals, Inc., offers these suggestions to help reduce the potential for future errors: Place TOPAMAX and TOPROL-XL apart from one another on the pharmacy shelf; we advise using the downloadable "shelf talker" (if applicable). Confirm the brand and generic names prescribed on written and oral prescriptions. Use both the brand and generic names when communicating the drug names within the pharmacy. Counsel patients about the brand name, indication and proper use of each medication.

Medication Guides Glossary

For drug database content providers, Janssen Pharmaceuticals, Inc., suggests these errorreduction tactics: Install sound-alike/look-alike name-alert warnings for the name-pair confusion between TOPAMAX and TOPROL-XL. Use "tall man" lettering to highlight the end of each name-that is, topAMAX and topROLXL. Avoid the use of confusing drug mnemonics such as "TOP". Use both the brand and generic names when communicating the drug names.

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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Medication Guides
Patient Medication Guides (Med Guides) are handouts given to patients, families, and caregivers when a medicine is dispensed. The guides contain FDA-approved patient information to make patients aware of risks with use of a product that could help prevent serious adverse events. The inclusion of a Med Guide in the package insert is mandatory for selected products identified by the FDA. Below is a listing of products that require a Medication Guide. Patients being treated with these products should read the information before using the medication and talk to their doctors if they have any questions or concerns.

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CONCERTA (methylphenidate HCl) Extended-release Tablets C-II


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Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

ORTHO ALL-FLEX DIAPHRAGM FITTING SET


NDC 0062-3644-03

HOW TO FIT THE ORTHO ALL-FLEX DIAPHRAGM 1. To measure for diaphragm size: Hold index and middle fingers together and insert into vagina up to the posterior fornix. Raise hand to bring surface of index finger into contact with pubic arch. Use tip of thumb to mark the point directly beneath the inferior margin of the pubic bone and withdraw finger in this position. 2. To determine diaphragm size: Place one end of rim of fitting diaphragm on tip of middle finger. The opposite end should lie just in front of the thumb tip. This is the approximate diameter of the diaphragm needed. Insert a fitting diaphragm of the appropriate size into the vagina. Try both a larger and smaller size before making a decision. 3. The proper size will fit snugly in the posterior fornix and behind the pubic arch without undue pressure. CLEANING OPTIONS FOR THE ORTHO ALL-FLEX DIAPHRAGM FITTING SET Fitting diaphragms, being devices that come in contact with intact mucous membranes, are semicritical devices that require processing with a high level disinfectant according to current guidelines. The following cleaning methods have been found to be compatible with the ORTHO ALL-FLEX Diaphragm Fitting Set. The first and critically important step in preparation for any of the methods listed below is to clean the device thoroughly by scrubbing with liquid detergent and water, then rinsing well with water. This step serves to remove the majority of the bioburden in question. AUTOCLAVE METHOD 1. Autoclave at 121 degrees C and 15 psi for between 20 and 30 minutes. The time variation is dependent on whether the articles are wrapped or unwrapped. 2. Allow to air dry and then place in container until ready for use. CHLORINATION METHOD 1. Soak in a 1:10 dilution of 5 % sodium hypochlorite (bleach) for 30 minutes at room temperature. 2. Rinse thoroughly with tap water. 3. Soak in 70% ethyl or isopropyl alcohol for 15 minutes. 4. Allow to air dry and then place the fitting set in a container until ready for use. GLUTARALDEHYDE METHOD Note: This method requires adequate ventilation and sterile water. 1. Immerse in 2.5% glutaraldehyde solution for 20 minutes at room temperature. 2. Rinse thoroughly with sterile water. 3. Allow to air dry and then place the fitting set in a container until ready for use. Alternatively to the above: Follow the disinfectant solution manufacturers instructions. CONTRAINDICATIONS A history of Toxic Shock Syndrome or hypersensitivity to silicone SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE This device is not intended for contraception. Duration of Use: This device is intended for the sole purpose of properly fitting a diaphragm. It is intended to be inserted only for the time necessary for the diaphragm to be sized. Diaphragm Fitting: The size and shape of the vagina change and this may require a new size diaphragm. As a matter of routine, each time a pelvic examination is performed, refitting should be done. THE FOLLOWING IS FOUND IN THE LABELING FOR THE ORTHO ALL-FLEX DIAPHRAGM: The ORTHO ALL-FLEX Diaphragm is a molded, buff-colored, vaginal diaphragm made from silicone. It contains a distortion-free, dual spring-within-a-spring (arcing spring) that provides a unique arcing action no matter where the rim is compressed. ACTIONS A diaphragm, when properly fitted, serves two purposes: To stop sperm from entering the cervical canal and to hold spermicide. INDICATIONS The ORTHO ALL-FLEX Diaphragm, in conjunction with an appropriate spermicide, is indicated for the prevention of pregnancy in women who elect to use diaphragms as a method of contraception. CONTRAINDICATIONS Known hypersensitivity to silicone or a prior history of Toxic Shock Syndrome (TSS)

WARNINGS An association has been reported between diaphragm use and Toxic Shock Syndrome (TSS), a serious condition that can be fatal. To reduce the risk of TSS, but also to maintain contraceptive effectiveness, the diaphragm should be removed six to eight hours (depending on which brand of spermicide you use) after intercourse. Continuous wearing of a diaphragm for more than 24 hours is not recommended. Wearing the diaphragm for any period of time may encourage the growth of certain bacteria in the vaginal tract. It has been suggested that under certain as yet unestablished conditions, overgrowth of these bacteria may lead to symptoms of TSS. Primary symptoms of TSS are sudden high fever (usually 39C [102F] or more), and vomiting, diarrhea, fainting or near fainting when standing up, dizziness, or a rash that looks like sunburn. There may also be other signs of TSS, such as aching of muscles and joints, redness of the eyes, sore throat, and weakness. If you have sudden high fever and one or more of the other symptoms, remove your diaphragm and consult your doctor or health care provider immediately. Women with a known or suspected history of TSS should not use diaphragms. PRECAUTIONS Diaphragm users should be instructed to consult their physician or health care provider: 1. If they are not sure about the insertion and placement of the diaphragm 2. If they or their partner feel, or are made uncomfortable by the presence of the diaphragm 3. If they experience any discomfort or pain while the diaphragm is in place. This may be due to incorrect diaphragm insertion, an abnormal pelvic condition, constipation or incorrect diaphragm size. 4. If the diaphragm slips out of place when walking, coughing, sneezing or straining 5. If the diaphragm no longer fits snugly above the pubic bone 6. If at times other than menstruation there is blood on the diaphragm when it is removed 7. If there are any holes, tears or other deterioration of the diaphragm 8. If unable to remove the diaphragm 9. IMPORTANT - For contraceptive effectiveness, the diaphragm should remain in place for six to eight hours (depending on the brand of spermicide used) after intercourse and it should be removed thereafter. Continuous wearing of a contraceptive diaphragm for more than twenty-four hours is not recommended. Removal of the diaphragm before six to eight hours may increase the risk of becoming pregnant. Wearing the diaphragm for any period of time may encourage the growth of certain bacteria in the vaginal tract. It has been suggested that under certain as yet unestablished conditions, overgrowth of these bacteria may lead to symptoms of toxic shock syndrome. Primary symptoms of TSS are sudden high fever (usually 102 or more), and vomiting, diarrhea, fainting or near fainting when standing up, dizziness or a rash that looks like a sunburn. There may also be other signs of TSS such as aching of muscles and joints, redness of the eyes, sore throat and weakness. If the patient has a sudden high fever and one or more of the other symptoms, the diaphragm should be removed immediately and TSS should be considered. 10. The size and shape of the vagina change and this may require a new size diaphragm. As a matter of routine, each time a pelvic examination is performed, refitting should be done. Even if the diaphragm size does not change, it is advisable to replace the diaphragm every two years or sooner. 11. Diaphragms may increase the risk of urinary tract infections especially if not properly fitted. Patients should be instructed to consult their physician if they experience any of the signs or symptoms of this type of infection, which include pain on urination, blood in the urine, elevated temperature, frequent urination, or a sensation of obstruction while urinating. 12. Persons sensitive to silicone or spermicides used with the diaphragm should discontinue use of the spermicide/diaphragm method of contraception. HOW SUPPLIED ORTHO ALL-FLEX Diaphragm Fitting Kits are available individually.

please verify this is the current PI

MANUFACTURER Johnson & Johnson do Brasil Indstria e Comrcio de Produtos para Sade Ltda. Rod, Presidente Dutra, KM 154 Sao Jose Dos Campos, SP Brazil For: Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560 OMJPI 2008 Revised August 2008 10116800

DITROPANXL
(oxybutynin chloride)
DESCRIPTION
DITROPAN XL (oxybutynin chloride) is an antispasmodic, anticholinergic agent. Each DITROPAN XL Extended Release Tablet contains 5 mg, 10 mg, or 15 mg of oxybutynin chloride USP, formulated as a once-a-day controlled-release tablet for oral administration. Oxybutynin chloride is administered as a racemate of R- and S-enantiomers. Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin chloride is C22H31NO3HCl. Its structural formula is:

Figure 1. Mean R-oxybutynin plasma concentrations following a single dose of DITROPANXL 10 mg and oxybutynin 5 mg administered every 8hours (n=23 for each treatment).

Extended Release Tablets

Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is readily soluble in water and acids, but relatively insoluble in alkalis. DITROPAN XL also contains the following inert ingredients: cellulose acetate, hypromellose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, synthetic iron oxides, titanium dioxide, polysorbate 80, sodium chloride, and butylated hydroxytoluene.

System Components and Performance


DITROPAN XL uses osmotic pressure to deliver oxybutynin chloride at a controlled rate over approximately 24 hours. The system, which resembles a conventional tablet in appearance, comprises an osmotically active bilayer core surrounded by a semipermeable membrane. The bilayer core is composed of a drug layer containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice in the semipermeable membrane on the drug-layer side of the tablet. In an aqueous environment, such as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing the drug to go into suspension and the push layer to expand. This expansion pushes the suspended drug out through the orifice. The semipermeable membrane controls the rate at which water permeates into the tablet core, which in turn controls the rate of drug delivery. The controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or gastrointestinal motility. The function of DITROPAN XL depends on the existence of an osmotic gradient between the contents of the bilayer core and the fluid in the gastrointestinal tract. Since the osmotic gradient remains constant, drug delivery remains essentially constant. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

Steady state oxybutynin plasma concentrations are achieved by Day 3 of repeated DITROPANXL dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters. DITROPAN XL steady state pharmacokinetics were studied in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The children were on DITROPANXL total daily dose ranging from 5 to 20 mg (0.10 to 0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg per day DITROPAN XL, the mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. The plasma-time concentration profiles for R- and S-oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin when all available data are normalized to an equivalent of 5 mg per day. Table 2 Mean SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5-15 Following Administration of 5 to 20 mg DITROPANXL Once Daily (n=19), All Available Data Normalized to an Equivalent of DITROPANXL 5 mg Once Daily R-Oxybutynin Cmax (ng/mL) Tmax (h) AUC(ngh/mL) 0.7 0.4 5.0 12.8 7.0 S-Oxybutynin 1.3 0.8 5.0 23.7 14.4 R-Desethyloxybutynin S-Desethyloxybutynin 7.8 3.7 5.0 125.1 66.7 4.2 2.3 5.0 73.6 47.7

Figure 2. Mean steady state ( SD) R-oxybutynin plasma concentrations following administration of 5 to 20 mg DITROPANXL once daily in children aged 5-15. Plot represents all available data normalized to an equivalent of DITROPAN XL 5 mg once daily.

CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits only one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects). Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. Oxybutynin thus decreases urgency and the frequency of both incontinent episodes and voluntary urination. Antimuscarinic activity resides predominantly in the R-isomer. A metabolite, desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in invitro studies. Absorption Following the first dose of DITROPANXL (oxybutynin chloride), oxybutynin plasma concentrations rise for 4 to 6 hours; thereafter steady concentrations are maintained for up to 24 hours, minimizing fluctuations between peak and trough concentrations associated with oxybutynin. The relative bioavailabilities of R- and S-oxybutynin from DITROPAN XL are 156% and 187%, respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin. Table 1 Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single Dose of DITROPANXL 10 mg (n=43) Parameters (units) Cmax (ng/mL) Tmax (h) t1/2 (h) AUC(0-48) (ngh/mL) AUCinf (ngh/mL) R-Oxybutynin 1.0 12.7 13.2 18.4 21.3 (0.6) (5.4) (6.2) (10.3) (12.2) S-Oxybutynin 1.8 11.8 12.4 34.2 39.5 (1.0) (5.3) (6.1) (16.9) (21.2) Food Effects The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions. Distribution Plasma concentrations of oxybutynin decline biexponentially following intravenous or oral administration. The volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride. Metabolism Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active. Following DITROPANXL administration, plasma concentrations of R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with oxybutynin. Excretion Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose excreted unchanged in the urine. Also, less than 0.1% of theadministered dose is excreted as the metabolite desethyloxybutynin. Dose Proportionality Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following administration of 5-20 mg of DITROPANXL are dose proportional. Special Populations Geriatric: The pharmacokinetics of DITROPANXL were similar in all patients studied (up to 78 years of age). Pediatric: The pharmacokinetics of DITROPAN XL were evaluated in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of DITROPANXL in these pediatric patients were consistent with those reported for adults (see Tables 1 and 2, and Figures 1 and 2 above).

Pharmacokinetics

Gender: There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of DITROPANXL. Race: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of DITROPANXL. Renal Insufficiency: There is no experience with the use of DITROPANXL in patients with renal insufficiency. Hepatic Insufficiency: There is no experience with the use of DITROPANXL in patients with hepatic insufficiency. Drug-Drug Interactions: See PRECAUTIONS: Drug Interactions. DITROPAN XL (oxybutynin chloride) was evaluated for the treatment of patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in three controlled studies and one open-label study. The majority of patients were Caucasian (89.0%) and female (91.9%) with a mean age of 59 years (range, 18 to 98 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge) as evidenced by 6 urge incontinence episodes per week and 10 micturitions per day. Study 1 was a fixed-dose escalation design, whereas the other studies used a dose-adjustment design in which each patients final dose was adjusted to a balance between improvement of incontinence symptoms and tolerability of side effects. Controlled studies included patients known to be responsive to oxybutynin or other anticholinergic medications, and these patients were maintained on a final dose for up to 2 weeks. The efficacy results for the three controlled trials are presented in the following tables and figures.

INDICATIONS AND USAGE


DITROPAN XL (oxybutynin chloride) is a once-daily controlled-release tablet indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. DITROPANXL is also indicated in the treatment of pediatric patients aged 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida).

CONTRAINDICATIONS
DITROPAN XL (oxybutynin chloride) is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. DITROPAN XL is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.

CLINICAL STUDIES

WARNINGS
Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

PRECAUTIONS
Central Nervous System Effects Oxybutynin is associated with anticholinergic central nervous system (CNS) effects (see ADVERSE REACTIONS). A variety of CNS anticholinergic effects have been reported, including hallucinations, agitation, confusion and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. DITROPAN XL should be used with caution in patients with preexisting dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms. General DITROPANXL (oxybutynin chloride) should be used with caution in patients with hepatic or renal impairment and in patients with myasthenia gravis due to the risk of symptom aggravation. Urinary Retention DITROPAN XL should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS). Gastrointestinal Disorders DITROPAN XL should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS). DITROPANXL, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis and intestinal atony. DITROPAN XL should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis. As with any other nondeformable material, caution should be used when administering DITROPAN XL to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations. Information for Patients Patients should be informed that oxybutynin may produce angioedema that could result in lifethreatening airway obstruction. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing. Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutynin chloride are administered in the presence of high environmental temperature. Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence) or blurred vision, patients should be advised to exercise caution. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin. Patients should be informed that DITROPANXL should be swallowed whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. DITROPANXL should be taken at approximately the same time each day. Drug Interactions The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPANXL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Carcinogenesis, Mutagenesis, Impairment of Fertility A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and 160 mg/kg/day showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50 times the maximum human exposure, based on surface area. Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, and Salmonella typhimurium test systems. Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no definite evidence of impaired fertility.

Number of Urge Urinary Incontinence Episodes Per Week


Study 1 Mean Baseline Mean (SD) Change from Baseline 95% Confidence Interval for Difference (DITROPAN XL - Placebo)
* The difference between DITROPANXL and placebo was statistically significant. Covariate adjusted mean with missing observations set to baseline values

n 34 34

DITROPAN XL 15.9 -15.8 (8.9) (-13.6, -2.8)*

n 16 16

Placebo 20.9 -7.6 (8.6)

Study 2 Mean Baseline Mean (SD) Change from Baseline 95% Confidence Interval for Difference (DITROPAN XL - oxybutynin)

n 53 53

DITROPAN XL 27.6 -17.6 (11.9) (-2.8, 6.5)

n 52 52

oxybutynin 23.0 -19.4 (11.9)

Covariate adjusted mean with missing observations set to baseline values

Study 3 Mean Baseline Mean (SD) Change from Baseline 95% Confidence Interval for Difference (DITROPAN XL - oxybutynin)

n 111 111

DITROPAN XL 18.9 -14.5 (8.7) (-3.0, 1.6)**

n 115 115

oxybutynin 19.5 -13.8 (8.6)

** The difference between DITROPANXL and oxybutynin fulfilled the criteria for comparable efficacy. Covariate adjusted mean with missing observations set to baseline values

Pregnancy: Teratogenic Effects Pregnancy Category B Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no definite evidence of impaired fertility or harm to the animal fetus. The safety of DITROPAN XL administration to women who are or who may become pregnant has not been established. Therefore, DITROPAN XL should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards. Nursing Mothers It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DITROPANXL is administered to a nursing woman. Pediatric Use The safety and efficacy of DITROPAN XL were studied in 60 children in a 24-week, open-label trial. Patients were aged 6-15 years, all had symptoms of detrusor overactivity in association with a neurological condition (e.g., spina bifida), all used clean intermittent catheterization, and all were current users of oxybutynin chloride. Study results demonstrated that administration of DITROPAN XL 5 to 20 mg/day was associated with an increase from baseline in mean urine volume per catheterization from 108 mL to 136 mL, an increase from baseline in mean urine volume after morning awakening from 148 mL to 189 mL, and an increase from baseline in the mean percentage of catheterizations without a leaking episode from 34% to 51%. Urodynamic results were consistent with clinical results. Administration of DITROPANXL resulted in an increase from baseline in mean maximum cystometric capacity from 185 mL to 254 mL, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 cm H2O to 33 cm H2O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H2O) from 60% to 28%. DITROPAN XL is not recommended in pediatric patients who cannot swallow the tablet whole without chewing, dividing, or crushing, or in children under the age of 6 (See DOSAGE AND ADMINISTRATION). Geriatric Use The rate and severity of anticholinergic effects reported by patients less than 65 years old and those 65 years and older were similar (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations: Geriatric).

connective tissue disorders: back pain, arthralgia, pain in extremity; Renal and urinary disorders: urinary retention, urinary hesitation, dysuria; General disorders and administration site conditions: fatigue, edema peripheral, asthenia, chest pain; Investigations: blood pressure increased. Postmarketing Surveillance Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse drug reactions have been reported from worldwide postmarketing experience with DITROPAN XL: Psychiatric Disorders: psychotic disorder, agitation, hallucinations, memory impairment; Nervous System Disorders: convulsions; Cardiac Disorders: arrhythmia, tachycardia, QT interval prolongation; Vascular Disorders: flushing; Skin and Subcutaneous Tissue Disorders: rash; Renal and Urinary Disorders: impotence; General Disorders and Administration Site Conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; rare anaphylactic reactions requiring hospitalization for emergency treatment; Injury, poisoning and procedural complications: fall. Additional adverse events reported with some other oxybutynin chloride formulations include: cycloplegia, mydriasis, and suppression of lactation.

OVERDOSAGE
The continuous release of oxybutynin from DITROPAN XL (oxybutynin chloride) should be considered in the treatment of overdosage. Patients should be monitored for at least 24 hours. Treatment should be symptomatic and supportive. Activated charcoal as well as a cathartic may be administered. Overdosage with oxybutynin chloride has been associated with anticholinergic effects including central nervous system excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in a 13-yearold boy who experienced memory loss, and a 34-year-old woman who developed stupor, followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients fully recovered with symptomatic treatment.

DOSAGE AND ADMINISTRATION


DITROPANXL (oxybutynin chloride) must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. DITROPANXL may be administered with or without food. Adults: The recommended starting dose of DITROPAN XL is 5 or 10 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals. Pediatric Patients Aged 6 Years of Age and Older: The recommended starting dose of DITROPAN XL is 5 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

ADVERSE REACTIONS
Adverse Events with DITROPANXL The safety and efficacy of DITROPAN XL (oxybutynin chloride) were evaluated in a total of 580 participants who received DITROPANXL in 4 clinical trials (429 patients) and four pharmacokinetic studies (151 healthy volunteers). The 429 patients were treated with 5-30 mg/day for up to 4.5 months. Three of the 4 clinical trials allowed dose adjustments based on efficacy and adverse events and one was a fixed-dose escalation design. Safety information is provided for 429 patients from these three controlled clinical studies and one open-label study in the first column of Table 3 below. Adverse events from two additional fixed-dose, active-controlled, 12-week treatment duration, postmarketing studies, in which 576 patients were treated with DITROPANXL 10 mg/day, are also listed in Table 3 (second column). The adverse events are reported regardless of causality. Table 3 Incidence (%) of Adverse Events Reported by 5% of Patients Using DITROPANXL (5-30 mg/day) and % of Corresponding Adverse Events in Two Fixed-Dose (10mg/day) Studies DITROPAN XL Body System General Adverse Event headache asthenia pain dry mouth constipation diarrhea nausea dyspepsia somnolence dizziness rhinitis blurred vision dry eyes urinary tract infection 5-30 mg/day (n=429) 10 7 7 61 13 9 9 7 12 6 6 8 6 5 DITROPAN XL 10 mg/day (n=576) 6 3 4 29 7 7 2 5 2 4 2 1 3 5

HOW SUPPLIED
DITROPAN XL (oxybutynin chloride) Extended Release Tablets are available in three dosage strengths, 5 mg (pale yellow), 10 mg (pink), and 15 mg (gray) and are imprinted with 5 XL, 10XL, or 15XL. DITROPANXL Extended Release Tablets are supplied in bottles of 100 tablets. 5 mg 100 count bottle NDC 50458-805-01 10 mg 100 count bottle NDC 50458-810-01 15 mg 100 count bottle NDC 50458-815-01

Storage
Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from moisture and humidity. For more information call 1-888-395-1232 or visit www.DITROPANXL.com

Digestive

Manufactured by: ALZA Corporation, Vacaville, CA 95688

Nervous Respiratory Special senses Urogenital

DITROPANXL and OROS are registered trademarks of ALZA Corporation. Manufactured for: Ortho Womens Health & Urology, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869

The most common adverse events reported by the 429 patients receiving 5-30 mg/day DITROPAN XL were the expected side effects of anticholinergic agents. The incidence of dry mouth was dose-related. The discontinuation rate for all adverse events was 6.8% in the 429 patients from the 4 studies of efficacy and safety who received 5-30 mg/day. The most frequent adverse event causing early discontinuation of study medication was nausea (1.9%), while discontinuation due to dry mouth was 1.2%. In addition, the following adverse events were reported by 1 to < 5% of all patients who received DITROPAN XL in the 6 adjustable and fixed-dose efficacy and safety studies. Infections and infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, cystitis; Psychiatric disorders: insomnia, depression, nervousness, confusional state; Nervous System Disorders: dysgeusia; Cardiac disorders: palpitations; Vascular disorders: hypertension; Respiratory, thoracic and mediastinal disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat; Gastrointestinal Disorders: gastroesophageal reflux disease, abdominal pain, loose stools, flatulence, vomiting; Skin and subcutaneous tissue disorders: dry skin, pruritis; Musculoskeletal and

Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998

10192602

Revised July 2011

replace with Dec 2011

DURAGESIC

DURAGESIC

(Fentanyl Transdermal System)


Full Prescribing Information
FOR USE IN OPIOID-TOLERANT PATIENTS ONLY DURAGESIC contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (DURAGESIC) may be a particular target for abuse and diversion. DURAGESIC is indicated for management of persistent, moderate to severe chronic pain that: equires continuous, around-the-clock opioid administration for an extended r period of time, and cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids DURAGESIC should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to DURAGESIC 25 mcg/h. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could occur, DURAGESIC (fentanyl transdermal system) is contraindicated: in patients who are not opioid-tolerant n the management of acute pain or in patients who require opioid analgesia for a i short period of time n the management of post-operative pain, including use after out-patient or day i surgeries (e.g., tonsillectomies) in the management of mild pain n the management of intermittent pain (e.g., use on an as needed basis [prn]) i (See CONTRAINDICATIONS for further information.) Since the peak fentanyl concentrations generally occur between 20 and 72 hours of treatment, prescribers should be aware that serious or life threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period. The concomitant use of DURAGESIC with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY Drug Interactions, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information). The safety of DURAGESIC has not been established in children under 2 years of age. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS - Pediatric Use). DURAGESIC is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the DURAGESIC dose when converting patients from another opioid medication can result in fatal overdose with the first dose (see DOSAGE AND ADMINISTRATION Initial DURAGESIC Dose Selection). Due to the mean half-life of approximately 20-27 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours. DURAGESIC can be abused in a manner similar to other opioid agonists, legal or illicit. This risk should be considered when administering, prescribing, or dispensing DURAGESIC in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction. DURAGESIC patches are intended for transdermal use (on intact skin) only. Do not use a DURAGESIC patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way. Avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. Patients wearing DURAGESIC systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the DURAGESIC dose should be adjusted if necessary.

(Fentanyl Transdermal System)


DESCRIPTION DURAGESIC (fentanyl transdermal system) is a transdermal system providing continuous systemic delivery of fentanyl, a potent opioid analgesic, for 72 hours. The chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is:

The molecular weight of fentanyl base is 336.5, and the empirical formula is C22H28N2O. The n-octanol:water partition coefficient is 860:1. The pKa is 8.4. System Components and Structure The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/h per 10.5 cm2). The composition per unit area of all system sizes is identical. Dose* (mcg/h) 12** 25 50 75 100 *Nominal delivery rate per hour **Nominal delivery rate is 12.5 mcg/hr DURAGESIC is a rectangular transparent unit comprising a protective liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are: 1) a backing layer of polyester/ethyl vinyl acetate film; 2) a drug-in-adhesive layer. Before use, a protective liner covering the adhesive layer is removed and discarded. Size (cm2) 5.25 10.5 21 31.5 42 Fentanyl Content (mg) 2.1 4.2 8.4 12.6 16.8

Protective Liner Drug Containing Layer Backing Layer

The active component of the system is fentanyl. The remaining components are pharmacologically inactive. CLINICAL PHARMACOLOGY Pharmacology Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, fentanyl exerts its principal pharmacologic effects on the central nervous system. In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting directly by stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain. While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination. At therapeutic dosages, fentanyl usually does not exert major effects on the cardiovascular system. However, some patients may exhibit orthostatic hypotension and fainting. Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg. Pharmacokinetics (see graph and tables) The DURAGESIC (fentanyl transdermal system) is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin. While there is variation in dose delivered among patients, the nominal flux of the systems (12.5, 25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. Following DURAGESIC application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial DURAGESIC application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application (see Table A).

DURAGESIC

(Fentanyl Transdermal System)


Serum fentanyl concentrations achieved are proportional to the DURAGESIC delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size. Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl. After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12) hours.

DURAGESIC

(Fentanyl Transdermal System)


Geriatric Use Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the DURAGESIC fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration. DURAGESIC should be used with caution in elderly, cachectic or debilitated patients as they may have alteredpharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see DOSAGE AND ADMINISTRATION). Drug Interactions The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%-420%) increase in fentanyl AUC0-. Coadministration of ritonavir in patients receiving DURAGESIC has not been studied; however, an increase in fentanyl AUC is expected (see BOX WARNING, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore, potential interactions may occur when DURAGESIC is given concurrently with agents that affect CYP3A4 activity. Coadminstration with agents that induce CYP3A4 activity may reduce the efficacy of DURAGESIC. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information). PHARMACODYNAMICS Ventilatory Effects Because of the risk for serious or life-threatening hypoventilation, DURAGESIC is CONTRAINDICATED in the treatment of post-operative and acute pain and in patients who are not opioid-tolerant. In clinical trials of 357 patients with acute pain treated with DURAGESIC, 13 patients experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in patients weighing less than 63 kg (9 of 13). Although patients with impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with DURAGESIC. While most adult and pediatric patients using DURAGESIC chronically develop tolerance to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during therapy. Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive usual doses of opioids or other CNS drugs associated with hypoventilation in addition to DURAGESIC. The use of DURAGESIC is contraindicated in patients who are not tolerant to opioid therapy. The use of DURAGESIC should be monitored by clinical evaluation, especially within the initial 24-72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older. See BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE for additional information on hypoventilation. Cardiovascular Effects Fentanyl may infrequently produce bradycardia. The incidence of bradycardia in clinical trials with DURAGESIC was less than 1%. CNS Effects Central nervous system effects increase with increasing serum fentanyl concentrations. INDICATIONS AND USAGE DURAGESIC is indicated for management of persistent, moderate to severe chronic pain that: equires continuous, around-the-clock opioid administration for an extended period of time, r and annot be managed by other means such as non-steroidal analgesics, opioid combination c products, or immediate-release opioids. DURAGESIC should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to DURAGESIC 25 mcg/h (see DOSAGE AND ADMINISTRATION). Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could result, DURAGESIC is contraindicated for use on an as needed basis (i.e., prn), for the management of post-operative or acute pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS). An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

TABLE A: FENTANYL PHARMACOkINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION OF DURAGESIC Mean (SD) Time to Mean (SD) Maximal Concentration Maximal Concentration Tmax Cmax (ng/mL) (h) DURAGESIC 12 mcg/h 28.8 (13.7) 0.38 (0.13)* DURAGESIC 25 mcg/h 31.7 (16.5) 0.85 (0.26) DURAGESIC 50 mcg/h 32.8 (15.6) 1.72 (0.53) DURAGESIC 75 mcg/h 35.8 (14.1) 2.32 (0.86) DURAGESIC 100 mcg/h 29.9 (13.3) 3.36 (1.28) *Cmax values dose normalized from 4 x 12.5 mcg/h NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20-27 hours. TABLE B: RANGE OF PHARMACOkINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS Clearance Volume of Distribution Half-Life t1/2 (L/h) Vss Range (L/kg) (h) [70 kg] Range Range Surgical Patients Hepatically Impaired Patients Renally Impaired Patients
+Estimated

27 - 75 3 - 80+ 30 - 78

3-8 0.8 - 8+

3 - 12 4 - 12+

NOTE: Information on volume of distribution and half-life not available for renally impaired patients. Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8). Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%. Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation. Special Populations Hepatic or Renal Disease Insufficient information exists to make recommendations regarding the use of DURAGESIC in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. Pediatric Use In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to DOSAGE AND ADMINISTRATION section.

DURAGESIC

(Fentanyl Transdermal System)


Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modifiedrelease opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. CONTRAINDICATIONS Because serious or life-threatening hypoventilation could occur, DURAGESIC (fentanyl transdermal system) is contraindicated: in patients who are not opioid-tolerant n the management of acute pain or in patients who require opioid analgesia for a short i period of time n the management of post-operative pain, including use after out-patient or day i surgeries, (e.g., tonsillectomies) in the management of mild pain n the management of intermittent pain (e.g., use on an as needed basis [prn]) i n situations of significant respiratory depression, especially in unmonitored settings i where there is alack of resuscitative equipment in patients who have acute or severe bronchial asthma DURAGESIC (fentanyl transdermal system) is contraindicated in patients who have or are suspected of having paralytic ileus. DURAGESIC (fentanyl transdermal system) is contraindicated in patients with known hypersensitivity to fentanyl or any components of this product. WARNINGS DURAGESIC patches are intended for transdermal use (on intact skin) only. Do not use a DURAGESIC patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way. The safety of DURAGESIC (fentanyl transdermal system) has not been established in children under 2 years of age. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS Pediatric Use). DURAGESIC is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the DURAGESIC dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean half-life is approximately 20-27 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after DURAGESIC removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 20-27 hours after system removal. DURAGESIC should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists. All patients and their caregivers should be advised to avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. A clinical pharmacology trial conducted in healthy adult subjects has shown that the application of heat over the DURAGESIC system increased mean fentanyl AUC values by 120% and mean Cmax values by 61%. Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40C (104F) due to temperaturedependent increases in fentanyl released from the system and increased skin permeability. Patients wearing DURAGESIC systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the DURAGESIC dose should be adjusted if necessary. Death and other serious medical problems have occurred when people were accidentally exposed to DURAGESIC. Examples of accidental exposure include transfer of a DURAGESIC patch from an adults body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregivers skin to the medication in the patch while the caregiver was applying or removing the patch. Placing DURAGESIC in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death. Misuse, Abuse and Diversion of Opioids Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when prescribing or dispensing DURAGESIC in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. DURAGESIC has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Hypoventilation (Respiratory Depression) Serious or life-threatening hypoventilation may occur at any time during the use of DURAGESIC especially during the initial 24-72 hours following initiation of therapy and following increases in dose. Because significant amounts of fentanyl continue to be absorbed from the skin for 20-27 hours or more after the patch is removed, hypoventilation may persist beyond the removal of DURAGESIC.

DURAGESIC

(Fentanyl Transdermal System)


Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized. The use of concomitant CNS active drugs requires special patient care and observation. Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in DURAGESIC. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the sighing pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. DURAGESIC should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of DURAGESIC may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. Chronic Pulmonary Disease Because potent opioids can cause serious or life-threatening hypoventilation, DURAGESIC should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure. Head Injuries and Increased Intracranial Pressure DURAGESIC should not be used in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. DURAGESIC should be used with caution in patients with brain tumors. Interactions with Other CNS Depressants The concomitant use of DURAGESIC (fentanyl transdermal system) with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced. Interactions with Alcohol and Drugs of Abuse Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Interactions with CYP3A4 Inhibitors The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY Drug Interactions, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information). PRECAUTIONS General DURAGESIC (fentanyl transdermal system) should not be used to initiate opioid therapy in patients who are not opioid-tolerant. Children converting to DURAGESIC should be opioidtolerant and 2 years of age or older (see BOX WARNING). Patients, family members, and caregivers should be instructed to keep patches (new and used) out of the reach of children and others for whom DURAGESIC was not prescribed. A considerable amount of active fentanyl remains in DURAGESIC even after use as directed. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death. Cardiac Disease Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias. Hepatic or Renal Disease Insufficient information exists to make recommendations regarding the use of DURAGESIC in patients with impaired renal or hepatic function. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. Use in Pancreatic/Biliary Tract Disease DURAGESIC may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like DURAGESIC may cause increases in the serum amylase concentration. Tolerance Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drugs effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical Dependence Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood concentration of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION Discontinuation of DURAGESIC). Ambulatory Patients Strong opioid analgesics impair the mental or physical abilities required for the performance of potentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given DURAGESIC should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.

DURAGESIC

(Fentanyl Transdermal System)


Information for Patients Patients and their caregivers should be provided with a Medication Guide each time DURAGESIC is dispensed because new information may be available. Patients receiving DURAGESIC patches should be given the following instructions by the physician: 1. Patients should be advised that DURAGESIC patches contain fentanyl, an opioid pain medicine similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone. 2. Patients should be advised that each DURAGESIC patch may be worn continuously for 72 hours, and that each patch should be applied to a different skin site after removal of the previous transdermal patch. 3. Patients should be advised that DURAGESIC patches should be applied to intact, nonirritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients should be advised of the following: n young children or persons with cognitive impairment, the patch should be put on the I upper back to lower the chances that the patch will be removed and placed in the mouth. air at the application site should be clipped (not shaved) prior to patch application. H f the site of DURAGESIC application must be cleansed prior to application of the patch, I do so with clear water. o not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or D alter its characteristics. Allow the skin to dry completely prior to patch application. 4. Patients should be advised that DURAGESIC should be applied immediately upon removal from the sealed pouch and after removal of the protective liner. Additionally the patient should be advised of the following: he DURAGESIC patch should not be used if the pouch seal is broken, or if the patch is T cut, damaged, or changed in any way. he transdermal patch should be pressed firmly in place with the palm of the hand for T 30 seconds, making sure the contact is complete, especially around the edges. he patch should not be folded so that only part of the patch is exposed. T 5. Patients should be advised that the dose of DURAGESIC or the number of patches applied to the skin should NEVER be adjusted without the prescribing healthcare professionals instruction. 6. Patients should be advised that while wearing the patch, they should avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources, such as: heating pads, electric blankets, sunbathing, heat or tanning lamps, saunas, hot tubs or hot baths, and heated water beds, etc. 7. Patients should also be advised of a potential for temperature-dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body temperature due to strenuous exertion while wearing the patch should contact their physician. 8. Patients should be advised that if they experience problems with adhesion of the DURAGESIC patch, they may tape the edges of the patch with first aid tape. If problems with adhesion persist, patients may overlay the patch with a transparent adhesive film dressing (e.g., Bioclusive or Tegaderm). 9. Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a different skin site. 10. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down the toilet used DURAGESIC patches after removal from the skin. 11. Patients should be advised that DURAGESIC may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). 12. Patients should be advised to refrain from any potentially dangerous activity when starting on DURAGESIC or when their dose is being adjusted, until it is established that they have not been adversely affected. 13. Patients should be advised that DURAGESIC should not be combined with alcohol or other CNS depressants (e.g. sleep medications, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death. 14. Patients should be advised to consult their physician or pharmacist if other medications are being or will be used with DURAGESIC. 15. Patients should be advised of the potential for severe constipation. 16. Patients should be advised that if they have been receiving treatment with DURAGESIC and cessation of therapy is indicated, it may be appropriate to taper the DURAGESIC dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. 17. Patients should be advised that DURAGESIC contains fentanyl, a drug with high potential for abuse. 18. Patients, family members, and caregivers should be advised to protect DURAGESIC from theft or misuse in the work or home environment. 19. Patients should be instructed to keep DURAGESIC in a secure place out of the reach of children due to the high risk of fatal respiratory depression. 20. Patients should be advised that DURAGESIC should never be given to anyone other than the individual for whom it was prescribed because of the risk of death or other serious medical problems to that person for whom it was not intended. 21. Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person, they should immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual. 22. When DURAGESIC is no longer needed, the unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet. 23. Women of childbearing potential who become, or are planning to become pregnant, should be advised to consult a physician prior to initiating or continuing therapy with DURAGESIC. 24. Patients should be informed that accidental exposure or misuse may lead to death or other serious medical problems.

DURAGESIC

(Fentanyl Transdermal System)


Drug Interactions Agents Affecting Cytochrome P450 3A4 Isoenzyme System Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when DURAGESIC is given concurrently with agents that affect CYP3A4 activity. Coadminstration with agents that induce CYP3A4 activity may reduce the efficacy of DURAGESIC. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY Drug Interactions, WARNINGS, and DOSAGE AND ADMINISTRATION for further information). Central Nervous System Depressants The concomitant use of DURAGESIC (fentanyl transdermal system) with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced. MAO Inhibitors DURAGESIC is not recommended for use in patients who have received MAOI within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Carcinogenesis, Mutagenesis, and Impairment of Fertility In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 g/kg/day in males or 100 g/kg/ day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC0-24h comparison). There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays. The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a100mcg/hr patch on a mg/m2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days. Pregnancy Pregnancy Category C No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 g/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. DURAGESIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on amg/m2 basis. Labor and Delivery Fentanyl readily passes across the placenta to the fetus; therefore, DURAGESIC is not recommended for analgesia during labor and delivery. Nursing Mothers Fentanyl is excreted in human milk; therefore, DURAGESIC is not recommended for use in nursing women because of the possibility of effects in their infants. Pediatric Use The safety of DURAGESIC was evaluated in three open-label trials in 291 pediatric patients with chronic pain, 2years of age through 18 years of age. Starting doses of 25 mcg/h and higher were

DURAGESIC

(Fentanyl Transdermal System)


used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of DURAGESIC therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. Approximately 90% of the total daily opioid requirement (DURAGESIC plus rescue medication) was provided by DURAGESIC. DURAGESIC was not studied in children under 2 years of age. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older (see DOSAGE AND ADMINISTRATION and BOX WARNING). To guard against accidental ingestion by children, use caution when choosing the application site for DURAGESIC (see DOSAGE AND ADMINISTRATION) and monitor adhesion of the system closely. Geriatric Use Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and aprolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. Astudy conducted with the DURAGESIC fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. DURAGESIC should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS In post-marketing experience, deaths from hypoventilation due to use of DURAGESIC (fentanyl transdermal system) have been reported (see BOX WARNING and CONTRAINDICATIONS). Pre-Marketing Clinical Trial Experience Although DURAGESIC use in post-operative or acute pain and in patients who are not opioidtolerant is CONTRAINDICATED, the safety of DURAGESIC was originally evaluated in 357 postoperative adult patients for 1to 3 days and 153 cancer patients for a total of 510 patients. The duration of DURAGESIC use varied in cancer patients; 56% of patients used DURAGESIC for over 30 days, 28% continued treatment for more than 4 months, and 10% used DURAGESIC for more than 1 year. Hypoventilation was the most serious adverse reaction observed in 13 (4%) post-operative patients and in 3 (2%) of the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients. Various adverse events were reported; a causal relationship to DURAGESIC was not always determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who received DURAGESIC. There has been no attempt to correct for a placebo effect, concomitant use of other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials. Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in Table 1; similar reactions were seen in the 357 post-operative patients. In the pediatric population, the safety of DURAGESIC has been evaluated in 291 patients with chronic pain 2-18 years of age. The duration of DURAGESIC use varied; 20% of pediatric patients were treated for 15 days; 46% for 16-30 days; 16% for 31-60 days; and 17% for at least 61 days. Twenty-five patients were treated with DURAGESIC for at least 4 months and 9 patients for more than 9 months. There was no apparent pediatric-specific risk associated with DURAGESIC use in children as young as 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), and nausea (24%). Adverse events reported in pediatric patients at a rate of 1% are presented in Table 1. TABLE 1: ADVERSE EVENTS (at rate of 1%) Adult (N=380) and Pediatric (N=291) Clinical Trial Experience Body System Body as a Whole Cardiovascular Digestive Adults Abdominal pain*, headache*,fatigue*, back pain, fever, influenza-like symptoms*, accidental injury, rigors Arrhythmia, chest pain Nausea**, vomiting**, constipation**, dry mouth**, anorexia*, diarrhea*, dyspepsia*, flatulence Somnolence**, insomnia, confusion**, asthenia**, dizziness*, nervousness*, hallucinations*, anxiety*, depression*, euphoria*, tremor, abnormal coordination, speech disorder, abnormal thinking, abnormal gait, abnormal dreams, agitation, paresthesia, amnesia, syncope, paranoid reaction Dyspnea*, hypoventilation*, apnea*, hemoptysis, pharyngitis*, hiccups, bronchitis, rhinitis, sinusitis, upper respiratory tract infection* Sweating**, pruritus*, rash, application site reaction erythema, papules, itching, edema Urinary retention*, Micturition disorder Pediatrics Pain*, headache*, fever, syncope, abdominal pain, allergic reaction,flushing Hypertension, tachycardia Nausea**, vomiting**, constipation*, dry mouth, diarrhea Somnolence*, nervousness*, insomnia*, asthenia*, hallucinations, anxiety, depression, convulsions, dizziness, tremor, speech disorder, agitation, stupor, confusion, paranoid reaction

DURAGESIC

(Fentanyl Transdermal System)


The following adverse effects have been reported in less than 1% of the 510 adult post-operative and cancer patients studied: Cardiovascular: bradycardia Digestive: abdominal distention Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility Respiratory: stertorous breathing, asthma, respiratory disorder Skin and Appendages, General: exfoliative dermatitis, pustules Special Senses: amblyopia Urogenital: bladder pain, oliguria, urinary frequency Post-Marketing Experience - Adults The following adverse reactions have been reported in association with the use of DURAGESIC and not reported in the pre-marketing adverse reactions section above: Body as a Whole: edema Cardiovascular: tachycardia Metabolic and Nutritional: weight loss Special Senses: blurred vision Urogenital: decreased libido, anorgasmia, ejaculatory difficulty DRUG ABUSE AND ADDICTION DURAGESIC contains a high concentration of fentanyl, a potent Schedule II opioid agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (DURAGESIC) may be a particular target for abuse and diversion. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Drug seeking behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). Doctor shopping to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since DURAGESIC may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. DURAGESIC patches are intended for transdermal use (to be applied on the skin) only. Do not use a DURAGESIC patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way. OVERDOSAGE Clinical Presentation The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most serious significant effect being hypoventilation. Treatment For the management of hypoventilation, immediate countermeasures include removing the DURAGESIC (fentanyl transdermal system) system and physically or verbally stimulating the patient. These actions can be followed by administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following an overdose may be longer than the effects of the narcotic antagonists action (the half-life of naloxone ranges from 30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibility of re-narcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and the release of catecholamines. Always ensure a patent airway is established and maintained, administer oxygen and assist or control respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body temperature and fluid intake should be maintained. If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. DOSAGE AND ADMINISTRATION Special Precautions DURAGESIC contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (DURAGESIC) may be a particular target for abuse and diversion. DURAGESIC patches are intended for transdermal use (on intact skin) only. The DURAGESIC patch should not be used if the pouch seal is broken, or the patch is cut, damaged, or changed in any way. Each DURAGESIC patch may be worn continuously for 72 hours. The next patch should be applied to a different skin site after removal of the previous transdermal system. If problems with adhesion of the DURAGESIC patch occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing (e.g., Bioclusive or Tegaderm). If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site.

Nervous

Respiratory

Dyspnea, respiratory depression, rhinitis, coughing

Skin and Appendages

Pruritus*, application site reaction*, sweating increased, rash, rash erythematous, skin reaction localized Urinary retention

Urogenital

*Reactions occurring in 3% - 10% of DURAGESIC patients **Reactions occurring in 10% or more of DURAGESIC patients

DURAGESIC

(Fentanyl Transdermal System)


DURAGESIC is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the DURAGESIC dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean half-life of approximately 20-27 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours. The concomitant use of DURAGESIC with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY Drug Interactions, WARNINGS and PRECAUTIONS for further information). Pediatric patients converting to DURAGESIC with a 25 mcg/h patch should be opioid-tolerant and receiving at least 60 mg of oral morphine or the equivalent per day. The dose conversion schedule described in Table C, and method of titration described below are recommended in opioid-tolerant pediatric patients over 2 years of age with chronic pain (see PRECAUTIONS Pediatric Use). Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. DURAGESIC should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see CLINICAL PHARMACOLOGY Special Populations, Geriatric Use). General Principles DURAGESIC is indicated for management of persistent, moderate to severe chronic pain that: equires continuous, around-the-clock opioid administration for an extended period of r time annot be managed by other means such as non-steroidal analgesics, opioid c combination products, or immediate-release opioids. DURAGESIC should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to DURAGESIC 25 mcg/h. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg oral hydromorphone daily, or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could occur, DURAGESIC (fentanyl transdermal system) is contraindicated: in patients who are not opioid-tolerant n the management of acute pain or in patients who require opioid analgesia for a short i period of time. n the management of post-operative pain, including use after out-patient or day i surgeries (e.g., tonsillectomies) in the management of mild pain in the management of intermittent pain (e.g., use on an as needed basis [prn]) (See CONTRAINDICATIONS for further information.) Safety of DURAGESIC has not been established in children under 2 years of age. DURAGESIC should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS - Pediatric Use). Prescribers should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society. With all opioids, the safety of patients using the products is dependent on health care practitioners prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use. As with all opioids, dosage should be individualized. The most important factor to be considered in determining the appropriate dose is the extent of pre-existing opioid-tolerance (see BOX WARNING and CONTRAINDICATIONS). Initial doses should be reduced in elderly or debilitated patients (see PRECAUTIONS). DURAGESIC (fentanyl transdermal system) should be applied to intact, non-irritated and nonirradiated skin on aflat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site should be clipped (not shaved) prior to system application. If the site of DURAGESIC application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application. DURAGESIC should be applied immediately upon removal from the sealed package. Do not use if the pouch seal is broken. Do not alter the patch (e.g., cut) in any way prior to application and do not use cut or damaged patches. The transdermal system should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. DURAGESIC should be kept out of the reach of children. Used patches should be folded so that the adhesive side of the patch adheres to itself, then the patch should be flushed down the toilet immediately upon removal. Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed. Unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet. Dose Selection Doses must be individualized based upon the status of each patient and should be assessed at regular intervals after DURAGESIC application. Reduced doses of DURAGESIC are suggested for the elderly and other groups discussed in PRECAUTIONS. DURAGESIC is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression.

DURAGESIC

(Fentanyl Transdermal System)


In selecting an initial DURAGESIC dose, attention should be given to 1) the daily dose, potency, and characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist-antagonist), 2) the reliability of the relative potency estimates used to calculate the DURAGESIC dose needed (potency estimates may vary with the route of administration), 3) the degree of opioid tolerance and 4) the general condition and medical status of the patient. Each patient should be maintained at the lowest dose providing acceptable pain control. Initial DURAGESIC Dose Selection Overestimating the DURAGESIC dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean half-life of approximately 20-27 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours. There has been no systematic evaluation of DURAGESIC as an initial opioid analgesic in the management of chronic pain, since most patients in the clinical trials were converted to DURAGESIC from other narcotics. The efficacy of DURAGESIC 12 mcg/h as an initiating dose has not been determined. In addition, patients who are not opioid-tolerant have experienced hypoventilation and death during use of DURAGESIC. Therefore, DURAGESIC should be used only in patients who are opioid-tolerant. To convert adult and pediatric patients from oral or parenteral opioids to DURAGESIC, use Table C: Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table C, use the following methodology: 1. Calculate the previous 24-hour analgesic requirement. 2. Convert this amount to the equianalgesic oral morphine dose using Table D. 3. Table E displays the range of 24-hour oral morphine doses that are recommended for conversion to each DURAGESIC dose. Use this table to find the calculated 24-hour morphine dose and the corresponding DURAGESIC dose. Initiate DURAGESIC treatment using the recommended dose and titrate patients upwards (no more frequently than every 3 days after the initial dose or than every 6 days thereafter) until analgesic efficacy is attained. The recommended starting dose when converting from other opioids to DURAGESIC is likely too low for 50% of patients. This starting dose is recommended to minimize the potential for overdosing patients with the first dose. For delivery rates in excess of 100 mcg/h, multiple systems may be used. TABLE C1: DOSE CONVERSION GUIDELINES Current Analgesic Daily Dosage (mg/d) Oral morphine 60-134 135-224 225-314 315-404 IM/IV morphine 10-22 23-37 38-52 53-67 Oral oxycodone 30-67 67.5-112 112.5-157 157.5-202 IM/IV oxycodone 15-33 33.1-56 56.1-78 78.1-101 Oral codeine 150-447 448-747 748-1047 1048-1347 Oral hydromorphone 8-17 17.1-28 28.1-39 39.1-51 IV hydromorphone 1.5-3.4 3.5-5.6 5.7-7.9 8-10 IM meperidine 75-165 166-278 279-390 391-503 Oral methadone 20-44 45-74 75-104 105-134 IM methadone 10-22 23-37 38-52 53-67 Recommended 25 mcg/h 50 mcg/h 75 mcg/h 100 mcg/h Dose DURAGESIC Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table C, use the conversion methodology outlined above with Table D. 1 Table C should not be used to convert from DURAGESIC to other therapies because this conversion to DURAGESIC is conservative. Use of table C for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible (see DOSAGE AND ADMINISTRATION - Discontinuation of DURAGESIC). TABLE D1a: EQUIANALGESIC POTENCY CONVERSION Name Morphine Hydromorphone (Dilaudid) Methadone (Dolophine) Oxycodone Levorphanol (Levo-Dromoran) Oxymorphone (Numorphan) Meperidine (Demerol) Codeine
1

Equianalgesic Dose (mg) PO 60 (30)d 7.5 20 30 4 10 (PR) 200

IMb,c 10 1.5 10 15 2 1 75 130

Table D should not be used to convert from DURAGESIC to other therapies because this conversion to DURAGESIC is conservative. Use of Table D for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible (see Dosage And Administration - Discontinuation of DURAGESIC). a All IM and PO doses in this chart are considered equivalent to 10 mg of IM morphine in analgesic effect. IMdenotes intramuscular, PO oral, and PR rectal. b Based on single-dose studies in which an intramuscular dose of each drug listed was compared with morphine to establish the relative potency. Oral doses are those recommended when changing from parenteral to an oral route. Reference: Foley, K.M. (1985) The treatment of cancer pain. NEJM 313(2):84-95. c Although controlled studies are not available, in clinical practice it is customary to consider the doses of opioid given IM, IV, or subcutaneously to be equivalent. There may be some differences in pharmacokinetic parameters such as Cmax and Tmax.

DURAGESIC
d

(Fentanyl Transdermal System)


The conversion ratio of 10 mg parenteral morphine = 30 mg oral morphine is based on clinical experience in patients with chronic pain. The conversion ratio of 10 mg parenteral morphine = 60 mg oral morphine is based on a potency study in acute pain. Reference: Ashburn and Lipman (1993) Management of pain in the cancer patient. Anesth Analg 76:402-416.

DURAGESIC

(Fentanyl Transdermal System)


Safety and Handling DURAGESIC is supplied in sealed transdermal systems which pose little risk of exposure to health care workers. Do not use a DURAGESIC patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way. kEEP DURAGESIC OUT OF THE REACH OF CHILDREN AND PETS. Store in original unopened pouch. Store up to 25C (77F); excursions permitted to 15 - 30C (59 - 86F). Apply immediately after removal from individually sealed pouch. Do not use if the pouch seal is broken. For transdermal use only. Bioclusive is a trademark of Ethicon, Inc. Tegaderm is a trademark of 3M A schedule CII narcotic. DEA order form required. Manufactured by: ALZA Corporation Vacaville, CA 95688 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

TABLE E1: RECOMMENDED INITIAL DURAGESIC DOSE BASED UPON DAILY ORAL MORPHINE DOSE Oral 24-hour DURAGESIC Morphine Dose (mg/day) (mcg/h) 60-134 135-224 225-314 315-404 405-494 495-584 585-674 675-764 765-854 855-944 945-1034 1035-1124 25 50 75 100 125 150 175 200 225 250 275 300

NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to DURAGESIC. 1 Table E should not be used to convert from DURAGESIC to other therapies because this conversion to DURAGESIC is conservative. Use of Table E for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible (see DOSAGE AND ADMINISTRATION - Discontinuation of DURAGESIC). The majority of patients are adequately maintained with DURAGESIC administered every 72 hours. Some patients may not achieve adequate analgesia using this dosing interval and may require systems to be applied every 48 hours rather than every 72 hours. An increase in the DURAGESIC dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen. Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended. Because of the increase in serum fentanyl concentration over the first 24 hours following initial system application, the initial evaluation of the maximum analgesic effect of DURAGESIC cannot be made before 24 hours of wearing. The initial DURAGESIC dose may be increased after 3 days (see DOSAGE AND ADMINISTRATION - Dose Titration). During the initial application of DURAGESIC, patients should use short-acting analgesics as needed until analgesic efficacy with DURAGESIC is attained. Thereafter, some patients still may require periodic supplemental doses of other short-acting analgesics for breakthrough pain. Dose Titration The recommended initial DURAGESIC dose based upon the daily oral morphine dose is conservative, and 50% of patients are likely to require a dose increase after initial application of DURAGESIC. The initial DURAGESIC dose may be increased after 3 days based on the daily dose of supplemental opioid analgesics required by the patient in the second or third day of the initial application. Physicians are advised that it may take up to 6 days after increasing the dose of DURAGESIC for the patient to reach equilibrium on the new dose (see graph in CLINICAL PHARMACOLOGY). Therefore, patients should wear a higher dose through two applications before any further increase in dosage is made on the basis of the average daily use of a supplemental analgesic. Appropriate dosage increments should be based on the daily dose of supplementary opioids, using the ratio of 45mg/24 hours of oral morphine to a 12.5 mcg/h increase in DURAGESIC dose. DURAGESIC-12 delivers 12.5 mcg/h of fentanyl. Discontinuation of DURAGESIC To convert patients to another opioid, remove DURAGESIC and titrate the dose of the new analgesic based upon the patients report of pain until adequate analgesia has been attained. Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion or dose adjustment. For patients requiring discontinuation of opioids, a gradual downward titration is recommended since it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal. Tables C, D, and E should not be used to convert from DURAGESIC to other therapies. Because the conversion to DURAGESIC is conservative, use of Tables C, D, and E for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible. HOW SUPPLIED DURAGESIC (fentanyl transdermal system) is supplied in cartons containing 5 individually packaged systems. See chart for information regarding individual systems. DURAGESIC Dose (mcg/h) DURAGESIC-12 DURAGESIC-25 DURAGESIC-50 DURAGESIC-75 DURAGESIC-100 System Size (cm2) 5.25 10.5 21 31.5 42 Fentanyl Content (mg) 2.1 4.2 8.4 12.6 16.8

Revised October 2011 Janssen Pharmaceuticals, Inc. 2009 10235700

NDC Number 50458-090-05 50458-091-05 50458-092-05 50458-093-05 50458-094-05

NIZORAL (ketoconazole) 2% Shampoo


For topical application only. Rx only.
DESCRIPTION NIZORAL (ketoconazole) 2% Shampoo is a red-orange liquid for topical application, containing the broad-spectrum synthetic antifungal agent ketoconazole in a concentration of 2% in an aqueous suspension. It also contains: coconut fatty acid diethanolamide, disodium monolauryl ether sulfosuccinate, F.D.&C. Red No. 40, hydrochloric acid, imidurea, laurdimonium hydrolyzed animal collagen, macrogol 120 methyl glucose dioleate, perfume bouquet, sodium chloride, sodium hydroxide, sodium lauryl ether sulfate, and purified water. Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)- 2-(1H-imidazol-1-ylmethyl)-1,3dioxolan-4-yl]methoxy]phenyl]piperazine and has the following structural formula:

PRECAUTIONS General: If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. Information for Patients: May be irritating to mucous membranes of the eyes and contact with this area should be avoided. There have been reports that use of the shampoo resulted in removal of the curl from permanently waved hair. Carcinogenesis, Mutagenesis, Impairment of Fertility: The dominant lethal mutation test in male and female mice revealed that single oral doses of ketoconazole as high as 80 mg/kg produced no mutation in any stage of germ cell development. The Ames Salmonella microsomal activator assay was also negative. A long-term feeding study of ketoconazole in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. Pregnancy: Teratogenic effects: Pregnancy Category C: Ketoconazole is not detected in plasma after chronic shampooing. Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given orally in the diet at 80 mg/kg/day (10 times the maximum recommended human oral dose). However, these effects may be related to maternal toxicity, which was seen at this and higher dose levels. There are no adequate and well-controlled studies in pregnant women. Ketoconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

CLINICAL PHARMACOLOGY Tinea (pityriasis) versicolor is a non-contagious infection of the skin caused by Pityrosporum orbiculare (Malassezia furfur). This commensal organism is part of the normal skin flora. In susceptible individuals the condition is often recurrent and may give rise to hyperpigmented or hypopigmented patches on the trunk which may extend to the neck, arms and upper thighs. Treatment of the infection may not immediately result in restoration of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental skin exposure. The rate of recurrence of infection is variable. When ketoconazole 2% shampoo was applied dermally to intact or abraded skin of rabbits for 28 days at doses up to 50 mg/kg and allowed to remain one hour before being washed away, there were no detectable plasma ketoconazole levels using an assay method having a lower detection limit of 5 ng/mL. NIZORAL (ketoconazole) was not detected in plasma in 39 patients who shampooed 4-10 times per week for 6 months or in 33 patients who shampooed 2-3 times per week for 3-26 months (mean: 16 months). An exaggerated use washing test on the sensitive antecubital skin of 10 subjects twice daily for five consecutive days showed that the irritancy potential of ketoconazole 2% shampoo was significantly less than that of 2.5% selenium sulfide shampoo. A human sensitization test, a phototoxicity study, and a photoallergy study conducted in 38 male and 22 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no phototoxicity and no photoallergenic potential due to NIZORAL (ketoconazole) 2% Shampoo. Mode of Action: Interpretations of in vivo studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. It is postulated, but not proven, that the therapeutic effect of ketoconazole in tinea (pityriasis) versicolor is due to the reduction of Pityrosporum orbiculare (Malassezia furfur) and that the therapeutic effect in dandruff is due to the reduction of Pityrosporum ovale. Support for the therapeutic effect in tinea versicolor comes from a three-arm, parallel, double-blind, placebo-controlled study in patients who had moderately severe tinea (pityriasis) versicolor. Successful response rates in the primary efficacy population for each of both three-day and single-day regimens of ketoconazole 2% shampoo were statistically significantly greater (73% and 69%, respectively) than a placebo regimen (5%). There had been mycological confirmation of fungal disease in all cases at baseline. Mycological clearing rates were 84% and 78%, respectively, for the three-day and one-day regimens of the 2% shampoo and 11% in the placebo regimen. While the differences in the rates of successful response between either of the two active treatments and placebo were statistically significant, the difference between the two active regimens was not. Microbiology: NIZORAL (ketoconazole) is a broad-spectrum synthetic antifungal agent which inhibits the growth of the following common dermatophytes and yeasts by altering the permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum; yeasts: Candida albicans, C. tropicalis, Pityrosporum ovale (Malassezia ovale) and Pityrosporum orbiculare (M. furfur). Development of resistance by these microorganisms to ketoconazole has not been reported. INDICATIONS AND USAGE NIZORAL (ketoconazole) 2% Shampoo is indicated for the treatment of tinea (pityriasis) versicolor caused by or presumed to be caused by Pityrosporum orbiculare (also known as Malassezia furfur or M. orbiculare). Note: Tinea (pityriasis) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk which may extend to the neck, arms and upper thighs. Treatment of the infection may not immediately result in normalization of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure. Although tinea versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora. CONTRAINDICATIONS NIZORAL (ketoconazole) 2% Shampoo is contraindicated in persons who have shown hypersensitivity to the active ingredient or excipients of this formulation.

Nursing mothers: Ketoconazole is not detected in plasma after chronic shampooing. Nevertheless, caution should be exercised when NIZORAL (ketoconazole) 2% Shampoo is administered to a nursing woman. Pediatric Use: Safety and effectiveness in children have not been established. ADVERSE REACTIONS In 11 double-blind trials in 264 patients using ketoconazole 2% shampoo for the treatment of dandruff or seborrheic dermatitis, an increase in normal hair loss and irritation occurred in less than 1% of patients. In three open-label safety trials in which 41 patients shampooed 4-10 times weekly for six months, the following adverse experiences each occurred once: abnormal hair texture, scalp pustules, mild dryness of the skin, and itching. As with other shampoos, oiliness and dryness of hair and scalp have been reported. In a double-blind, placebo-controlled trial in which patients with tinea versicolor were treated with either a single application of NIZORAL (ketoconazole) 2% Shampoo (n=106), a daily application for three consecutive days (n=107), or placebo (n=105), drug-related adverse events occurred in 5 (5%), 7 (7%) and 4 (4%) of patients, respectively. The only events that occurred in more than one patient in any one of the three treatment groups were pruritus, application site reaction, and dry skin; none of these events occurred in more than 3% of the patients in any one of the three groups. In worldwide experience with NIZORAL Shampoo there have been rare reports of hair discoloration. OVERDOSAGE NIZORAL (ketoconazole) 2% Shampoo is intended for external use only. In the event of accidental ingestion, supportive measures should be employed. Induced emesis and gastric lavage should usually be avoided. DOSAGE AND ADMINISTRATION Apply the shampoo to the damp skin of the affected area and a wide margin surrounding this area. Lather, leave in place for 5 minutes, and then rinse off with water. One application of the shampoo should be sufficient. HOW SUPPLIED NIZORAL (ketoconazole) 2% Shampoo is a red-orange liquid supplied in a 4-fluid ounce nonbreakable plastic bottle (NDC 50458-680-08). Storage conditions: Store at a temperature not above 25C (77F). Protect from light. Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium

Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2004 Revised: January 2009 U.S. Patent No. 4,335,125 US - 971374

replace with July 2010

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

ORTHO-CEPT TAblETS (desogestrel and ethinyl estradiol)


DESCRIPTION ORTHO-CEPT Tablets provide an oral contraceptive regimen of 21 light orange round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18, 19-dinor-17 alpha-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17,diol). Inactive ingredients include colloidal silicone dioxide, corn starch, ferric oxide, hypromellose, lactose, polyethylene glycol, povidone, stearic acid, talc, titanium dioxide, and vitamin E. Each green tablet contains the following inactive ingredients: FD&C Blue No.1 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate, polyethylene glycol, pregelatinized starch, talc and titanium dioxide. desogestrel ethinyl estradiol

TAblE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAl USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR. UNITED STATES. % of Women Experiencing an Unintended Pregnancy within the First Year of Use Method (1) Chance# Spermicidesp Periodic abstinence Calendar Ovulation Method Sympto-Thermal Post-Ovulation Withdrawal Cap Parous Women Nulliparous Women Sponge Parous Women Nulliparous Women Diaphragm Condom Female (Reality) Male Pill Progestin Only Combined IUD Progesterone T Copper T380A LNg 20 Depo-Provera Norplant and Norplant-2 Female Sterilization Male Sterilization Typical Use (2) 85 26 25 Perfect Use (3) 85 6 9 3 2 1 4 26 9 20 9 6 5 3 0.5 0.1 2.0 0.8 0.1 0.3 0.05 0.5 0.15 1.5 0.6 0.1 0.3 0.05 0.5 0.10 81 78 81 70 88 100 100 42 56 42 56 56 56 61 71 % of Women Continuing Use at One Year* (4) 40 63

19 40 20 40 20 20 21 14 5

ClINICAl PHARMACOlOGY Pharmacodynamics Combined oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus, which increase the difficulty of sperm entry into the uterus, and changes in the endometrium which reduce the likelihood of implantation. Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity.91,92 The relevance of this latter finding in humans is unknown. Pharmacokinetics Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%. In the third cycle of use after a single dose of ORTHO-CEPT, maximum concentrations of 3-keto-desogestrel of 2,805 1,203 pg/mL (mean SD) are reached at 1.4 0.8 hours. The area under the curve (AUC0-) is 33,858 11,043 pg/mLhr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840 1,667 pg/mL are reached at 1.4 0.9 hours. The minimum plasma levels of 3-ketodesogestrel at steady state are 1,400 560 pg/mL. The AUC0-24 at steady state is 52,299 17,878 pg/mLhr. The mean AUC0- for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-ketodesogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 64 nmol/L) to day 21 (230 59 nmol/L). The elimination half-life for 3-keto-desogestrel is approximately 38 20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3-OH-desogestrel, 3-OH-desogestrel, and 3-OH-5-Hdesogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides. Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of ORTHO-CEPT, the relative bioavailability is approximately 83%. In the third cycle of use after a single dose of ORTHO-CEPT, maximum concentrations of ethinyl estradiol of 95 34 pg/mL are reached at 1.5 0.8 hours. The AUC0- is 1,471 268 pg/mLhr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 48 pg/mL are reached at about 1.4 0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24 8.3 pg/mL. The AUC0-24 at steady state is 1,117 302 pg/mLhr. The mean AUC0- for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol. The elimination half-life is 26 6.8 hours at steady state. Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation. INDICATIONS AND USAGE ORTHO-CEPT Tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates. In a clinical trial with ORTHO-CEPT, 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.

Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception. Source: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY; Irvington Publishers, 1998. * Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 4 yellow pills). However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. # The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. p Foams, creams, gels, vaginal suppositories, and vaginal film. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. With spermicidal cream or jelly. Without spermicides.
Among

ORTHO-CEPT has not been studied for and is not indicated for use in emergency contraception. CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: Thrombophlebitis or thromboembolic disorders A past history of deep vein thrombophlebitis or thromboembolic disorders Cerebral vascular or coronary artery disease (current or history) Valvular heart disease with complications Severe hypertension Diabetes with vascular involvement Headaches with focal neurological symptoms Major surgery with prolonged immobilization Known or suspected carcinoma of the breast or personal history of breast cancer Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Acute or chronic hepatocellular disease with abnormal liver function Hepatic adenomas or carcinomas Known or suspected pregnancy Hypersensitivity to any component of this product

WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of adisease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the authors permission). For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorder and Other Vascular Problems a. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2 Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate 2-fold increased risk, which corresponds to an additional 1-2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this 2-fold increase in risk. A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed. b. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4-10 The risk is very low in women under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives. (See Table II.) TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMANYEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE (Adapted from P.M. Layde and V. Beral, ref #12.)

smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3 d. Dose-Related Risk of Vascular Disease from Oral Contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. Persistence of Risk of Vascular Disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 0.050 mg or higher of estrogens. 2. Estimates of Mortality from Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. TAblE III: ANNUAl NUMbER OF bIRTH-RElATED OR METHOD-RElATED DEATHS ASSOCIATED WITH CONTROl OF FERTIlITY PER 100,000 NONSTERIlE WOMEN, bY FERTIlITY CONTROl METHOD ACCORDING TO AGE Method of control and outcome No fertilitycontrol methods* Oral contraceptives non-smoker Oral contraceptives smoker IUD Condom* Diaphragm/ spermicide* Periodic abstinence*
Adapted from H.W. Ory, ref. #35.

15-19 7.0 0.3 2.2 0.8 1.1 1.9 2.5

20-24 7.4 0.5 3.4 0.8 1.6 1.2 1.6

25-29 9.1 0.9 6.6 1.0 0.7 1.2 1.6

30-34 14.8 1.9 13.5 1.0 0.2 1.3 1.7

35-39 25.7 13.8 51.1 1.4 0.3 2.2 2.9

40-44 28.2 31.6 117.2 1.4 0.4 2.8 3.6

* Deaths are birth-related Deaths are method-related 3. Carcinoma of the Reproductive Organs and breasts Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combined oral contraceptives. However, this excess risk appears to decrease over time after discontinuation of combined oral contraceptives and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use combined oral contraceptives before age 20. Most studies show a similar pattern of risk with combined oral contraceptives regardless of a womans reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers. Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. There is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater. Receptor binding and animal studies have shown that desogestrel or its active metabolite has minimal androgenic activity (see CLINICAL PHARMACOLOGY), although these findings have not been confirmed in adequate and well-controlled clinical trials. c. Cerebrovascular Diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (> 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29 In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for nonWomen who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5. Ocular lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. Oral Contraceptive Use before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56-57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when oral contraceptives are taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 8. Carbohydrate and lipid Metabolic Effects Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 In general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 In the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 9. Elevated blood Pressure Women with significant hypertension should not be started on hormonal contraception.98 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity and concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives,69 and there is no difference in the occurrence of hypertension among former and never users.68,70,71 10. Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent. 12. Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. PRECAUTIONS 1. General Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 2. Physical Examination and Follow-Up It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. lipid Disorders Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. liver Function If jaundice develops in any woman receiving oral contraceptives, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Emotional Disorders Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7. Contact lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8. Drug Interactions Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products: Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant

administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results. Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combined hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. Johns Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. Concurrent use of bosentan and ethinyl estradiol-containing products may result in decreased concentrations of these contraceptive hormones, thereby increasing the risk of unintended pregnancy and unscheduled bleeding. Increase in Plasma Levels Associated with Co-Administered Drugs: Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Changes in Plasma Levels of Co-Administered Drugs: Combined hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives. Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Healthcare professionals are advised to also refer to prescribing information of co-administered drugs for recommendations regarding management of concomitant therapy. 9. Interactions with laboratory Tests Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrineinduced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex hormone binding globulins are increased and result in elevated levels of total circulating sex steroids however, free or biologically active levels either decrease or remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 10. Carcinogenesis See WARNINGS. 11. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS. 12. Nursing Mothers Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. Pediatric Use Safety and efficacy of ORTHO-CEPT Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 14. Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population. INFORMATION FOR THE PATIENT See Patient Labeling printed below. ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS). Thrombophlebitis and venous thrombosis with or without embolism Arterial thromboembolism Pulmonary embolism Myocardial infarction Cerebral hemorrhage Cerebral thrombosis Hypertension Gallbladder disease Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives: Mesenteric thrombosis Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: Nausea Vomiting Gastrointestinal symptoms (such as abdominal cramps and bloating) Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea Temporary infertility after discontinuation of treatment Edema

Melasma which may persist Breast changes: tenderness, enlargement, secretion Change in weight (increase or decrease) Change in cervical erosion and secretion Diminution in lactation when given immediately postpartum Cholestatic jaundice Migraine Allergic reaction, including rash, urticaria, and angioedema Mental depression Reduced tolerance to carbohydrates Vaginal candidiasis Change in corneal curvature (steepening) Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted: Pre-menstrual syndrome Cataracts Changes in appetite Cystitis-like syndrome Headache Nervousness Dizziness Hirsutism Loss of scalp hair Erythema multiforme Erythema nodosum Hemorrhagic eruption Vaginitis Porphyria Impaired renal function Hemolytic uremic syndrome Acne Changes in libido Colitis Budd-Chiari Syndrome

postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) If the patient starts on ORTHO-CEPT postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a light orange active tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) light orange active tablet in Weeks 1, 2, or 3, the light orange active tablet should be taken as soon as she remembers. If the patient misses two (2) light orange active tablets in Week 1 or Week 2, the patient should take two (2) light orange active tablets the day she remembers and two (2) light orange active tablets the next day; and then continue taking one (1) light orange active tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) light orange active tablets in the third week or misses three (3) or more light orange active tablets in a row, the patient should continue taking one light orange active tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. ADDITIONAl INSTRUCTIONS FOR All DOSING REGIMENS Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. Use of oral contraceptives in the event of a missed menstrual period: 1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued if pregnancy is confirmed. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. HOW SUPPlIED ORTHO-CEPT Tablets are available in a blister card (NDC 0062-1796-01 or NDC 50458-196-01) with a tablet dispenser (unfilled). The blister card contains 28 tablets, as follows: 21 light orange, round, convex, beveled edged, coated tablets imprinted ORTHO on one side and D 150 on the other side containing 0.15 mg desogestrel together with 0.03 mg ethinyl estradiol, and 7 green, round, convex, beveled edged, coated tablets imprinted ORTHO P on both sides containing inert ingredients. ORTHO-CEPT Tablets are packaged in a carton (NDC 0062179615 or NDC 50458-196-15) containing 6 blister cards and 6 unfilled tablet dispensers. STORAGE: Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F).
1. Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998, in press. 2. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt.1). N Engl J Med 1981; 305: 612-618. 3. Stadel BV. Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305: 672-677. 4. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet and Gynecol 1981; 88:838-845. 5. Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975; 2 (5965):245-248. 6. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 1975;2(5956):241-245. 7. 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JAMA 1975; 231:718-722. 31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970; 2:203-209. 32. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980; 280 (6224):1157-1161. 33. Kay CR. Progestogens and arterial disease-evidence from the Royal College of General Practitioners Study. Am J Obstet Gynecol 1982; 142:762-765. 34. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983; 33:75-82. 35. Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983; 15:50-56. 36. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of breast cancer. N Engl J Med 1986; 315:405-411. 37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer risk in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926-929. 38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723-725. 39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868. 40. Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; 1(8431):748-749. 41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987; 56:653-660. 42. Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril 1987; 47:733-761. 43. McPherson K, Drife JO. The pill and breast cancer: why the uncertainty? Br Med J 1986; 293:709-710. 44. Shapiro S. Oral contraceptives time to take stock. N Engl J Med 1987; 315:450-451. 45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976;124:573-577. 46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930. 47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339-344. 48. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives.

OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEAlTH bENEFITS The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.73-78 Effects on menses: increased menstrual cycle regularity decreased blood loss and decreased incidence of iron deficiency anemia decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: decreased incidence of functional ovarian cysts decreased incidence of ectopic pregnancies Effects from long-term use: decreased incidence of fibroadenomas and fibrocystic disease of the breast decreased incidence of acute pelvic inflammatory disease decreased incidence of endometrial cancer decreased incidence of ovarian cancer

REFERENCES

DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ORTHO-CEPT must be taken exactly as directed and at intervals not exceeding 24 hours. ORTHO-CEPT is available in a blister card with a tablet dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Day 1 Start The dosage of ORTHO-CEPT for the initial cycle of therapy is one light orange active tablet administered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow as Day 1. Tablets are taken without interruption as follows: One light orange active tablet daily for 21 days, then one green reminder tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a light orange active tablet is taken the next day. The use of ORTHO-CEPT for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) If the patient starts on ORTHO-CEPT postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a light orange active tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) light orange active tablet in Weeks 1, 2, or 3, the light orange active tablet should be taken as soon as she remembers. If the patient misses two (2) light orange active tablets in Week 1 or Week 2, the patient should take two (2) light orange active tablets the day she remembers and two (2) light orange active tablets the next day; and then continue taking one (1) light orange active tablet a day until she finishes the pack. The patient should be instructed to use aback-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) light orange active tablets in the third week or misses three (3) or more light orange active tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Sunday Start When taking ORTHO-CEPT, the first light orange active tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first light orange active tablet is taken on that day. If switching directly from another oral contraceptive, the first light orange active tablet should be taken on the first Sunday after the last ACTIVE tablet of the previous product. Tablets are taken without interruption as follows: One light orange active tablet daily for 21 days, then one green reminder tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a light orange active tablet is taken the next day (Sunday). When initiating a Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. The use of ORTHO-CEPT for contraception may be initiated 4 weeks postpartum. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the

Br Med J 1985; 290:961-965. 49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648. 50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433435. 51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386394. 52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437-440. 53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357. 54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357-1361. 55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452. 56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981; 140:521-524. 57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980; 112:73-79. 58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239. 59. Rothman KJ, Fyler DC, Goldbatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109:433-439. 60. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gall-bladder disease, and breast tumors. Lancet 1973;1:13991404. 61. Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman, 1974. 62. Layde PM, Vessey MP, Yeates D. Risk of gall bladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274-278. 63. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119:796-805. 64. Strom BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gall bladder disease. Clin Pharmacol Ther 1986; 39:335-341. 65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049. 66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In Progesterone and Progestin. Edited by Bardin CW, Milgrom E, Mauvis-Jarvis P. New York, Raven Press, 1983; pp. 395-410. 67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857-864. 68. Royal College of General Practitioners Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503. 70. Laragh AJ. Oral contraceptive induced hypertension - nine years later. Am J Obstet Gynecol 1976; 126:141-147. 71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort. In Pharmacology of Steroid Contraceptive Drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288. (Monographs of the Mario Negri Institute for Pharmacological Research, Milan). 72.Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143. 73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599. 74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800. 75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69. 76. Ory HW, Cole P, Macmahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419422. 77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182184. 78. Ory HW, Forrest JD, Lincoln R. Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p.1. 79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast Cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-controlled study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42. 81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br. J. Cancer 1986; 54:311-317. 82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use in breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC. Breast cancer and the pill A further report from the Royal College of General Practitioners oral contraception study. Br. J. Cancer 1988; 58:675-680. 84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am. J. Epidemiol 1989; 129:269-280. 86. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982. 87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38. 88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br. J. Cancer 1989; 59:613-617. 89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br. J. Cancer 1989; 59:618-621. 90. Godsland, I et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323:1375-81. 91. Kloosterboer, HJ et al. Selectivity in progesterone and androgen receptor binding of progestogens used in oral contraception. Contraception 1988; 38:325-32. 92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim Forsch/ Drug Res, 1983; 33(I),2:231-6. 93. Data on file, Organon Inc. 94. Fotherby, K. Oral contraceptives, lipids and cardiovascular diseases. Contraception 1985; Vol. 31; 4:367-94. 95. Lawrence, DM et al. Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne. Clinical Endocrinology 1981;15:87-91. 96. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727. 97. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882. 98. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 99. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-298. 100. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118. 101. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484-489.

The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis) or lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes, and subsequent serious medical consequences. 2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed patient labeling given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, bosentan, as well as some anticonvulsants and some antibiotics and herbal preparations containing St. Johns Wort (hypericum perforatum) may decrease oral contraceptive effectiveness. Oral contraceptives may interact with lamotrigine (LAMICTAL), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare professional. Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information labeling gives you further information which you should read and discuss with your healthcare professional. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis b, and syphilis. HOW TO TAKE THE PIll IMPORTANT POINTS TO REMEMbER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. bEFORE YOU START TAKING YOUR PIllS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK: The pill pack has 21 light orange active pills (with hormones) to take for 3weeks, followed by 1 week of green reminder pills (without hormones). 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills, 3) check picture of pill pack and additional instructions for using this package below. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as aback-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PIllS You have a choice of which day to start taking your first pack of pills. ORTHO-CEPT is available in a blister card with a tablet dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. DAY 1 START: 1. Take the first light orange active pill of the first pack during the first 24 hours of your period. 2. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

bRIEF SUMMARY PATIENT PACKAGE INSERT ORTHO-CEPT (desogestrel and ethinyl estradiol) Tablets This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Oral contraceptives, also known as birth control pills or the pill, are taken to prevent pregnancy, and when taken correctly without missing any pills, have a failure rate of approximately 1% per year. The typical failure rate is approximately 5% per year when women who miss pills are included. For most women, oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: smoke have high blood pressure, diabetes, high cholesterol have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, nonsmoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, headache, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use.

SUNDAY START: 1. Take the first light orange active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). WHAT TO DO DURING THE MONTH 1. TAKE ONE PIll AT THE SAME TIME EVERY DAY UNTIl THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR bRAND OF PIllS: Start the next pack on the day after your last green reminder pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PIllS If you MISS 1 light orange active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 light orange active pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 light orange active pills in a row in THE 3RD WEEK: 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE light orange active pills in a row (during the first 3 weeks): 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER: If you forget any of the 7 green reminder pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINAllY, IF YOU ARE STIll NOT SURE WHAT TO DO AbOUT THE PIllS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE LIGHT ORANGE ACTIVE PILL EACH DAY until you can reach your healthcare professional. INSTRUCTIONS FOR USE 1. Open the compact. Place the blister into the compact, with the tablets facing up, so that the V notch in the blister card matches up with the V shaped post at the top of the compact. Press down firmly on each edge of the blister card and make sure that the edge of the blister card is firmly seated under each of the nibs inside the compact (see picture). There are 21 light orange active pills and 7 green reminder pills.

STORAGE: Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F). DETAIlED PATIENT lAbElING This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. PlEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully. The following oral contraceptive product contains a combination of a progestogen and estrogen, the two kinds of female hormones: ORTHO-CEPT (desogestrel and ethinyl estradiol) Tablets Each light orange tablet contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol. Each green tablet contains inert ingredients. INTRODUCTION Any woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This patient labeling will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this labeling is not a replacement for a careful discussion between you and your healthcare professional. You should discuss the information provided in this labeling with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professionals advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAl CONTRACEPTIVES Oral contraceptives or birth control pills or the pill are used to prevent pregnancy and are more effective than most other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates, including women who do not always take the pills exactly as directed, are approximately 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other non-surgical methods of birth control during the first year of use are as follows: Implant: < 1% Injection: < 1% IUD: 1 to 2% Diaphragm with spermicides: 20% Spermicides alone: 26% Vaginal sponge: 20 to 40% Female sterilization: < 1% WHO SHOUlD NOT TAKE ORAl CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions: A history of heart attack or stroke Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes A history of blood clots in the deep veins of your legs Chest pain (angina pectoris) Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare professional) Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill Liver tumor (benign or cancerous) Known or suspected pregnancy If you plan to have surgery with prolonged bed rest Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend another method of birth control. OTHER CONSIDERATIONS bEFORE TAKING ORAl CONTRACEPTIVES Tell your healthcare professional if you have or have had: Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram Diabetes Elevated cholesterol or triglycerides High blood pressure Migraine or other headaches or epilepsy Mental depression Gallbladder, liver, heart or kidney disease History of scanty or irregular menstrual periods Women with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives. Also, be sure to inform your healthcare professional if you smoke or are on any medications. RISKS OF TAKING ORAl CONTRACEPTIVES 1. Risk of Developing blood Clots Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, aclot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. The risks of these side effects may be greater with desogestrel-containing oral contraceptives, such as ORTHO-CEPT, than with certain other low-dose pills. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for aprolonged illness or injury or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare professional about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on Breastfeeding in General Precautions.) The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills. The risk of venous thromboembolic disease associated with oral contraceptives does not increase with length of use and Male sterilization: < 1% Cervical Cap with spermicides: 20 to 40% Condom alone (male): 14% Condom alone (female): 21% Periodic abstinence: 25% Withdrawal: 19% No methods: 85%

2. If you are to start pill-taking on Sunday, take your first light orange pill on the first Sunday after your menstrual period begins. If your period begins on Sunday, take your first pill that day. Remove the first pill at the top of the dispenser (Sunday) by pressing the pill through the hole in the bottom of the dispenser. 3. If you are to start pill-taking on Day 1, choose a light orange pill that corresponds with the day of the week on which you are taking the first pill. Remove that light orange pill by pressing the pill through the hole in the bottom of the dispenser. 4. Continue taking one pill daily, clockwise, until no pills remain in the outer ring. 5. The next day take the green pill from the inner ring that corresponds with the day of the week it happens to be. Take a green pill each day until all seven pills are taken. During this time your period should begin. 6. After you have taken all the green pills, begin a new blister card (see Step 1 above in Instructions for Use) and take the first light orange active pill on the next day, even if your period is not yet over.

disappears after pill use is stopped. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers. 2. Heart Attacks and Strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder Disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. liver Tumors In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 5. Cancer of the Reproductive Organs and breasts Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at ayounger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that pills may cause such cancers. ESTIMATED RISK OF DEATH FROM A bIRTH CONTROl METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. ANNUAl NUMbER OF bIRTH-RElATED OR METHOD-RElATED DEATHS ASSOCIATED WITH CONTROl OF FERTIlITY PER 100,000 NONSTERIlE WOMEN, bY FERTIlITY CONTROl METHOD ACCORDING TO AGE Method of control and outcome No fertilitycontrol methods* Oral contraceptives non-smoker Oral contraceptives smoker IUD Condom* Diaphragm/ spermicide* Periodic abstinence* * Deaths are birth-related Deaths are method-related 15-19 7.0 0.3 2.2 0.8 1.1 1.9 2.5 20-24 7.4 0.5 3.4 0.8 1.6 1.2 1.6 25-29 9.1 0.9 6.6 1.0 0.7 1.2 1.6 30-34 14.8 1.9 13.5 1.0 0.2 1.3 1.7 35-39 25.7 13.8 51.1 1.4 0.3 2.2 2.9 40-44 28.2 31.6 117.2 1.4 0.4 2.8 3.6

Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare professional. 2. Contact lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare professional. 3. Fluid Retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional. 4. Melasma A spotty darkening of the skin is possible, particularly of the face, which may persist. 5. Other Side Effects Other side effects may include nausea and vomiting, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections and allergic reactions. If any of these side effects bother you, call your healthcare professional. GENERAl PRECAUTIONS 1. Missed Periods and Use of Oral Contraceptives before or During Early Pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare professional before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Stop taking oral contraceptives if pregnancy is confirmed. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy. 2. While breastfeeding If you are breastfeeding, consult your healthcare professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely. 3. laboratory Tests If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug Interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin; drugs used for epilepsy such as barbiturates (for example, phenobarbital); topiramate (TOPAMAX), carbamazepine (Tegretol is one brand of this drug), phenytoin (Dilantin is one brand of this drug); phenylbutazone (Butazolidin is one brand); certain drugs used in the treatment of HIV or AIDS; and possibly certain antibiotics. Medicine for pulmonary hypertension, such as bosentan (Tracleer). Pregnancies and breakthrough bleeding have been reported by women who used some form of the herbal supplement St. Johns Wort while using combined hormonal contraceptives. Hormonal contraceptives may interact with lamotrigine (LAMICTAL), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. You may need to use additional contraception when you take other products which can make oral contraceptives less effective. Be sure to tell your healthcare professional if you are taking or start taking any medications while taking birth control pills. 5. Sexually Transmitted Diseases This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis b, and syphilis. HOW TO TAKE THE PIll IMPORTANT POINTS TO REMEMbER bEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. bEFORE YOU START TAKING YOUR PIllS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK: The pill pack has 21 light orange active pills (with hormones) to take for 3 weeks, followed by 1 week of green reminder pills (without hormones). 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills.

In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death is always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. Older women, as all women, who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with the individual patient needs. WARNING SIGNAlS If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately: Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) Pain in the calf (indicating a possible clot in the leg) Crushing chest pain or heaviness in the chest (indicating a possible heart attack) Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) Sudden partial or complete loss of vision (indicating a possible clot in the eye) Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts) Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAl CONTRACEPTIVES 1. Vaginal bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period.

CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as aback-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PIllS You have a choice of which day to start taking your first pack of pills. ORTHO-CEPT is available in a blister card with a tablet dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. DAY 1 START: 1. Take the first light orange active pill of the first pack during the first 24 hours of your period. 2. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1. Take the first light orange active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7days). WHAT TO DO DURING THE MONTH 1. TAKE ONE PIll AT THE SAME TIME EVERY DAY UNTIl THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR bRAND OF PIllS: Start the next pack on the day after your last green reminder pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PIllS If you MISS 1 light orange active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 light orange active pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 light orange active pills in a row in THE 3RD WEEK: 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE light orange active pills in a row (during the first 3 weeks): 1. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER: If you forget any of the 7 green reminder pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINAllY, IF YOU ARE STIll NOT SURE WHAT TO DO AbOUT THE PIllS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE lIGHT ORANGE ACTIVE PIll EACH DAY until you can reach your healthcare professional. PREGNANCY DUE TO PIll FAIlURE When taken correctly without missing any pills, oral contraceptives are highly effective; however the typical failure rate of large numbers of pill users is 5% per year when women who miss pills are included. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PIll There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare professional. OTHER INFORMATION Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare

professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare professional because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEAlTH bENEFITS FROM ORAl CONTRACEPTIVES In addition to preventing pregnancy, use of combined oral contraceptives may provide certain benefits. They are: menstrual cycles may become more regular blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur. pain or other symptoms during menstruation may be encountered less frequently ectopic (tubal) pregnancy may occur less frequently noncancerous cysts or lumps in the breast may occur less frequently acute pelvic inflammatory disease may occur less frequently oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your healthcare professional or pharmacist. They have a more technical leaflet called the Professional Labeling, which you may wish to read. The professional labeling is also published in a book entitled Physicians Desk Reference, available in many book stores and public libraries. STORAGE: Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F). Manufactured for Ortho Womens Health & Urology, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869 Jointly Manufactured by Janssen Ortho, LLC Manati, Puerto Rico 00674 and NV Organon Oss, The Netherlands

Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998 PRINTED IN U.S.A. Revised July 2010 10217900

ORTHO TRI-CYCLEN TabLETs ORTHO-CYCLEN TabLETs (norgestimate/ethinyl estradiol)


Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. DESCRIPTION Each of the following products is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. ORTHO TRI-CYCLEN Tablets. Each white tablet contains 0.180 mg of the progestational compound, norgestimate (18,19-Dinor-17-pregn-4en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water and titanium dioxide. Each light blue tablet contains 0.215 mg of the progestational compound norgestimate (18,19-Dinor-17-pregn-4en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water and titanium dioxide. Each blue tablet contains 0.250 mg of the progestational compound norgestimate (18,19-Dinor-17-pregn-4-en20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water and titanium dioxide. Each dark green tablet contains only inert ingredients, as follows: FD & C Blue No. 2 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium dioxide. ORTHO-CYCLEN Tablets. Each blue tablet contains 0.250 mg of the progestational compound norgestimate (18,19-Dinor-17-pregn-4-en20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water and titanium dioxide. Each dark green tablet contains only inert ingredients, as follows: FD & C Blue No. 2 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium dioxide.

Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0-24h = area under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC = not calculated. NGMN and NG: Cmax = ng/mL, AUC0-24h = hng/mL EE: Cmax = pg/mL, AUC0-24h = hpg/mL The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN has not been studied. Distribution Norelgestromin and norgestrel are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG. Ethinyl estradiol is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG. Metabolism Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimates primary active metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is also active, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates. Excretion The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45-49%) and 37% (16-49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged norgestimate was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of norgestimate have been identified in human urine following administration of radiolabeled norgestimate. These include 18, 19-Dinor-17-pregn-4-en-20-yn-3one,17-hydroxy-13-ethyl,(17)-(-);18,19-Dinor-5-17-pregnan-20-yn,3,17-dihydroxy-13-ethyl,(17), various hydroxylated metabolites and conjugates of these metabolites. Special Populations The effects of body weight, body surface area or age on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN have not been studied. Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN have not been studied. However, steroid hormones may be poorly metabolized in women with impaired liver function (see PRECAUTIONS). Renal Impairment The effects of renal impairment on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN have not been studied. Drug-Drug Interactions No formal drug-drug interaction studies were conducted with ORTHO-CYCLEN or ORTHO TRI-CYCLEN. Interactions between contraceptive steroids and other drugs have been reported in the literature (see PRECAUTIONS). Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki ). INDICATIONS AND USAGE ORTHO-CYCLEN and ORTHO TRI-CYCLEN Tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. ORTHO TRI-CYCLEN is indicated for the treatment of moderate acne vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. ORTHO TRI-CYCLEN should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. Oral contraceptives are highly effective for pregnancy prevention. Table II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Table II: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing an % of Women Unintended Pregnancy Continuing Use within the First Year of Use at One Year* Method Typical Use Perfect Use (1) (2) (3) (4) 85 85 Chance# 26 6 40 Spermicides Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 2 Sympto-Thermal Post-Ovulation 1 Cap Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 20 6 56 Diaphragm Withdrawal 19 4 Condom 21 5 56 Female (Reality) Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 0.3 0.3 70 Depo-Provera 0.05 0.05 88 Norplant and Norplant-2 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Hatcher et al, 1998, Ref. #1. Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. * Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

Norgestimate

Ethinyl Estradiol

CLINICAL PHARMACOLOGY Oral Contraception Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). Receptor binding studies, as well as studies in animals and humans, have shown that norgestimate and 17-deacetyl norgestimate, the major serum metabolite, combine high progestational activity with minimal intrinsic androgenicity.90-93 Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower serum testosterone.90,91,94 Acne Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. PHARMACOKINETICS Absorption Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration. Norgestimate is rapidly and completely metabolized by firstpass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate. Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of ORTHO-CYCLEN or ORTHO TRI-CYCLEN. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of norgestrel is observed as a result of high affinity binding to SHBG (sex hormone-binding globulin), which limits its biological activity. Table 1. Summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters. Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN During a Three Cycle Study Analyte NGMN Cycle 3 Day 7 14 21 NG 3 7 14 21 EE 3 7 14 21 Analyte NGMN NG EE Cycle 1 3 1 3 1 3 Day 1 21 1 21 1 21 Cmax 1.80 (0.46) 2.12 (0.56) 2.66 (0.47) 1.94 (0.82) 3.00 (1.04) 3.66 (1.15) 124 (39.5) 128 (38.4) 126 (34.7) Cmax 1.78 (0.397) 2.19 (0.655) 0.649 (0.49) 2.65 (1.11) 92.2 (24.5) 147 (41.5) tmax (h) 1.42 (0.73) 1.21 (0.26) 1.29 (0.26) 3.15 (4.05) 2.21 (2.03) 2.58 (2.97) 1.27 (0.26) 1.32 (0.25) 1.31 (0.56) tmax (h) 1.19 (0.250) 1.43 (0.680) 1.42 (0.69) 1.67 (1.32) 1.2 (0.26) 1.13 (0.23) AUC0-24h 15.0 (3.88) 16.1 (4.97) 21.4 (3.46) 34.8 (16.5) 55.2 (23.5) 69.3 (23.8) 1130 (420) 1130 (324) 1090 (359) AUC0-24h 9.90 (3.25) 18.1 (5.53) 6.22 (2.46) 48.2 (20.5) 629 (138) 1210 (294) t1/2 (h) NC NC 22.3 (6.54) NC NC 40.2 (15.4) NC NC 15.9 (4.39) t1/2 (h) 18.4 (5.91) 24.9 (9.04) 37.8 (14.0) 45.0 (20.4) 10.1 (1.90) 15.0 (2.36)

Mean (SD) Pharmacokinetic Parameters of ORTHO-CYCLEN During a Three Cycle Study

Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills). However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. # The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. With spermicidal cream or jelly. Without spermicides. ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied for and are not indicated for use in emergency contraception. In clinical trials with ORTHO-CYCLEN, 1,651 subjects completed 24,272 cycles and the overall use-efficacy (typical user efficacy) pregnancy rate was approximately 1 pregnancy per 100 women-years. This rate includes patients who did not take the drug correctly. In four clinical trials with ORTHO TRI-CYCLEN, a total of 4,756 subjects completed 45,244 cycles, and the use-efficacy pregnancy rate was approximately 1 pregnancy per 100 women-years. ORTHO TRI-CYCLEN was evaluated for the treatment of acne vulgaris in two randomized, doubleblind, placebo-controlled, multicenter, Phase 3, six (28 day) cycle studies. 221 patients received ORTHO TRI-CYCLEN and 234 patients received placebo. Mean age at enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count changes from 55 to 31 (42% reduction) in patients treated with ORTHO TRI-CYCLEN and from 54 to 38 (27% reduction) in patients similarly treated with placebo. Table III summarizes the changes in lesion count for each type of lesion in the ITT population. Based on the investigators global assessment conducted at the final visit, patients treated with ORTHO TRI-CYCLEN showed a statistically significant improvement in total lesions compared to those treated with placebo.

population (adapted from refs. 2 and 3 with the authors permission). For further information, the reader is referred to a text on epidemiological methods. 1. Thromboembolic Disorders and Other Vascular Problems a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4-10 The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older, and in nonsmokers over the age of 40 among women who use oral contraceptives. Figure 1. Circulatory Disease Mortality Rates per 100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use

Table III: Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-Controlled Trials. Observed Means at Six Months (LOCF)* and at Baseline. Intent-to-Treat Population. ORTHO TRI-CYCLEN Placebo Difference in (N=221) (N=234) Counts between ORTHO TRI-CYCLEN and Placebo at 6 Months % % # of Lesions Counts Reduction Counts Reduction INFLAMMATORY LESIONS Baseline Mean 19 19 Sixth Month Mean 10 48% 13 30% 3 (95% CI: -1.2, 5.1) NON-INFLAMMATORY LESIONS Baseline Mean 36 35 Sixth Month Mean 22 34% 25 21% 3 (95% CI: -0.2, 7.8) TOTAL LESIONS Baseline Mean 55 54 Sixth Month Mean 31 42% 38 27% 7 (95% CI: 2.0, 11.9) *LOCF: Last Observation Carried Forward CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: Thrombophlebitis or thromboembolic disorders A past history of deep vein thrombophlebitis or thromboembolic disorders Cerebral vascular or coronary artery disease (current or past history) Valvular heart disease with complications Severe hypertension Diabetes with vascular involvement Headaches with focal neurological symptoms Major surgery with prolonged immobilization Known or suspected carcinoma of the breast or personal history of breast cancer Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Cholestatic jaundice of pregnancy or jaundice with prior pill use Acute or chronic hepatocellular disease with abnormal liver function Hepatic adenomas or carcinomas Known or suspected pregnancy Hypersensitivity to any component of this product WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the

(Adapted from P.M. Layde and V. Beral, ref. #12.) Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Norgestimate has minimal androgenic activity (see CLINICAL PHARMACOLOGY), and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater.97 b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2 A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed. c. Cerebrovascular Diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29 In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3 d. Dose-Related Risk of Vascular Disease From Oral Contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contraceptives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. Persistence of Risk of Vascular Disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens. 2. Estimates of Mortality From Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table IV). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked

to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women, who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. Table IV: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Non-Sterile Women, by Fertility Control Method According to Age Method of control 15-19 20-24 25-29 30-34 35-39 40-44 and outcome No fertility 7.0 7.4 9.1 14.8 25.7 28.2 control methods* Oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker Oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker IUD 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 Adapted from H.W. Ory, ref. #35. *Deaths are birth-related Deaths are method-related 3. Carcinoma of the Reproductive Organs and Breasts Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives (COCs). However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a womans reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-andeffect relationship has not been established. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intraabdominal hemorrhage.50,51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. Oral Contraceptive Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 8. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. In clinical studies with ORTHO-CYCLEN there were no clinically significant changes in fasting blood glucose levels. No statistically significant changes in mean fasting blood glucose levels were observed over 24 cycles of use. Glucose tolerance tests showed minimal, clinically insignificant changes from baseline to cycles 3, 12, and 24. In clinical studies with ORTHO TRI-CYCLEN there were no clinically significant changes in fasting blood glucose levels. Minimal statistically significant changes were noted in glucose levels over 24 cycles of use. Glucose tolerance tests showed no clinically significant changes from baseline to cycles 3, 12, and 24. 9. Elevated Blood Pressure Women with significant hypertension should not be started on hormonal contraception.98 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.

Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68-71 It should be noted that in two separate large clinical trials (N=633 and N=911), no statistically significant changes in mean blood pressure were observed with ORTHO-CYCLEN. 10. Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. 12. Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. PRECAUTIONS 1. General Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 2. Physical Examination and Follow-up It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. Lipid Disorders Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. Liver Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Emotional Disorders Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8. Drug Interactions Changes in contraceptive effectiveness associated with co-administration of other products Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan. Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. Johns Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. Concurrent use of bosentan and ethinyl estradiol-containing products may result in decreased concentrations of these contraceptive hormones, thereby increasing the risk of unintended pregnancy and unscheduled bleeding. Increase in plasma levels associated with co-administered drugs Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Changes in plasma levels of co-administered drugs Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives. Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.101 Healthcare professionals are advised to also refer to prescribing information of co- administered drugs for recommendations regarding management of concomitant therapy. 9. Interactions with Laboratory Tests Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrineinduced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex hormone binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

10. Carcinogenesis See WARNINGS. 11. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS. 12. Nursing Mothers Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. Pediatric Use Safety and efficacy of ORTHO TRI-CYCLEN Tablets and ORTHO-CYCLEN Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. There was no significant difference between ORTHO TRI-CYCLEN Tablets and placebo in mean change in total lumbar spine (L1-L4) and total hip bone mineral density between baseline and Cycle 13 in 123 adolescent females with anorexia nervosa in a doubleblind, placebo-controlled, multicenter, one-year treatment duration clinical trial for the Intent To Treat (ITT) population. Use of this product before menarche is not indicated. 14. Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population. INFORMATION FOR THE PATIENT See Patient Labeling printed below. ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS). Thrombophlebitis and venous thrombosis Cerebral thrombosis with or without embolism Hypertension Arterial thromboembolism Gallbladder disease Pulmonary embolism Hepatic adenomas or benign Myocardial infarction liver tumors Cerebral hemorrhage There is evidence of an association between the following conditions and the use of oral contraceptives: Mesenteric thrombosis Retinal thrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: Nausea Change in weight (increase or decrease) Vomiting Change in cervical erosion and secretion Gastrointestinal symptoms (such as Diminution in lactation when given abdominal cramps and bloating) immediately postpartum Breakthrough bleeding Cholestatic jaundice Spotting Migraine Change in menstrual flow Allergic reaction, including rash, urticaria, Amenorrhea angioedema Temporary infertility after Mental depression discontinuation of treatment Reduced tolerance to carbohydrates Edema Vaginal candidiasis Melasma which may persist Change in corneal curvature (steepening) Breast changes: tenderness, Intolerance to contact lenses enlargement, secretion The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted: Pre-menstrual syndrome Erythema nodosum Cataracts Hemorrhagic eruption Changes in appetite Vaginitis Cystitis-like syndrome Porphyria Headache Impaired renal function Nervousness Hemolytic uremic syndrome Dizziness Acne Hirsutism Changes in libido Loss of scalp hair Colitis Erythema multiforme Budd-Chiari Syndrome OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of combination oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.73-78 Effects on menses: increased menstrual cycle regularity decreased blood loss and decreased incidence of iron deficiency anemia decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: decreased incidence of functional ovarian cysts decreased incidence of ectopic pregnancies Other effects: decreased incidence of fibroadenomas and fibrocystic disease of the breast decreased incidence of acute pelvic inflammatory disease decreased incidence of endometrial cancer decreased incidence of ovarian cancer DOSAGE AND ADMINISTRATION Oral Contraception To achieve maximum contraceptive effectiveness, ORTHO TRI-CYCLEN Tablets and ORTHO-CYCLEN Tablets must be taken exactly as directed and at intervals not exceeding 24 hours. The possibility of ovulation and conception prior to initiation of medication should be considered. ORTHO TRI-CYCLEN and ORTHO-CYCLEN are available with the DIALPAK Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Sunday Start When taking ORTHO TRI-CYCLEN and ORTHO-CYCLEN the first tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first tablet should be taken that day. Take one active tablet daily for 21 days followed by one dark green inactive tablet daily for 7 days. After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as a

condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section). Day 1 Start The dosage of ORTHO TRI-CYCLEN and ORTHO-CYCLEN, for the initial cycle of therapy, is one active tablet administered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow as Day 1 followed by one dark green inactive tablet daily for 7 days. Tablets are taken without interruption for 28 days. After 28 tablets have been taken, a new course is started the next day. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section). The use of ORTHO TRI-CYCLEN and ORTHO-CYCLEN for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) The possibility of ovulation and conception prior to initiation of medication should be considered. (See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.) ADDITIONAL INSTRUCTIONS Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. Use of oral contraceptives in the event of a missed menstrual period: 1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued if pregnancy is confirmed. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. ACNE The timing of initiation of dosing with ORTHO TRI-CYCLEN for acne should follow the guidelines for use of ORTHO TRI-CYCLEN as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section for oral contraceptives. The dosage regimen for ORTHO TRI-CYCLEN for treatment of facial acne, as available with a DIALPAK Tablet Dispenser, utilizes a 21-day active and a 7-day placebo schedule. Take one active tablet daily for 21 days followed by one dark green inactive tablet for 7 days. After 28 tablets have been taken, a new course is started the next day. HOW SUPPLIED ORTHO TRI-CYCLEN Tablets are available in a blister card (NDC 0062-1910-00 or NDC 50458-191-00) with a DIALPAK Tablet Dispenser (unfilled). The blister card contains 28 tablets. Each white tablet contains 0.180 mg of the progestational compound, norgestimate, together with 0.035 mg of the estrogenic compound, ethinyl estradiol. Each light blue tablet contains 0.215 mg of the progestational compound, norgestimate, together with 0.035 mg of the estrogenic compound, ethinyl estradiol. Each blue tablet contains 0.250 mg of the progestational compound, norgestimate, together with 0.035 mg of the estrogenic compound, ethinyl estradiol. Each dark green tablet contains inert ingredients. ORTHO TRI-CYCLEN Tablets are packaged in a carton (NDC 0062-1910-15 or NDC 50458-191-15) containing 6 blister cards and 6 unfilled DIALPAK Tablet Dispensers. 0.180/0.035 mg tablets - White, round, biconvex, coated tablet imprinted O 180 on one side and 35 on the other side of the tablet. 0.215/0.035 mg tablets - Light blue, round, biconvex, coated tablet imprinted O 215 on one side and 35 on the other side of the tablet. 0.250/0.035 mg tablets - Blue, round, biconvex, coated tablet imprinted O 250 on one side and 35 on the other side of the tablet. Each dark green reminder pill is a round, biconvex, coated tablet imprinted O-M on one side and P on the other side. ORTHO TRI-CYCLEN Tablets are available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 0062-1910-20 or NDC 50458-191-20). ORTHO-CYCLEN Tablets are available in a blister card (NDC 0062-1907-00 or NDC 50458-197-00) with a DIALPAK Tablet Dispenser (unfilled). The blister card contains 28 tablets as follows: 21 blue tablets containing 0.250 mg of the progestational compound, norgestimate, together with 0.035 mg of the estrogenic compound, ethinyl estradiol, and 7 dark green tablets containing inert ingredients. ORTHO-CYCLEN Tablets are packaged in a carton (NDC 0062-1907-15 or NDC 50458-197-15) containing 6 blister cards and 6 unfilled DIALPAK Tablet Dispensers. ORTHO-CYCLEN Tablets are available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 0062-1907-20 or NDC 50458-197-20). Keep out of reach of children. Store at 25C (77F); excursions permitted to 1530C (5986F). Protect from light. REFERENCES 1. Trussel J. Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998, in press. 2. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 1). N Engl J Med 1981; 305:612618. 3. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305:672-677. 4. Adam SA, Thorogood M. Oral contraception and myo cardial infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet Gynaecol 1981; 88:838-845. 5. Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975; 2(5965):245-248. 6. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 1975; 2(5956):241-245. 7. Royal College of General Practitioners Oral Contraception Study: Further analyses of mortality in oral contraceptive users. Lancet 1981; 1:541-546. 8. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med 1981; 305:420-424. 9. Vessey MP. Female hormones and vascular disease an epidemiological overview. Br J Fam Plann 1980; 6 (Supplement): 1-12. 10. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent Med 1986; 15:352-362. 11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339-1342. 12. Layde PM, Beral V. Further analyses of mortality in oral contraceptive users; Royal College of General Practitioners Oral Contraception Study. (Table 5) Lancet 1981; 1:541-546. 13. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod

Med 1986; 31(9) (Supplement): 913-921. 14. Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high -density lipoproteins subclasses. Am J Obstet 1983; 145:446-452. 15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983; 308:862-867. 16. Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high density lipoproteins. Am J Obstet Gynecol 1982; 142:766-771. 17. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986; 31(9)(Supplement):892-897. 18. LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod Med 1986; 31(9)(Supplement): 906-912. 19. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 1968; 2(5599):193199. 20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol 1979; 110(2):188-195. 21. Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontra ceptive estrogens, and other factors. JAMA 1979; 242:1150-1154. 22. Vessey MP, Doll R, Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2(5599):199-205. 23. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 1969; 2(5658):651-657. 24. Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular disease recent experience. Obstet Gynecol 1982; 59(3):299-302. 25. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception: an interim report. J Biosocial Sci 1976; 8:375-427. 26. Royal College of General Practitioners: Oral Contraceptives, venous thrombosis, and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399. 27. Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 1973; 288:871-878. 28. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234-236. 29. Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979; 2(6203):1468-1470. 30. Collaborative Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718-722. 31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970; 2:203-209. 32. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980; 280(6224):1157-1161. 33. Kay CR. Progestogens and arterial disease evidence from the Royal College of General Practitioners Study. Am J Obstet Gynecol 1982; 142:762-765. 34. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983; 33:75-82. 35. Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983; 15:50-56. 36. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of breast cancer. N Engl J Med 1986; 315:405-411. 37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926-929. 38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723-725. 39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868. 40. Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; 1(8431):748-749. 41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987; 56:653-660. 42. Huggins GR, Zucker PF. Oral contraceptives and neoplasia; 1987 update. Fertil Steril 1987; 47:733-761. 43. McPherson K, Drife JO. The pill and breast cancer: why the uncertainty? Br Med J 1986; 293:709-710. 44. Shapiro S. Oral contraceptives time to take stock. N Engl J Med 1987; 315:450-451. 45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976; 124:573-577. 46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930. 47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339344. 48. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med J 1985; 290:961-965. 49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648. 50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433-435. 51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386-394. 52. Henderson BE, PrestonMartin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437-440. 53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357. 54. Forman D, Vincent TJ, Doll R, Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357-1361. 55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452. 56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981; 140:521-524. 57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980; 112:7379. 58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239. 59. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109:433-439. 60. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404. 61. Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman 1974. 62. Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274-278. 63. Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119:796-805. 64. Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335-341. 65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049. 66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds. New York, Raven Press 1983; pp. 395-410. 67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857-864. 68. Royal College of General Practitioners Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503. 70. Laragh AJ. Oral contraceptive induced hypertension nine years later. Am J Obstet Gynecol 1976; 126:141-147. 71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan.) 72. Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140143. 73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599. 74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800. 75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69. 76. Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419-422. 77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182-184. 78. Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1. 79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42. 81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br J Cancer 1986; 54:311-317. 82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use and breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC. Breast cancer and the pill A further report from the Royal College of General

Practitioners oral contraception study. Br J Cancer 1988; 58:675-680. 84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989; 129:269-280. 86. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982. 87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38. 88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br J Cancer 1989; 59:613-617. 89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989; 59:618-621. 90. Anderson FD, Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand 1992; 156 (Supplement):15-21. 91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical evidence of minimal androgenic activity of norgestimate. Int J Fertil 1989; 34(51):347-352. 92. Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL. Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins. Contraception 1989; 41(4):399-409. 93. Phillips A, Hahn DW, Klimek S, McGuire JL. A comparison of the potencies and activities of progestogens used in contraceptives. Contraception 1987; 36(2):181-192. 94. Janaud A, Rouffy J, Upmalis D, Dain M-P. A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel. Acta Obstet Gynecol Scand 1992; 156 (Supplement):34-38. 95. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727. 96. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882. 97. Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M, on behalf of Transnational Research Group on Oral Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. Br Med J, 1996;312:88-90. 98. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 99. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-298. 100. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118. 101. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484-489. BRIEF SUMMARY PATIENT PACKAGE INSERT This product (like all oral contraceptives) does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Oral contraceptives, also known as birth control pills or the pill, are taken to prevent pregnancy. When taken correctly to prevent pregnancy, oral contraceptives have a failure rate of approximately 1% per year (1 pregnancy per 100 women per year of use) when used without missing any pills. The typical failure rate is approximately 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy. ORTHO TRI-CYCLEN may also be taken to treat moderate acne in females at least 15 years of age, who have started having menstrual periods, are able to take the pill and want to use the pill for birth control. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be fatal or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: smoke have high blood pressure, diabetes, high cholesterol have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Most side effects of the pill are not serious. The most common side effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics may decrease oral contraceptive effectiveness. Oral contraceptives may interact with lamotrigine (LAMICTAL), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. Taking the combination pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare professional. Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. Your pharmacist should have given you the detailed patient information labeling which gives you further information which you should read and discuss with your healthcare professional.

HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach or have spotting or light bleeding, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK The pill pack has 21 active pills (with hormones) to take for 3 weeks. This is followed by 1 week of reminder dark green pills (without hormones). ORTHO TRI-CYCLEN: There are 7 white active pills, 7 light blue active pills, 7 blue active pills, and 7 dark green reminder pills. ORTHO-CYCLEN: There are 21 blue active pills, and 7 dark green reminder pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO TRI-CYCLEN and ORTHO-CYCLEN are available with the DIALPAK Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. Sunday Start: ORTHO TRI-CYCLEN: Take the first white active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. ORTHO-CYCLEN: Take the first blue active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Day 1 Start: ORTHO TRI-CYCLEN: Take the first white active pill of the first pack during the first 24 hours of your period. ORTHO-CYCLEN: Take the first blue active pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last reminder pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO TRI-CYCLEN: If you MISS 1 white, light blue, or blue active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light blue active pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 blue active pills in a row in THE 3RD WEEK: 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you MISS 3 OR MORE white, light blue or blue active pills in a row (during the first 3 weeks): 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. ORTHO-CYCLEN: If you MISS 1 blue active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 blue active pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 blue active pills in a row in THE 3RD WEEK: 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE blue active pills in a row (during the first 3 weeks): 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER: If you forget any of the 7 dark green reminder pills in WEEK 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE ACTIVE PILL EACH DAY until you can reach your healthcare professional. INSTRUCTIONS FOR USING YOUR DIALPAK TABLET DISPENSER PLEASE READ ME! Sunday Start or Day 1 Start There are two ways to start taking birth control pills, Sunday Start or Day 1 Start. Your healthcare professional will tell you which to use. SAVE THESE INSTRUCTIONS. 1. If this is the first time you are taking birth control pills, or if you have not taken birth control pills for 10 days or more, your first step is to wait until the first day you get your menstrual period. Then, follow these instructions for either Sunday Start or Day 1 Start.

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Sunday Start Day 1 Start

2. When you get your period: You will use a Sunday Start if your doctor told you to take your first pill on a Sunday. Take pill 1 on the Sunday after your period starts. If your period starts on a Sunday, take pill 1 that day. You will use a Day 1 Start if your doctor told you to take pill 1 on the first day of your period. 3. SET THE DAY: Sunday Start: the arrow on your empty Dialpak should point to SU (Sunday). Day 1 Start: turn the dial on your empty Dialpak until the arrow points to the first day of your period (if your period starts on Tuesday, the arrow will point to TU). 4. Insert the new refill by lining up the V shape on the refill with the V shape at the top of your Dialpak. Snap the refill in place. You are ready to take pill 1. You should always begin your pill cycle with pill 1, as shown on the inner part of the refill ring.

5. Remove pill 1 by pushing down on the pill. The pill will come out through a hole in the back of the Dialpak.

6. Swallow the pill. You will take one pill each day. If you use a Sunday Start and you are taking the pill for the FIRST TIME, YOU MUST USE A BACK-UP METHOD OF BIRTH CONTROL FOR THE FIRST 7 DAYS. If you use a Day 1 Start, you are protected from becoming pregnant as soon as you take your first pill.

7. Wait 24 hours to take your next pill. To take pill 2, turn the dial on your Dialpak to the next day. Continue to take one pill each day until all the pills have been taken.

8. Take your pill at the same time every day. It is important to take the correct pill each day and not miss any pills. To help you remember, take your pill at the same time as another daily activity, like turning off your alarm clock or brushing your teeth.

Tell your healthcare professional if you have had any of these conditions. Your healthcare professional can recommend a safer method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your healthcare professional if you have or have had: Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram Diabetes Elevated cholesterol or triglycerides High blood pressure Migraine or other headaches or epilepsy Mental depression Gallbladder, liver, heart or kidney disease History of scanty or irregular menstrual periods Women with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives. Also, be sure to inform your healthcare professional if you smoke or are on any medications. RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of Developing Blood Clots Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or injury or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare professional about stopping oral contraceptives four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on Breastfeeding in General Precautions.) The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers. 2. Heart Attacks and Strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder Disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver Tumors In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 5. Cancer of the Reproductive Organs and Breasts Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Nonsterile Women, by Fertility Control Method According to Age Method of control 15-19 20-24 25-29 30-34 35-39 40-44 and outcome No fertility 7.0 7.4 9.1 14.8 25.7 28.2 control methods* Oral contraceptives 0.3 0.5 0.9 1.9 13.8 31.6 non-smoker Oral contraceptives 2.2 3.4 6.6 13.5 51.1 117.2 smoker IUD 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 Adapted from H.W. Ory, ref. #35. *Deaths are birth-related Deaths are method-related In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group less than 40. Over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy in that age group. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking women over

9. When your refill is empty, keep your Dialpak case. You will start a new refill on the day after pill 28.

10. Turn the dial to the pill 1 position to remove the empty refill and insert a new refill. THE FIRST PILL IN EVERY REFILL WILL ALWAYS BE TAKEN ON THE SAME DAY OF THE WEEK, NO MATTER WHEN YOUR NEXT PERIOD STARTS.

DETAILED PATIENT LABELING PLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully. This product (like all oral contraceptives) does not protect against HIV infection (AIDS) and other sexually transmitted diseases. ORTHO TRI-CYCLEN Regimen Each white tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol. Each light blue tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol. Each blue tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol. Each dark green tablet contains inert ingredients. ORTHO-CYCLEN Regimen Each blue tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol. Each dark green tablet contains inert ingredients. INTRODUCTION Any woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This patient labeling will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this labeling is not a replacement for a careful discussion between you and your healthcare professional. You should discuss the information provided in this labeling with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professionals advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES FOR CONTRACEPTION Oral contraceptives or birth control pills or the pill are used to prevent pregnancy and are more effective than most other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1% per year (1 pregnancy per 100 women per year of use). Typical failure rates, including women who do not always take the pill correctly, are approximately 5% per year (5 pregnancies per 100 women per year of use). The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other non-surgical methods of birth control during the first year of use are as follows: Implant: <1% Male sterilization: <1% Injection: <1% Cervical Cap with spermicides: 20 to 40% IUD: 1 to 2% Condom alone (male): 14% Diaphragm with spermicides: 20% Condom alone (female): 21% Spermicides alone: 26% Periodic abstinence: 25% Vaginal sponge: 20 to 40% Withdrawal: 19% Female sterilization: <1% No methods: 85% ORTHO TRI-CYCLEN may also be taken to treat moderate acne if all of the following are true: You have started having menstrual cycles You are at least 15 years old Your healthcare professional says it is safe for you to use the pill You want to use the pill for birth control WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions: A history of heart attack or stroke Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes A history of blood clots in the deep veins of your legs Chest pain (angina pectoris) Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare professional) Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill Liver tumor (benign or cancerous) or active liver disease Known or suspected pregnancy Valvular heart disease with complications Severe hypertension Diabetes with vascular involvement Headaches with focal neurological symptoms Major surgery with prolonged immobilization Hypersensitivity to any component of this product

40 years of age may outweigh the possible risks. Older women, as all women, who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with the individual patient needs. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately: Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) Pain in the calf (indicating a possible clot in the leg) Crushing chest pain or heaviness in the chest (indicating a possible heart attack) Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) Sudden partial or complete loss of vision (indicating a possible clot in the eye) Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts) Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAL CONTRACEPTIVES In addition to the risks and more serious side effects discussed above, the following may also occur: 1. Irregular Vaginal Bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare professional. 2. Contact Lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare professional. 3. Fluid Retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional. 4. Melasma A spotty darkening of the skin is possible, particularly of the face, which may persist. 5. Other Side Effects Other side effects may include nausea and vomiting, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, and allergic reactions. If any of these side effects bother you, call your healthcare professional. GENERAL PRECAUTIONS 1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare professional. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Stop taking your pills if you are pregnant. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy. 2. While Breastfeeding If you are breastfeeding, consult your healthcare professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, combination oral contraceptives may decrease the amount and quality of your milk. If possible, do not use combination oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting combination oral contraceptives only after you have weaned your child completely. 3. Laboratory Tests If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug Interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital), topiramate (Topamax), carbamazepine (Tegretol is one brand of this drug), or phenytoin (Dilantin is one brand of this drug), phenylbutazone (Butazolidin is one brand), certain drugs used in the treatment of HIV or AIDS, and possibly certain antibiotics. Medicine for pulmonary hypertension, such as bosentan (Tracleer). Pregnancies and breakthrough bleeding have been reported by women who also used some form of the herbal supplement St. Johns Wort while using combined hormonal contraceptives. Hormonal contraceptives may interact with lamotrigine (LAMICTAL), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. You may need to use additional contraception when you take drugs which can make oral contraceptives less effective. Be sure to tell your healthcare professional if you are taking or start taking any medications while taking birth control pills. 5. Sexually Transmitted Diseases ORTHO-CYCLEN and ORTHO TRI-CYCLEN (like all oral contraceptives) are intended to prevent pregnancy. Oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach or have spotting or light bleeding, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional.

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK The pill pack has 21 active pills (with hormones) to take for 3 weeks. This is followed by 1 week of reminder dark green pills (without hormones). ORTHO TRI-CYCLEN: There are 7 white active pills, 7 light blue active pills, 7 blue active pills, and 7 dark green reminder pills. ORTHO-CYCLEN: There are 21 blue active pills and 7 dark green reminder pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO TRI-CYCLEN and ORTHO-CYCLEN are available with the DIALPAK Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. Sunday Start: ORTHO TRI-CYCLEN: Take the first white active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. ORTHO-CYCLEN: Take the first blue active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Day 1 Start: ORTHO TRI-CYCLEN: Take the first white active pill of the first pack during the first 24 hours of your period. ORTHO-CYCLEN: Take the first blue active pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. Take One Pill at the Same Time Every Day Until the Pack is Empty. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. When You Finish a Pack or Switch Your Brand of Pills: Start the next pack on the day after your last reminder pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO TRI-CYCLEN: If you MISS 1 white, light blue, or blue active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light blue active pills in a row in WEEK 1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 blue active pills in a row in THE 3RD WEEK: 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white, light blue or blue active pills in a row (during the first 3 weeks): 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. ORTHO-CYCLEN: If you MISS 1 blue active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 blue active pills in a row in WEEK 1 OR WEEK 2 of your pack:

1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 blue active pills in a row in THE 3RD WEEK: 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE blue active pills in a row (during the first 3 weeks): 1. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER: If you forget any of the 7 dark green reminder pills in WEEK 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE ACTIVE PILL EACH DAY until you can reach your healthcare professional. PREGNANCY DUE TO PILL FAILURE The incidence of pill failure resulting in pregnancy is approximately 5%, including women who do not always take the pills exactly as directed. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare professional or pharmacist. OTHER INFORMATION Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare professional, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of combination oral contraceptives may provide certain benefits. They are: menstrual cycles may become more regular blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur pain or other symptoms during menstruation may be encountered less frequently ectopic (tubal) pregnancy may occur less frequently noncancerous cysts or lumps in the breast may occur less frequently acute pelvic inflammatory disease may occur less frequently oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your healthcare professional or pharmacist. They have a more technical leaflet called the Professional Labeling, which you may wish to read. The professional labeling is also published in a book entitled Physicians Desk Reference, available in many book stores and public libraries. Keep out of reach of children. Store at 25C (77F); excursions permitted to 1530C (5986F). Protect from light.

Mfd. for: Ortho Womens Health & Urology, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869 Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998

Mfd. by: Janssen Ortho, LLC Manati, Puerto Rico 00674 Revised June 2010 10215400

ORTHO MICRONOR
(norethindrone)

Tablets

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. DESCRIPTION ORTHO MICRONOR Tablets Each tablet contains 0.35 mg norethindrone. Inactive ingredients include D&C Green No. 5, D&C Yellow No. 10, lactose, magnesium stearate, modified corn starch, and povidone.

norethindrone
Meets USP Dissolution Test 2 CLINICAL PHARMACOLOGY 1. Mode of Action ORTHO MICRONOR progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the midcycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium. 2. Pharmacokinetics Serum progestin levels peak about two hours after oral administration, followed by rapid distribution and elimination. By 24 hours after drug ingestion, serum levels are near baseline, making efficacy dependent upon rigid adherence to the dosing schedule. There are large variations in serum levels among individual users. Progestin-only administration results in lower steady-state serum progestin levels and a shorter elimination half-life than concomitant administration with estrogens. INDICATIONS AND USAGE 1. Indications Progestin-only oral contraceptives are indicated for the prevention of pregnancy. 2. Efficacy If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. Table 1 lists the pregnancy rates for users of all major methods ofcontraception. Table 1: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing % of Women an Unintended Pregnancy Continuing Use at within the First Year of Use One Year* Method Typical Perfect Use Use (1) (2) (3) (4) 85 85 Chance# Spermicides 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal 2 Post-Ovulation 1 Cap Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 20 6 56 Withdrawal 19 4 Condom Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 and Norplant-2 Norplant 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Adapted from Hatcher et al, 1998, Ref. #1. Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.

Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception. Source: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. * Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. The treatment schedule is one dose within 72hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1dose is 2light-orange pills), Lo/Ovral (1 dose is 4white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills). However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. # The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. With spermicidal cream or jelly. Without spermicides. ORTHO MICRONOR Tablets have not been studied for and are not indicated for use in emergency contraception. CONTRAINDICATIONS Progestin-only oral contraceptives (POPs) should not be used by women who currently have the following conditions: Knownorsuspectedpregnancy Knownorsuspectedcarcinomaofthebreast Undiagnosedabnormalgenitalbleeding ypersensitivitytoanycomponentofthisproduct H Benignormalignantlivertumors Acuteliverdisease WARNINGS Cigarette smoking increases the risk of serious cardiovascular disease. Women who use oral contraceptives should be strongly advised not tosmoke. ORTHO MICRONOR does not contain estrogen and, therefore, this insert does not discuss the serious health risks that have been associated with the estrogen component of combined oral contraceptives (COCs). The healthcare professional is referred to the prescribing information of combined oral contraceptives for a discussion of those risks. The relationship between progestin-only oral contraceptives and these risks is not fully defined. The healthcare professional should remain alert to the earliest manifestation of symptoms of any serious disease and discontinue oral contraceptive therapy when appropriate. 1. Ectopic Pregnancy The incidence of ectopic pregnancies for progestin-only oral contraceptive users is 5 per 1000 woman-years. Up to 10% of pregnancies reported in clinical studies of progestinonly oral contraceptive users are extrauterine. Although symptoms of ectopic pregnancy should be watched for, a history of ectopic pregnancy need not be considered a contraindication to use of this contraceptive method. Healthcare professionals should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while on progestin-only oral contraceptives. 2. Delayed Follicular Atresia/Ovarian Cysts If follicular development occurs, atresia of the follicle is sometimes delayed and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally these enlarged follicles disappear spontaneously. Often they are asymptomatic; in some cases they are associated with mild abdominal pain. Rarely they may twist or rupture, requiring surgical intervention. 3. Irregular Genital Bleeding Irregular menstrual patterns are common among women using progestin-only oral contraceptives. If genital bleeding is suggestive of infection, malignancy or other abnormal conditions, such nonpharmacologic causes should be ruled out. If prolonged amenorrhea occurs, the possibility of pregnancy should be evaluated. 4. Carcinoma of the Breast and Reproductive Organs Some epidemiological studies of oral contraceptive users have reported an increased relative risk of developing breast cancer, particularly at a younger age and apparently related to duration of use. These studies have predominantly involved combined oral contraceptives and there is insufficient data to determine whether the use of POPs similarly increases the risk.

A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use. Women with breast cancer should not use oral contraceptives because the role of female hormones in breast cancer has not been fullydetermined. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. There is insufficient data to determine whether the use of POPs increases the risk of developing cervical intraepithelial neoplasia. 5. Hepatic Neoplasia Benign hepatic adenomas are associated with combined oral contraceptive use, although the incidence of benign tumors is rare in the United States. Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in combined oral contraceptive users. However, these cancers are rare in the U.S. There is insufficient data to determine whether POPs increase the risk of developing hepatic neoplasia. PRECAUTIONS 1. General Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 2. Physical Examination and Follow-up It is considered good medical practice for sexually active women using oral contraceptives to have annual history and physical examinations. The physical examination may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the healthcare professional. 3. Carbohydrate and Lipid Metabolism Some users may experience slight deterioration in glucose tolerance, with increases in plasma insulin but women with diabetes mellitus who use progestin-only oral contraceptives do not generally experience changes in their insulin requirements. Nonetheless, prediabetic and diabetic women in particular should be carefully monitored while taking POPs. Lipid metabolism is occasionally affected in that HDL, HDL2, and apolipoprotein A-I and A-II may be decreased; hepatic lipase may be increased. There is usually no effect on total cholesterol, HDL3, LDL, or VLDL. 4. Drug Interactions The effectiveness of progestin-only pills is reduced by hepatic enzyme-inducing drugs such as the anticonvulsants phenytoin, carbamazepine, and barbiturates, and the antituberculosis drug rifampin. No significant interaction has been found with broadspectrum antibiotics. Herbal products containing St. Johns Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. Concurrent use of bosentan and norethindrone containing products may result in decreased concentrations of these contraceptive hormones thereby increasing the risk of unintended pregnancy and unscheduled bleeding. 5. Interactions with Laboratory Tests The following endocrine tests may be affected by progestin-only oral contraceptive use: exhormone-bindingglobulin(SHBG)concentrationsmaybedecreased. S hyroxineconcentrationsmaybedecreased,duetoadecreaseinthyroidbinding T globulin (TBG). 6. Carcinogenesis See WARNINGS. 7. Pregnancy Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted have not demonstrated significant adverse effects. It is nonetheless prudent to rule out suspected pregnancy before initiating any hormonal contraceptive use. 8. Nursing Mothers In general, no adverse effects have been found on breastfeeding performance or on the health, growth, or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers, resulting in detectable steroid levels in infant plasma. 9. Pediatric Use Safety and efficacy of ORTHO MICRONOR Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

10. Fertility Following Discontinuation The limited available data indicate a rapid return of normal ovulation and fertility following discontinuation of progestin-only oral contraceptives. 11. Headache The onset or exacerbation of migraine or development of severe headache with focal neurological symptoms which is recurrent or persistent requires discontinuation of progestin-only contraceptives and evaluation of the cause. INFORMATION FOR THE PATIENT 1. See Detailed Patient Labeling for detailed information. 2. Counseling issues The following points should be discussed with prospective users before prescribing progestin-only oral contraceptives: henecessityoftakingpillsatthesametimeeveryday,includingthroughoutall T bleeding episodes. heneedtouseabackupmethodsuchasacondomandspermicideforthenext T 48 hours whenever a progestin-only oral contraceptive is taken 3 or more hours late. he potential side effects of progestin-only oral contraceptives, particularly T menstrual irregularities. heneedtoinformthehealthcareprofessionalofprolongedepisodesofbleeding, T amenorrhea or severe abdominal pain. he importance of using a barrier method in addition to progestin-only oral T contraceptives if a woman is at risk of contracting or transmitting STDs/HIV. ADVERSE REACTIONS Adverse reactions reported with the use of POPs include: enstrualirregularityisthemostfrequentlyreportedsideeffect. M requent and irregular bleeding are common, while long duration of bleedng F i episodes and amenorrhea are less likely. eadache, breast tenderness, nausea, and dizziness are increased among H progestin-only oral contraceptive users in some studies. ndrogenicsideeffectssuchasacne,hirsutism,andweightgainoccurrarely. A OVERDOSAGE There have been no reports of serious ill effects from overdosage, including ingestion by children. DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ORTHO MICRONOR must be taken exactly as directed. One tablet is taken every day, at the same time. Administration is continuous, with no interruption between pill packs. See Detailed Patient Labeling for detailed instruction. HOW SUPPLIED ORTHO MICRONOR (0.35 mg norethindrone) Tablets are available in a blister card (NDC 0062-1411-01 or NDC 50458-194-00) with a DIALPAK Tablet Dispenser (unfilled). The blister card contains 28 lime green, round, flat faced, beveled edge tablets, imprinted ORTHO 0.35 on both sides. ORTHO MICRONOR Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK Tablet Dispensers (NDC 00621411-16 or NDC 50458-194-16). ORTHO MICRONOR (0.35 mg norethindrone) Tablets are available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 0062-1411-23 or NDC 50458-194-23). STORAGE: Store at 25C (77F); excursions permitted to 15-30C (59-86F). Keep out of reach of children. REFERENCE McCann M, and Potter L. Progestin-Only Oral Contraceptives: A Comprehensive Review. Contraception, 50:60 (Suppl. 1), December 1994. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3): 113-118. Truitt ST, Fraser A, Gallo ME, Lopez LM, Grimes DA and Schulz KF. Combined hormonal versus nonhormonal versus progestin-only contraception in lactation (Review). The Cochrane Collaboration. 2007, Issue 3. Halderman, LD and Nelson AL. Impact of early postpartum administration of progestinonly hormonal contraceptives compared with nonhormonal contraceptives on short-term breast-feeding patterns. Am J Obstet Gynecol.; 186 (6): 1250-1258. Ostrea EM, Mantaring III JB, Silvestre MA. Drugs that affect the fetus and newborn infant via the placenta or breast milk. Pediatr Clin N Am; 51(2004): 539-579. Cooke ID, Back DJ, Shroff NE: Norethisterone concentration in breast milk and infant and maternal plasma during ethynodiol diactetate administration. Contraception 1985; 31:611-21. 2008 USPC Official:12/1/08-4/30/09, USP Monographs: Norethindrone Tablets (page 1 of 5).

DETAILED PATIENT LABELING ORTHO MICRONOR (norethindrone) Tablets This product (like all oral contraceptives) is used to prevent pregnancy. It does not protect against HIV infection (AIDS) or other sexually transmitted diseases. DESCRIPTION ORTHO MICRONOR Tablets Each tablet contains 0.35 mg norethindrone. Inactive ingredients include D&C Green No. 5, D&C Yellow No. 10, lactose, magnesium stearate, modified corn starch and povidone. INTRODUCTION This leaflet is about birth control pills that contain one hormone, a progestin. Please read this leaflet before you begin to take your pills. It is meant to be used along with talking with your healthcare professional. Progestin-only pills are often called POPs or the minipill. POPs have less progestin than the combined birth control pill (or the pill) which contains both an estrogen and a progestin. HOW EFFECTIVE ARE POPs? About 1 in 200 POP users will get pregnant in the first year if they all take POPs perfectly (that is, on time, every day). About 1 in 20 typical POP users (including women who are late taking pills or miss pills) gets pregnant in the first year of use. Table 2 will help you compare the efficacy of different methods. Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing % of Women an Unintended Pregnancy Continuing Use at within the First Year of Use One Year* Method Typical Perfect Use Use (1) (2) (3) (4) 85 85 Chance# Spermicides 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal 2 Post-Ovulation 1 Cap Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm 20 6 56 Withdrawal 19 4 Condom Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 and Norplant-2 Norplant 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Adapted from Hatcher et al, 1998, Ref. #1. Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception. Source: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. * Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. The treatment schedule is one dose within 72hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills).

to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. # The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. With spermicidal cream or jelly. Without spermicides. ORTHO MICRONOR Tablets have not been studied for and are not indicated for use in emergency contraception. HOW DO POPs WORK? POPs can prevent pregnancy in different ways including: heymakethecervicalmucusattheentrancetothewomb(theuterus)toothick T for the sperm to get through to the egg. hey prevent ovulation (release of the egg from the ovary) in about half of T thecycles. heyalsoaffectotherhormones,thefallopiantubesandtheliningoftheuterus. T YOU SHOULD NOT TAKE POPs fthereisanychanceyoumaybepregnant. I fyouhavebreastcancer. I fyouhavebleedingbetweenyourperiodsthathasnotbeendiagnosed. I f you are taking certain drugs for epilepsy (seizures) or for TB, or medicine for I pulmonary hypertension or certain herbal products. (See Using POPs with Other Medicines below.) Iyouarehypersensitive,orallergic,toanycomponentofthisproduct. f fyouhavelivertumors,eitherbenignorcancerous. I fyouhaveacuteliverdisease. I RISKS OF TAKING POPs Cigarette smoking greatly increases the possibility of suffering heart attacks and strokes. Women who use oral contraceptives are strongly advised not to smoke. WARNING: If you have sudden or severe pain in your lower abdomen or stomach area, you may have an ectopic pregnancy or an ovarian cyst. If this happens, you should contact your healthcare professional immediately. Ectopic Pregnancy An ectopic pregnancy is a pregnancy outside the womb. Because POPs protect against pregnancy, the chance of having a pregnancy outside the womb is very low. If you do get pregnant while taking POPs, you have a slightly higher chance that the pregnancy will be ectopic than do users of some other birth control methods. Ovarian Cysts These cysts are small sacs of fluid in the ovary. They are more common among POP users than among users of most other birth control methods. They usually disappear without treatment and rarely causeproblems. Cancer of the Reproductive Organs and Breasts Some studies in women who use combined oral contraceptives that contain both estrogen and a progestin have reported an increase in the risk of developing breast cancer, particularly at a younger age and apparently related to duration of use. There is insufficient data to determine whether the use of POPs similarly increases this risk. A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives and there is insufficient data to determine whether the use of POPs increases the risk of developing cancer of the cervix. Liver Tumors In rare cases, combined oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer among women who use combined oral contraceptives. However, liver cancers are rare. There is insufficient data to determine whether POPs increase the risk of livertumors. Diabetic Women Diabetic women taking POPs do not generally require changes in the amount of insulin they are taking. However, your healthcare professional may monitor you more closely under these conditions. SEXUALLY TRANSMITTED DISEASES (STDs) WARNING: POPs do not protect against getting or giving someone HIV (AIDS) or any other STD, such as chlamydia, gonorrhea, genital warts orherpes.

However,

SIDE EFFECTS Irregular Bleeding: The most common side effect of POPs is a change in menstrual bleeding. Your periods may be either early or late, and you may have some spotting between periods. Taking pills late or missing pills can result in some spotting or bleeding. Other Side Effects: Less common side effects include headaches, tender breasts, nausea and dizziness. Weight gain, acne and extra hair on your face and body have been reported, but are rare. If you are concerned about any of these side effects, check with your healthcare professional. USING POPs WITH OTHER MEDICINES Before taking a POP, inform your healthcare professional of any other medication, including over-the-counter medicine, that you may be taking. These medicines can make POPs less effective: Medicines for seizures such as: Phenytoin(Dilantin) Carbamazepine(Tegretol) Phenobarbital Medicine for TB: Rifampin(Rifampicin) Medicine for pulmonary hypertension such as: Bosentan(Tracleer) Herbal products such as: St.JohnsWort Before you begin taking any new medicines be sure your healthcare professional knows you are taking a progestin-only birth control pill. HOW TO TAKE POPs IMPORTANT POINTS TO REMEMBER OPsmustbetakenatthesametimeeveryday,sochooseatimeandthentake P the pill at that same time every day. Every time you take a pill late, and especially if you miss a pill, you are more likely to get pregnant. tart the next pack the day after the last pack is finished. There is no break S between packs. Always have your next pack of pills ready. oumayhavesomemenstrualspottingbetweenperiods.Donotstoptakngyour Y i pills if this happens. fyouvomitsoonaftertakingapill,useabackupmethod(suchasacondomand/ I or a spermicide) for 48 hours. f you want to stop taking POPs, you can do so at any time, but, if you remain I sexually active and dont wish to become pregnant, be certain to use another birth control method. fyouarenotsureabouthowtotakePOPs,askyourhealthcareprofessional. I STARTING POPs tsbesttotakeyourfirstPOPonthefirstdayofyourmenstrualperiod. I fyoudecidetotakeyourfirstPOPonanotherday,useabackupmethod(suchas I a condom and/or a spermicide) every time you have sex during the next 48hours. fyouhavehadamiscarriageoranabortion,youcanstartPOPsthenextday. I IF YOU ARE LATE OR MISS TAKING YOUR POPs fyouaremorethan3hourslateoryoumissoneormorePOPs: I 1) TAKE a missed pill as soon as you remember that you missed it, 2) THEN go back to taking POPs at your regular time, 3) BUT be sure to use a backup method (such as a condom and/or a spermicide) every time you have sex for the next 48hours. fyouarenotsurewhattodoaboutthepillsyouhavemissed,keeptakingPOPs I and use a backup method until you can talk to your healthcare professional. IF YOU ARE BREASTFEEDING fyouarefullybreastfeeding(notgivingyourbabyanyfoodorformula),youmay I start your pills 6 weeks after delivery. f you are partially breastfeeding (giving your baby some food or formula), you I should start taking pills by 3 weeks after delivery. IF YOU ARE SWITCHING PILLS fyouareswitchingfromthecombinedpillstoPOPs,takethefirstPOPtheday I after you finish the last active combined pill. Do not take any of the 7 inactive pills from the combined pill pack. You should know that many women have irregular periods after switching to POPs, but this is normal and to be expected. fyouareswitchingfromPOPstothecombinedpills,takethefirstactivecombined I pill on the first day of your period, even if your POPs pack is notfinished. fyouswitchtoanotherbrandofPOPs,startthenewbrandanytime. I fyouarebreastfeeding,youcanswitchtoanothermethodofbirthcontrolatany I time, except do not switch to the combined pills until you stop breastfeeding or at least until 6months afterdelivery.

PREGNANCY WHILE ON THE PILL If you think you are pregnant, contact your healthcare professional. Even though research has shown that POPs do not cause harm to the unborn baby, it is always best not to take any drugs or medicines that you dont need when you are pregnant. You should get a pregnancy test: fyourperiodislateandyoutookoneormorepillslateormissedtakingthemand I had sex without a backup method. nytimeithasbeenmorethan45dayssincethebeginningofyourlastperiod. A WILL POPs AFFECT YOUR ABILITY TO GET PREGNANT LATER? If you want to become pregnant, simply stop taking POPs. POPs will not delay your ability to getpregnant. BREASTFEEDING If you are breastfeeding, POPs will not affect the quality or amount of your breast milk or the health of your nursing baby. However, isolated cases of decreased milk production have been reported. OVERDOSE No serious problems have been reported when many pills were taken by accident, even by a small child, so there is usually no reason to treat an overdose. OTHER QUESTIONS OR CONCERNS If you have any questions or concerns, check with your healthcare professional. You can also ask for the more detailed Professional Labeling written for doctors and other healthcare professionals. HOW TO STORE YOUR POPs Store at 25C (77F); excursions permitted to 15-30C (59-86F). Keep out of reach of children.

Mfd. for: Ortho Womens Health & Urology, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869 Mfd. by: Janssen Ortho, LLC Manati, Puerto Rico 00674 OMJPI 2001 Revised June 2010

10216800

ORTHO-NOVUM Tablets
(norethindrone /ethinyl estradiol) (norethindrone /ethinyl estradiol) Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. COMBINED ORAL CONTRACEPTIVES Each of the following products is a combined oral contraceptive containing the progestational compound norethindrone and the estrogenic compound ethinyl estradiol. ORTHO-NOVUM 7/7/7 Tablets: Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each light peach tablet contains 0.75 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as follows: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. ORTHO-NOVUM 1/35 Tablets: Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM 7/7/7. MODICON Tablets: Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM 7/7/7. The chemical name for norethindrone is 17-Hydroxy-19-nor-17-pregn-4-en-20-yn-3-one, and for ethinyl estradiol is 19-Nor-17-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural formulas are as follows:

and MODICON Tablets

Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998. * Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1dose is 4 yellow pills). However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. # The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. Foams, creams, gels, vaginal suppositories, and vaginal film. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. With spermicidal cream or jelly. Without spermicides. ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35 and MODICON have not been studied for and are not indicated for use in emergency contraception. CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: Thrombophlebitisorthromboembolicdisorders Apasthistoryofdeepveinthrombophlebitisorthromboembolicdisorders Cerebralvascularorcoronaryarterydisease(currentorhistory) Valvular heart disease with complications Severehypertension Diabeteswithvascularinvolvement Headacheswithfocalneurologicalsymptoms Majorsurgerywithprolongedimmobilization Knownorsuspectedcarcinomaofthebreast arcinomaoftheendometriumorotherknownorsuspectedestrogen-dependentneoplasia C Undiagnosedabnormalgenitalbleeding Cholestaticjaundiceofpregnancyorjaundicewithpriorpilluse Acuteorchronichepatocellulardiseasewithabnormalliverfunction Hepatic adenomas or carcinomas Knownorsuspectedpregnancy Hypersensitivitytoanycomponentofthisproduct WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the authors permission). For further information, the reader is referred to a text on epidemiological methods. 1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4-10 The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older, and in nonsmokers over the age of 40 among women who use oral contraceptives.

CLINICAL PHARMACOLOGY COMBINED ORAL CONTRACEPTIVES Combined oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). INDICATIONS AND USAGE ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the NORPLANT System depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Table I: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing an Unintended Pregnancy within the First Year of Use Method (1) Chance# Spermicides Periodic abstinence Calendar Ovulation Method Sympto-Thermal Post-Ovulation Cap Parous Women Nulliparous Women Sponge Parous Women Nulliparous Women Diaphragm Withdrawal Condom Female (Reality) Male Pill Progestin Only Combined IUD Progesterone T Copper T380A LNg 20 Depo-Provera Norplant and Norplant-2 Female Sterilization Male Sterilization Typical Use (2) 85 26 25 Perfect Use (3) 85 6 9 3 2 1 40 20 40 20 20 19 21 14 5 26 9 20 9 6 4 5 3 0.5 0.1 2.0 0.8 0.1 0.3 0.05 0.5 0.15 1.5 0.6 0.1 0.3 0.05 0.5 0.10 81 78 81 70 88 100 100 42 56 42 56 56 56 61 71 % of Women Continuing Use at One Year* (4) 40 63

Adapted from Hatcher et al, 1998, Ref. #1.

TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE

with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome No fertility-control methods* Oral contraceptives non-smoker Oral contraceptives smoker 15-19 7.0 0.3 2.2 0.8 1.1 1.9 2.5 20-24 7.4 0.5 3.4 0.8 1.6 1.2 1.6 25-29 9.1 0.9 6.6 1.0 0.7 1.2 1.6 30-34 14.8 1.9 13.5 1.0 0.2 1.3 1.7 35-39 25.7 13.8 51.1 1.4 0.3 2.2 2.9 40-44 28.2 31.6 117.2 1.4 0.4 2.8 3.6

(Adapted from P.M. Layde and V. Beral, ref. #12.) Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2 A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed. c. Cerebrovascular diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29 In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3 d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contraceptives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient. e. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 50micrograms or higher of estrogens. 2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased

IUD Condom* Diaphragm/spermicide* Periodic abstinence*

Adapted from H.W. Ory, ref. #35. *Deaths are birth-related Deaths are method-related 3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a womans reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established. 4. HEPATIC NEOPLASIA Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51 Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in longterm (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. 5. OCULAR LESIONS There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. 7. GALLBLADDER DISEASE Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9. ELEVATED BLOOD PRESSURE Women with significant hypertension should not be started on hormonal contraception.92 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity. Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68-71 10. HEADACHE The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. BLEEDING IRREGULARITIES Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. 12. ECTOPIC PREGNANCY Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. PRECAUTIONS 1. GENERAL Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 2. PHYSICAL EXAMINATION AND FOLLOW-UP It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 3. LIPID DISORDERS Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. LIVER FUNCTION If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 5. FLUID RETENTION Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. EMOTIONAL DISORDERS Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 7. CONTACT LENSES Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8. DRUG INTERACTIONS Changes in contraceptive effectiveness associated with co-administration of other products: Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results. Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combined hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. Johns Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding. Concurrent use of bosentan and norethisterone/ethinyl estradiol may result in decreased concentrations of these contraceptive hormones, thereby increasing the risk of unintended pregnancy and unscheduled bleeding. Increase in plasma levels associated with co-administered drugs: Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Changes in plasma levels of co-administered drugs: Combined hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives.

Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.95 Healthcare professionals are advised to also refer to prescribing information of co-administered drugs for recommendations regarding management of concomitant therapy. 9. INTERACTIONS WITH LABORATORY TESTS Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered. c. Other binding proteins may be elevated in serum. d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 10. CARCINOGENESIS See WARNINGS. 11. PREGNANCY Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS. 12. NURSING MOTHERS Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combined oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combined oral contraceptives but to use other forms of contraception until she has completely weaned her child. 13. PEDIATRIC USE Safety and efficacy of ORTHO-NOVUM Tablets and MODICON Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 14. GERIATRIC USE This product has not been studied in women over 65 years of age and is not indicated in this population. INFORMATION FOR THE PATIENT See Patient Labeling printed below. ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (See WARNINGS). Thrombophlebitisandvenousthrombosiswithorwithoutembolism Arterialthromboembolism Pulmonaryembolism Myocardialinfarction Cerebralhemorrhage Cerebralthrombosis Hypertension Gallbladderdisease Hepatic adenomas or benign liver tumors There is evidence of an association between the following conditions and the use of oral contraceptives: Mesentericthrombosis Retinalthrombosis The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: Nausea Vomiting Gastrointestinalsymptoms(suchasabdominalcrampsandbloating) Breakthroughbleeding Spotting Changeinmenstrualflow Amenorrhea Temporaryinfertilityafterdiscontinuationoftreatment Edema Melasmawhichmaypersist Breastchanges:tenderness,enlargement,secretion Changeinweight(increaseordecrease) Changeincervicalerosionandsecretion Diminutioninlactationwhengivenimmediatelypostpartum Cholestaticjaundice Migraine Allergic reaction, including rash, urticaria, angioedema Mentaldepression Reducedtolerancetocarbohydrates Vaginalcandidiasis Changeincornealcurvature(steepening) Intolerancetocontactlenses The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted: Pre-menstrualsyndrome Cataracts Changesinappetite Cystitis-like syndrome Headache Nervousness Dizziness Hirsutism Lossofscalphair

Erythemamultiforme Erythemanodosum Hemorrhagiceruption Vaginitis Porphyria Impairedrenalfunction Hemolyticuremicsyndrome Acne Changesinlibido Colitis Budd-ChiariSyndrome OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of combined oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.73-78 Effects on menses: increasedmenstrualcycleregularity decreasedbloodlossanddecreasedincidenceofirondeficiencyanemia decreasedincidenceofdysmenorrhea Effects related to inhibition of ovulation: decreasedincidenceoffunctionalovariancysts decreasedincidenceofectopicpregnancies Other effects: decreasedincidenceoffibroadenomasandfibrocysticdiseaseofthebreast decreasedincidenceofacutepelvicinflammatorydisease decreased incidence of endometrial cancer decreasedincidenceofovariancancer DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ORTHO-NOVUM Tablets and MODICON Tablets must be taken exactly as directed and at intervals not exceeding 24 hours. ORTHO-NOVUM Tablets and MODICON Tablets are available with the DIALPAK Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also available. Sunday Start When taking ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON, the first active tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first active tablet should be taken that day. Take one active tablet daily for 21 days followed by one green reminder tablet daily for 7 days. After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start regimen, another method of contraception such as a condom or spermicide should be used until after the first 7 consecutive days of administration. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section). Day 1 Start The dosage of ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON, for the initial cycle of therapy, is one active tablet administered daily from the 1st through the 21st day of the menstrual cycle, counting the first day of menstrual flow as Day 1 followed by one green reminder tablet daily for 7 days. Tablets are taken without interruption for 28 days. After 28tablets have been taken, a new course is started the next day. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (How to Take the Pill section). The use of ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) The possibility of ovulation and conception prior to initiation of medication should be considered. (See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.) ADDITIONAL INSTRUCTIONS Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. Use of oral contraceptives in the event of a missed menstrual period: 1.If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued if pregnancy is confirmed. 2.If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out.

HOW SUPPLIED ORTHO-NOVUM 7/7/7 Tablets are available in a blister card with a DIALPAK Tablet Dispenser (unfilled) (NDC 0062-1781-00 or NDC 50458-178-00). The blister card contains 28 tablets, as follows: 7 white, round, flat-faced, beveled edged tablets imprinted with Ortho 535 on both sides (0.5mg norethindrone and 0.035 mg ethinyl estradiol), 7 light peach, round, flat-faced, beveled edged tablets imprinted with Ortho 75 on both sides (0.75 mg norethindrone and 0.035 mg ethinyl estradiol), 7 peach, round, flat-faced, beveled edged tablets imprinted with Ortho 135 on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted Ortho on both sides containing inert ingredients. ORTHO-NOVUM 7/7/7 Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK Tablet Dispensers (NDC 0062-1781-15 or NDC 50458-178-15). ORTHO-NOVUM 7/7/7 is available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and VERIDATE refills (NDC 0062-1781-20 or NDC 50458-178-20). ORTHO-NOVUM 1/35 Tablets are available in a blister card with a DIALPAK Tablet Dispenser (unfilled) (NDC 0062-1761-00 or NDC 50458-176-00). The blister card contains 28 tablets, as follows: 21 peach, round, flat-faced, beveled edged tablets imprinted Ortho 135 on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted Ortho on both sides containing inert ingredients. ORTHO-NOVUM 1/35 Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK Tablet Dispensers (NDC 0062-1761-15 or NDC 50458-176-15). MODICON Tablets are available in a blister card with a DIALPAK Tablet Dispenser (unfilled) (NDC 0062-1714-00 or NDC 50458-171-00). The blister card contains 28 tablets, as follows: 21 white, round, flat-faced, beveled edged tablets imprinted Ortho 535 on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted Ortho on both sides containing inert ingredients. MODICON Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK Tablet Dispensers (NDC 0062-1714-15 or NDC 50458-171-15). Store at 25C (77F), excursions permitted to 15-30C (59-86F). REFERENCES 1. Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998, in press. 2.Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 1). N Engl J Med 1981; 305:612-618. 3. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305:672-677. 4. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet Gynaecol 1981; 88:838-845. 5. Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975; 2(5965):245-248. 6. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 1975; 2(5956):241-245. 7. Royal College of General Practitioners Oral Contraception Study: further analyses of mortality in oral contraceptive users. Lancet 1981; 1:541-546. 8. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med 1981; 305:420-424. 9. Vessey MP. Female hormones and vascular disease an epidemiological overview. Br J Fam Plann 1980; 6 (Supplement): 1-12. 10. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent Med 1986; 15:352-362. 11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339-1342. 12.Layde PM, Beral V. Further analyses of mortality in oral contraceptive users; Royal College of General Practitioners Oral Contraception Study. (Table 5) Lancet 1981; 1:541546. 13. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod Med 1986; 31(9) (Supplement): 913-921. 14. Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am J Obstet 1983; 145:446-452. 15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983; 308:862-867. 16. Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high density lipoproteins. Am J Obstet Gynecol 1982; 142:766-771. 17. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986; 31(9)(Supplement):892-897. 18. LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod Med 1986; 31(9)(Supplement):906-912. 19. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 1968; 2(5599):193-199. 20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol 1979; 110(2):188-195. 21. Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150-1154. 22. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2(5599):199-205. 23. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 1969; 2(5658):651-657. 24. Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular disease recent experience. Obstet Gynecol 1982; 59(3):299-302. 25. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception: an interim report. J Biosocial Sci 1976; 8:375-427. 26. Royal College of General Practitioners: Oral Contraceptives, venous thrombosis, and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399. 27. Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 1973; 288:871878. 28. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234-236. 29. Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979; 2(6203):1468-1470. 30. Collaborative Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718-722. 31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970; 2:203-209. 32. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980; 280(6224):1157-1161. 33. Kay CR. Progestogens and arterial disease evidence from the Royal College of General Practitioners Study. Am J Obstet Gynecol 1982; 142:762-765. 34. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983; 33:75-82. 35. Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983; 15:50-56. 36. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of breast cancer. N Engl J Med 1986; 315:405411. 37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926-929. 38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723-725. 39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868. 40. Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; 1(8431):748-749. 41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987;

56:653-660. 42. Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril 1987; 47:733-761. 43. McPherson K, Drife JO. The pill and breast cancer: why the uncertainty? Br Med J 1986; 293:709-710. 44.Shapiro S. Oral contraceptives time to take stock. N Engl J Med 1987; 315:450-451. 45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976; 124:573-577. 46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930. 47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339-344. 48. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med J 1985; 290:961-965. 49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648. 50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433-435. 51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386-394. 52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437-440. 53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357. 54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357-1361. 55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452. 56.Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981; 140:521-524. 57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980; 112:73-79. 58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239. 59. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109:433-439. 60. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404. 61. Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman 1974. 62. Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274-278. 63. Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119:796-805. 64. Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335-341. 65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049. 66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds. New York, Raven Press, 1983; pp. 395-410. 67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857-864. 68. Royal College of General Practitioners Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503. 70. Laragh AJ. Oral contraceptive induced hypertension nine years later. Am J Obstet Gynecol 1976; 126:141-147. 71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan.) 72. Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143. 73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599. 74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800. 75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69. 76. Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419-422. 77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182184. 78. Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1. 79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42. 81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br J Cancer 1986; 54:311-317. 82.Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use and breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC. Breast cancer and the pill A further report from the Royal College of General Practitioners oral contraception study. Br J Cancer 1988; 58:675-680. 84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989; 129:269-280. 86.The UK National CaseControl Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982. 87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38. 88.Vessey MP, McPherson K, VillardMackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br J Cancer 1989; 59:613-617. 89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989; 59:618-621. 90. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727. 91. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882. 92. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 93. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-298. 94. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118. 95. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a doubleblind, placebo-controlled trial. Epilepsia 2007;48(3):484-489. BRIEF SUMMARY PATIENT PACKAGE INSERT Oral contraceptives, also known as birth control pills or the pill, are taken to prevent pregnancy and when taken correctly without missing any pills, have a failure rate of approximately 1% per year. The typical failure rate is approximately 5% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be fatal or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: smoke havehighbloodpressure,diabetes,highcholesterol aveorhavehadclottingdisorders,heartattack,stroke,anginapectoris,cancerofthebreast h or sex organs, jaundice or malignant or benign liver tumors. Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: 1.Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. 2.In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 3.High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics may decrease oral contraceptive effectiveness. Oral contraceptives may interact with lamotrigine (LAMICTAL), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. Taking the combination pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your healthcare professional. Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. Your pharmacist should have given you the detailed patient information labeling which gives you further information which you should read and discuss with your healthcare professional. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK.

The pill pack has 21 active pills (with hormones) to take for 3weeks. This is followed by 1 week of green reminder pills (without hormones). ORTHO-NOVUM 7/7/7: There are 7 white active pills, 7 light peach active pills, 7 peach active pills and 7 green reminder pills. ORTHO-NOVUM 1/35: There are 21 peach active pills and 7 green reminder pills. MODICON: There are 21 white active pills and 7 green reminder pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON are available with the DIALPAK Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. SUNDAY START: ORTHO-NOVUM 7/7/7: Take the first white active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. ORTHO-NOVUM 1/35: Take the first peach active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. MODICON: Take the first white active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7days). DAY 1 START: ORTHO-NOVUM 7/7/7: Take the first white active pill of the first pack during the first 24 hours of your period. ORTHO-NOVUM 1/35: Take the first peach active pill of the first pack during the first 24 hours of your period. MODICON: Take the first white active pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last green reminder pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO-NOVUM 7/7/7: If you MISS 1 white, light peach, or peach active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light peach active pills in a row in WEEK1 OR WEEK 2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach active pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white, light peach, or peach active pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. ORTHO-NOVUM 1/35: If you MISS 1 peach active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 peach active pills in a row in WEEK 1 OR WEEK2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack.

3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach active pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE peach active pills in a row (during the first 3weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. MODICON: If you MISS 1 white active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white active pills in a row in WEEK 1 OR WEEK2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 white active pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white active pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER If you forget any of the 7 green reminder pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE ACTIVE PILL EACH DAY until you can reach your healthcare professional. Instructions for using your Dialpak Tablet Dispenser Please Read Me! Sunday Start or Day 1 Start There are two ways to start taking birth control pills, Sunday Start or Day 1 Start. Your healthcare professional will tell you which to use.

Save these instructions.

1 2

If this is the first time you are taking birth control pills, or if you have not taken birth control pills for 10days or more, your first step is to wait until the first day you get your menstrual period. Then, follow these instructions for either Sunday Start or Day 1 Start.

?
Sunday Start Day 1 Start

When you get your period: ouwilluseaSunday Start if your doctor told you to take your first pill Y on a Sunday. Take pill 1 on the Sunday after your period starts. If your period starts on a Sunday, take pill 1 that day. ouwilluseaDay 1 Start if your doctor told you to take pill 1 on the Y first day of your period.

SET THE DAY: Sunday Start: the arrow on your empty Dialpak should point to SU (Sunday). Day 1 Start: turn the dial on your empty Dialpak until the arrow points to the first day of your period (if your period starts on Tuesday, the arrow will point to TU). Insert the new refill by lining up the V shape on the refill with the V shape at the top of your Dialpak. Snap the refill in place. You are ready to take pill 1. You should always begin your pill cycle with pill 1, as shown on the inner part of the refill ring.

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions: Ahistoryofheartattackorstroke loodclotsinthelegs(thrombophlebitis),lungs(pulmonaryembolism),oreyes B Ahistoryofbloodclotsinthedeepveinsofyourlegs Chestpain(anginapectoris) Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina nexplainedvaginalbleeding(untiladiagnosisisreachedbyyourhealthcareprofessional) U ellowingofthewhitesoftheeyesoroftheskin(jaundice)duringpregnancyorduringprevious Y use of the pill Livertumor(benignorcancerous) Knownorsuspectedpregnancy alvularheartdiseasewithcomplications V everehypertension S iabeteswithvascularinvolvement D eadacheswithfocalneurologicalsymptoms H fyouplantohavesurgerywithprolongedbedrest I ypersensitivitytoanycomponentofthisproduct. H Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend a safer method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your healthcare professional if you have or have had: reastnodules,fibrocysticdiseaseofthebreast,anabnormalbreastx-rayormammogram B Diabetes Elevatedcholesterolortriglycerides Highbloodpressure Migraineorotherheadachesorepilepsy Mentaldepression Gallbladder, liver, heart or kidney disease Historyofscantyorirregularmenstrualperiods Women with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives. Also, be sure to inform your healthcare professional if you smoke or are on any medications. RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of developing blood clots Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or injury or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare professional about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding or four weeks after a second trimester abortion. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on Breastfeeding in General Precautions.) The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44, it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers. 2. Heart attacks and strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver tumors In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 5. Cancer of the reproductive organs and breasts Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers.

4 5

Remove pill 1 by pushing down on the pill. Thepill will come out through a hole in the back of the Dialpak.

6 7

Swallow the pill. You will take one pill each day. If you use a Sunday Start and you are taking the pill for the FIRST TIME, YOU MUST USE A BACK-UP METHOD OF BIRTH CONTROL FOR THE FIRST 7DAYS. If you use a Day 1 Start, you are protected from becoming pregnant as soon as you take your first pill. Wait 24 hours to take your next pill. To take pill 2, turn the dial on your Dialpak to the next day. Continue to take one pill each day until all the pills have been taken.

Take your pill at the same time every day. It is important to take the correct pill each day and not miss any pills. To help you remember, take your pill at the same time as another daily activity, like turning off your alarm clock or brushing your teeth.

9 10

When your refill is empty, keep your Dialpak case. You will start a new refill on the day after pill 28.

Turn the dial to the pill 1 position to remove the empty refill and insert a new refill. THE FIRST PILL IN EVERY REFILL WILL ALWAYS BE TAKEN ON THE SAME DAY OF THE WEEK, NO MATTER WHEN YOUR NEXT PERIOD STARTS.

DETAILED PATIENT LABELING PLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully. The following oral contraceptive products contain a combination of an estrogen and progestogen, the two kinds of female hormones: ORTHO-NOVUM 7/7/7 Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each light peach tablet contains 0.75 mg norethindrone and 0.035 mg ethinyl estradiol. Each peach tablet contains 1 mg norethindrone and 0.035mg ethinyl estradiol. Each green tablet contains inert ingredients. ORTHO-NOVUM 1/35 Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. MODICON Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients. INTRODUCTION Any woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This patient labeling will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this labeling is not a replacement for a careful discussion between you and your healthcare professional. You should discuss the information provided in this labeling with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professionals advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or birth control pills or the pill are used to prevent pregnancy and are more effective than other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates are approximately 5% per year including women who do not always take the pills exactly as directed. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: Implant: <1% Male sterilization: <1% Injection: <1% Cervical Cap with spermicides: 20 to 40% IUD: 1 to 2% Condom alone (male): 14% Diaphragm with spermicides: 20% Condom alone (female): 21% Spermicides alone: 26% Periodic abstinence: 25% Vaginal sponge: 20 to 40% Withdrawal: 19% Female sterilization: <1% No methods: 85%

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome No fertility-control methods* Oral contraceptives non-smoker Oral contraceptives smoker IUD Condom* Diaphragm/spermicide* Periodic abstinence*
Deaths

15-19 7.0 0.3 2.2 0.8 1.1 1.9 2.5

20-24 7.4 0.5 3.4 0.8 1.6 1.2 1.6

25-29 9.1 0.9 6.6 1.0 0.7 1.2 1.6

30-34 14.8 1.9 13.5 1.0 0.2 1.3 1.7

35-39 25.7 13.8 51.1 1.4 0.3 2.2 2.9

40-44 28.2 31.6 117.2 1.4 0.4 2.8 3.6

*Deaths are birth-related are method-related In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately: harpchestpain,coughingofblood,orsuddenshortnessofbreath(indicatingapossibleclot S in the lung) Paininthecalf(indicatingapossibleclotintheleg) rushingchestpainorheavinessinthechest(indicatingapossibleheartattack) C Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) uddenpartialorcompletelossofvision(indicatingapossibleclotintheeye) S reastlumps(indicatingpossiblebreastcancerorfibrocysticdiseaseofthebreast;askyour B healthcare professional to show you how to examine your breasts) everepainortendernessinthestomacharea(indicatingapossiblyrupturedlivertumor) S ifficultyinsleeping,weakness,lackofenergy,fatigue,orchangeinmood(possiblyindicating D severe depression) aundiceorayellowingoftheskinoreyeballs,accompaniedfrequentlybyfever,fatigue,loss J of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAL CONTRACEPTIVES 1. Vaginal bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare professional. 2. Contact lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare professional. 3. Fluid retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional. 4. Melasma A spotty darkening of the skin is possible, particularly of the face, which may persist. 5. Other side effects Other side effects may include nausea and vomiting, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections and allergic reactions. If any of these side effects bother you, call your healthcare professional. GENERAL PRECAUTIONS 1. Missed periods and use of oral contraceptives before or during early pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare professional before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy.

2. While breastfeeding If you are breastfeeding, consult your healthcare professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, combined oral contraceptives may decrease the amount and quality of your milk. If possible, do not use combined oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting combined oral contraceptives only after you have weaned your child completely. 3. Laboratory tests If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital), topiramate (TOPAMAX), carbamazepine (Tegretol is one brand of this drug), phenytoin (Dilantin is one brand of this drug), phenylbutazone (Butazolidin is one brand), certain drugs used in the treatment of HIV or AIDS, and possibly certain antibiotics. Medicine for pulmonary hypertension, such as bosentan (Tracleer). Pregnancies and breakthrough bleeding have been reported by users of combined hormonal contraceptives who also used some form of the herbal supplement St. Johns Wort. Hormonal contraceptives may interact with lamotrigine (LAMICTAL), an anticonvulsant used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. You may need to use additional contraception when you take other products which can make oral contraceptives less effective. Be sure to tell your healthcare professional if you are taking or start taking any medications while taking birth control pills. 5. Sexually transmitted diseases This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: 1. BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. 2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesnt go away, check with your healthcare professional. 4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well. Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill taking easier or about using another method of birth control. 7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. 2. LOOK AT YOUR PILL PACK. The pill pack has 21 active pills (with hormones) to take for 3weeks. This is followed by 1 week of green reminder pills (without hormones). ORTHO-NOVUM 7/7/7: There are 7 white active pills, 7 light peach active pills, 7 peach active pills and 7 green reminder pills. ORTHO-NOVUM 1/35: There are 21 peach active pills and 7 green reminder pills. MODICON: There are 21 white active pills and 7 green reminder pills. 3. ALSO FIND: 1) where on the pack to start taking pills, 2) in what order to take the pills. CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT. 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills. AN EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON are available with the DIALPAK Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. SUNDAY START: ORTHO-NOVUM 7/7/7: Take the first white active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. ORTHO-NOVUM 1/35: Take the first peach active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. MODICON: Take the first white active pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7days).

DAY 1 START: ORTHO-NOVUM 7/7/7: Take the first white active pill of the first pack during the first 24 hours of your period. ORTHO-NOVUM 1/35: Take the first peach active pill of the first pack during the first 24 hours of your period. MODICON: Take the first white active pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: Start the next pack on the day after your last green reminder pill. Do not wait any days between packs. WHAT TO DO IF YOU MISS PILLS ORTHO-NOVUM 7/7/7: If you MISS 1 white, light peach, or peach active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white or light peach active pills in a row in WEEK1 OR WEEK2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach active pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white, light peach, or peach active pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. ORTHO-NOVUM 1/35: If you MISS 1 peach active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 peach active pills in a row in WEEK 1 OR WEEK2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 peach active pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE peach active pills in a row (during the first 3weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. MODICON: If you MISS 1 white active pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.

2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white active pills in a row in WEEK 1 OR WEEK2 of your pack: 1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 white active pills in a row in THE 3RD WEEK: 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white active pills in a row (during the first 3 weeks): 1a. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 1b. If you are a Day 1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER If you forget any of the 7 green reminder pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE ACTIVE PILL EACH DAY until you can reach your healthcare professional. PREGNANCY DUE TO PILL FAILURE Combined Oral Contraceptives The incidence of pill failure resulting in pregnancy is approximately one percent (i.e., one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are 5%. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare professional or pharmacist. OTHER INFORMATION Your healthcare professional will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare professional, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of combined oral contraceptives may provide certain benefits. They are: menstrualcyclesmaybecomemoreregular loodflowduringmenstruationmaybelighterandlessironmaybelost.Therefore,anemiadue b to iron deficiency is less likely to occur. ainorothersymptomsduringmenstruationmaybeencounteredlessfrequently p ectopic(tubal)pregnancymayoccurlessfrequently oncancerouscystsorlumpsinthebreastmayoccurlessfrequently n acutepelvicinflammatorydiseasemayoccurlessfrequently ralcontraceptiveusemayprovidesomeprotectionagainstdevelopingtwoformsofcancer: o cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your healthcare professional. They have a more technical leaflet called the Professional Labeling, which you may wish to read. The professional labeling is also published in a book entitled Physicians Desk Reference, available in many book stores and public libraries. Store at 25C (77F), excursions permitted to 1530C (5986F).

Mfd. for: Ortho Womens Health & Urology, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869 Mfd. by: Janssen Ortho, LLC Manati, Puerto Rico 00674 Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998 Revised November 2010 10119300

PARAFON FORTE DSC


(chlorzoxazone) Caplets 500 mg For Painful Musculoskeletal Conditions
DESCRIPTION
Each caplet (capsule shaped tablet) contains: Chlorzoxazone*...............................................................................500 mg Inactive ingredients: FD&C Blue No. 1, microcrystalline cellulose, docusate sodium, lactose (hydrous), magnesium stearate, sodium benzoate, sodium starch glycolate, pregelatinized corn starch, D&C Yellow No. 10. *5-chlorobenzoxazolinone

allergic-type skin rashes, petechiae, or ecchymoses may develop during treatment. Angioneurotic edema or anaphylactic reactions are extremely rare. There is no evidence that the drug will cause renal damage. Rarely, a patient may note discoloration of the urine resulting from a phenolic metabolite of chlorzoxazone. This finding is of no known clinical significance.

DOSAGE AND ADMINISTRATION


Usual Adult Dosage One caplet three or four times daily. If adequate response is not obtained with this dose, it may be increased to 112 caplets (750 mg) three or four times daily. As improvement occurs dosage can usually be reduced.

OVERDOSAGE
Symptoms Initially, gastrointestinal disturbances such as nausea, vomiting, or diarrhea together with drowsiness, dizziness, lightheadedness or headache may occur. Early in the course there may be malaise or sluggishness followed by marked loss of muscle tone, making voluntary movement impossible. The deep tendon reflexes may be decreased or absent. The sensorium remains intact, and there is no peripheral loss of sensation. Respiratory depression may occur with rapid, irregular respiration and intercostal and substernal retraction. The blood pressure is lowered, but shock has not been observed. Treatment Gastric lavage or induction of emesis should be carried out, followed by administration of activated charcoal. Thereafter, treatment is entirely supportive. If respirations are depressed, oxygen and artificial respiration should be employed and a patent airway assured by use of an oropharyngeal airway or endotracheal tube. Hypotension may be counteracted by use of dextran, plasma, concentrated albumin or a vasopressor agent such as norepinephrine. Cholinergic drugs or analeptic drugs are of no value and should not be used.

ACTIONS
Chlorzoxazone is a centrally-acting agent for painful musculoskeletal conditions. Data available from animal experiments as well as human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex arcs involved in producing and maintaining skeletal muscle spasm of varied etiology. The clinical result is a reduction of the skeletal muscle spasm with relief of pain and increased mobility of the involved muscles. Blood levels of chlorzoxazone can be detected in people during the first 30 minutes and peak levels may be reached, in the majority of the subjects, in about 1 to 2 hours after oral administration of chlorzoxazone. Chlorzoxazone is rapidly metabolized and is excreted in the urine, primarily in a conjugated form as the glucuronide. Less than one percent of a dose of chlorzoxazone is excreted unchanged in the urine in 24 hours.

INDICATIONS
PARAFON FORTE DSC chlorzoxazone is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Chlorzoxazone does not directly relax tense skeletal muscles in man.

HOW SUPPLIED
PARAFON FORTE DSC (chlorzoxazone) 500 mg caplets, (capsule shaped tablet, colored light green, imprinted PARAFON FORTE DSC and McNEIL, scored). NDC 50458-625-60, bottles of 100. Dispense in tight container as defined in the official compendium. Store at controlled room temperature (15-30C, 59-86F). Manufactured by: Janssen Ortho, LLC Gurabo, Puerto Rico 00778

CONTRAINDICATIONS
PARAFON FORTE DSC chlorzoxazone is contraindicated in patients with known intolerance to the drug.

WARNINGS
Serious (including fatal) hepatocellular toxicity has been reported rarely in patients receiving chlorzoxazone. The mechanism is unknown but appears to be idiosyncratic and unpredictable. Factors predisposing patients to this rare event are not known. Patients should be instructed to report early signs and/or symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, or jaundice. Chlorzoxazone should be discontinued immediately and a physician consulted if any of these signs or symptoms develop. Chlorzoxazone use should also be discontinued if a patient develops abnormal liver enzymes (e.g. AST, ALT, alkaline phosphatase and bilirubin). The concomitant use of alcohol or other central nervous system depressants may have an additive effect. Usage in Pregnancy The safe use of PARAFON FORTE DSC chlorzoxazone has not been established with respect to the possible adverse effects upon fetal development. Therefore, it should be used in women of childbearing potential only when, in the judgment of the physician, the potential benefits outweigh the possible risks.

Raritan, New Jersey 08869 10190200

is this product commercially Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. available?
Revised October 2010

PRECAUTIONS
PARAFON FORTE DSC chlorzoxazone should be used with caution in patients with known allergies or with a history of allergic reactions to drugs. If a sensitivity reaction occurs such as urticaria, redness, or itching of the skin, the drug should be stopped. If any symptoms suggestive of liver dysfunction are observed, the drug should be discontinued.

ADVERSE REACTIONS
Chlorzoxazone containing products are usually well tolerated. It is possible in rare instances that chlorzoxazone may have been associated with gastrointestinal bleeding. Drowsiness, dizziness, light-headedness, malaise, or overstimulation may be noted by an occasional patient. Rarely,

RISPERDAL
(risperidone)

01RS11003 (11/11)

RISPERDAL (risperidone)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RISPERDAL safely and effectively. See full prescribing information for RISPERDAL. RISPERDAL (risperidone) tablets, RISPERDAL (risperidone) oral solution, RISPERDAL M-TAB (risperidone) orally disintegrating tablets Initial U.S. Approval: 1993 WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL is not approved for use in patients with dementiarelated psychosis. (5.1) ---------------------- RECENT MAJOR CHANGES ---------------------Warnings and Precautions, Metabolic Changes (5.5) September 2011 ---------------------- INDICATIONS AND USAGE ---------------------RISPERDAL is an atypical antipsychotic agent indicated for: reatment of schizophrenia in adults and adolescents aged T 13-17 years (1.1) lone, or in combination with lithium or valproate, for the A short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults, and alone in children and adolescents aged 10-17 years (1.2) reatment of irritability associated with autistic disorder in T children and adolescents aged 5-16 years (1.3) ------------------- DOSAGE AND ADMINISTRATION ----------------Effective Dose Target Dose Range 4-8 mg daily 4-16 mg/ day 3 mg/day 1-6 mg/ day 1-6 mg/day 2.5 mg/day 1-6 mg/ day 0.5-6 mg/ day 0.5-3 mg/ day

Schizophrenia adults (2.1) Schizophrenia adolescents (2.1) Bipolar mania adults (2.2) Bipolar mania in children/ adolescents (2.2) Irritability associated with autistic disorder (2.3)

Initial Dose Titration 2 mg/day 1-2 mg daily 0.5 mg/day 0.5-1 mg daily 2-3 mg/day 0.5 mg/day 1 mg daily 0.5-1 mg daily

0.25 mg/day 0.25-0.5 mg (<20 kg) at 2 0.5 mg/day weeks (20 kg)

0.5 mg/day (<20 kg) 1 mg/day (20 kg)

------------------DOSAGE FORMS AND STRENGTHS ---------------- Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3) Oral solution: 1 mg/mL (3) rally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and O 4 mg (3) -------------------------- CONTRAINDICATIONS ----------------------- Known hypersensitivity to the product (4) 1

-------------------- WARNINGS AND PRECAUTIONS ---------------- erebrovascular events, including stroke, in elderly patients C with dementia-related psychosis. RISPERDAL is not approved for use in patients with dementia-related psychosis (5.2) Neuroleptic Malignant Syndrome (5.3) Tardive dyskinesia (5.4) etabolic Changes: Atypical antipsychotic drugs have been M associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.5) yperglycemia and Diabetes Mellitus: Monitor patients for H symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.5) yslipidemia: Undesirable alterations have been observed D in patients treated with atypical antipsychotics. (5.5) eight Gain: Significant weight gain has been reported. W Monitor weight gain. (5.5) Hyperprolactinemia (5.6) Orthostatic hypotension (5.7) eukopenia, Neutropenia, and Agranulocytosis: has been L reported with antipsychotics, including RISPERDAL. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERDAL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (5.8) Potential for cognitive and motor impairment (5.9) Seizures (5.10) Dysphagia (5.11) Priapism (5.12) Thrombotic Thrombocytopenic Purpura (TTP) (5.13) Disruption of body temperature regulation (5.14) Antiemetic Effect (5.15) Suicide (5.16) ncreased sensitivity in patients with Parkinsons disease or I those with dementia with Lewy bodies (5.17) iseases or conditions that could affect metabolism or D hemodynamic responses (5.17) ---------------------------- ADVERSE REACTIONS ---------------------The most common adverse reactions in clinical trials (10%) were somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash. (6) The most common adverse reactions that were associated with discontinuation from clinical trials were nausea, somnolence, sedation, vomiting, dizziness, and akathisia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ----------------------------DRUG INTERACTIONS ---------------------- ue to CNS effects, use caution when administering with D other centrally-acting drugs. Avoid alcohol. (7.1) ue to hypotensive effects, hypotensive effects of other drugs D with this potential may be enhanced. (7.2) ffects of levodopa and dopamine agonists may be E antagonized. (7.3)

RISPERDAL (risperidone)

RISPERDAL (risperidone)

imetidine and ranitidine increase the bioavailability of C risperidone. (7.5) Clozapine may decrease clearance of risperidone. (7.6) luoxetine and paroxetine increase plasma concentrations of F risperidone. (7.10) arbamazepine and other enzyme inducers decrease plasma C concentrations of risperidone. (7.11) -----------------------USE IN SPECIFIC POPULATIONS -------------- Nursing Mothers: should not breast feed. (8.3) ediatric Use: safety and effectiveness not established for P schizophrenia less than 13 years of age, for bipolar mania less than 10 years of age, and for autistic disorder less than 5 years of age. (8.4) lderly or debilitated; severe renal or hepatic impairment; E predisposition to hypotension or for whom hypotension poses a risk: Lower initial dose (0.5 mg twice daily), followed by increases in dose in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should occur at intervals of at least 1 week. (8.5, 2.4) See 17 for PATIENT COUNSELING INFORMATION. Revised: 09/2011 FULL PRESCRIBING INFORMATION: CONTENTS* WARNINGS INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS 1 INDICATIONS AND USAGE 1.1 Schizophrenia 1.2 Bipolar Mania 1.3 Irritability Associated with Autistic Disorder 2 DOSAGE AND ADMINISTRATION 2.1 Schizophrenia 2.2 Bipolar Mania 2.3 rritability Associated with Autistic Disorder Pediatrics I (Children and Adolescents) 2.4 Dosage in Special Populations 2.5 Co-Administration of RISPERDAL with Certain Other Medications 2.6 Administration of RISPERDAL Oral Solution 2.7 Directions for Use of RISPERDAL M-TAB Orally Disintegrating Tablets 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 ncreased Mortality in Elderly Patients with DementiaI Related Psychosis 5.2 erebrovascular Adverse Events, Including Stroke, in C Elderly Patients with Dementia-Related Psychosis 5.3 Neuroleptic Malignant Syndrome (NMS) 5.4 Tardive Dyskinesia 5.5 Metabolic Changes 5.6 Hyperprolactinemia 5.7 Orthostatic Hypotension 5.8 Leukopenia, Neutropenia, and Agranulocytosis 5.9 Potential for Cognitive and Motor Impairment 5.10 Seizures 5.11 Dysphagia 5.12 Priapism 5.13 Thrombotic Thrombocytopenic Purpura (TTP) 5.14 Body Temperature Regulation 5.15 Antiemetic Effect 5.16 Suicide 5.17 Use in Patients with Concomitant Illness 5.18 Monitoring: Laboratory Tests 2

6 ADVERSE REACTIONS 6.1 ommonly-Observed Adverse Reactions in DoubleC Blind, Placebo-Controlled Clinical Trials - Schizophrenia 6.2 ommonly-Observed Adverse Reactions in DoubleC Blind, Placebo-Controlled Clinical Trials Bipolar Mania 6.3 ommonly-Observed Adverse Reactions in DoubleC Blind, Placebo-Controlled Clinical Trials - Autistic Disorder 6.4 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone 6.5 Discontinuations Due to Adverse Reactions 6.6 Dose Dependency of Adverse Reactions in Clinical Trials 6.7 Changes in ECG 6.8 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Centrally-Acting Drugs and Alcohol 7.2 Drugs with Hypotensive Effects 7.3 Levodopa and Dopamine Agonists 7.4 Amitriptyline 7.5 Cimetidine and Ranitidine 7.6 Clozapine 7.7 Lithium 7.8 Valproate 7.9 Digoxin 7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes 7.11 Carbamazepine and Other Enzyme Inducers 7.12 Drugs Metabolized by CYP 2D6 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Human Experience 10.2 Management of Overdosage 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Schizophrenia 14.2 Bipolar Mania - Monotherapy 14.3 Bipolar Mania Combination Therapy 14.4 Irritability Associated with Autistic Disorder 16 HOW SUPPLIED/STORAGE AND HANDLING Storage and Handling 17 PATIENT COUNSELING INFORMATION 17.1 Orthostatic Hypotension 17.2 Interference with Cognitive and Motor Performance 17.3 Pregnancy 17.4 Nursing 17.5 Concomitant Medication 17.6 Alcohol 17.7 Phenylketonurics *Sections or subsections omitted from the full prescribing information are not listed

RISPERDAL (risperidone)

RISPERDAL (risperidone)

FULL PRESCRIBING INFORMATION WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. RISPERDAL (risperidone) is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions (5.1)] 1 INDICATIONS AND USAGE 1.1 Schizophrenia Adults RISPERDAL (risperidone) is indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies (14.1)]. Adolescents RISPERDAL is indicated for the treatment of schizophrenia in adolescents aged 1317 years [see Clinical Studies (14.1)]. 1.2 Bipolar Mania Monotherapy - Adults and Pediatrics RISPERDAL is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults and in children and adolescents aged 10-17 years [see Clinical Studies (14.2)]. Combination Therapy Adults The combination of RISPERDAL with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical Studies (14.3)]. 1.3 Irritability Associated with Autistic Disorder Pediatrics RISPERDAL is indicated for the treatment of irritability associated with autistic disorder in children and adolescents aged 516 years, including symptoms of aggression towards others, deliberate selfinjuriousness, temper tantrums, and quickly changing moods [see Clinical Studies (14.4)]. 2 DOSAGE AND ADMINISTRATION 2.1 Schizophrenia Adults Usual Initial Dose RISPERDAL can be administered once or twice daily. Initial dosing is generally 2 mg/day. Dose increases should then occur at intervals not less than 24 hours, in increments of 1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4-16 mg/day [see Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a 3

single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials. Maintenance Therapy While it is unknown how long a patient with schizophrenia should remain on RISPERDAL, the effectiveness of RISPERDAL 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose. Adolescents The dosage of RISPERDAL should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above 3 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. There are no controlled data to support the longer term use of RISPERDAL beyond 8weeks in adolescents with schizophrenia. The physician who elects to use RISPERDAL for extended periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off RISPERDAL, the initial titration schedule should be followed. Switching From Other Antipsychotics There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to RISPERDAL , or treating patients with concomitant antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others. The period of overlapping antipsychotic administration should be minimized. When switching schizophrenic patients from depot antipsychotics, initiate RISPERDAL therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically. 2.2 Bipolar Mania Usual Dose Adults RISPERDAL should be administered on a once-daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1-6 mg per day [see Clinical Studies (14.2, 14.3)]. RISPERDAL doses higher than 6 mg per day were not studied. Pediatrics The dosage of RISPERDAL should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at

RISPERDAL (risperidone)

RISPERDAL (risperidone)

intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied. Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily. Maintenance Therapy There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with RISPERDAL. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of RISPERDAL in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. 2.3 Irritability Associated with Autistic Disorder Pediatrics (Children and Adolescents) The safety and effectiveness of RISPERDAL in pediatric patients with autistic disorder less than 5 years of age have not been established. The dosage of RISPERDAL should be individualized according to the response and tolerability of the patient. The total daily dose of RISPERDAL can be administered once daily, or half the total daily dose can be administered twice daily. Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for patients 20 kg. After a minimum of four days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for patients 20 kg. This dose should be maintained for a minimum of 14 days. In patients not achieving sufficient clinical response, dose increases may be considered at 2-week intervals in increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients 20 kg. Caution should be exercised with dosage for smaller children who weigh less than 15 kg. In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL between 0.5 mg and 2.5 mg per day. The maximum daily dose of RISPERDAL in one of the pivotal trials, when the therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients 20 kg, or 3mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg. Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient. Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose. 2.4 Dosage in Special Populations The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated, patients with severe renal or hepatic impairment, and patients either predisposed to 4

hypotension or for whom hypotension would pose a risk. Dosage increases in these patients should be in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate. Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate RISPERDAL than normal adults. Patients with impaired hepatic function may have increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)]. Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored [see Warnings and Precautions (5.2, 5.7, 5.17)]. If a once-daily dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing regimen can be done thereafter. 2.5 Co-Administration of RISPERDAL with Certain Other Medications Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with RISPERDAL would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of RISPERDAL treatment. The dose of RISPERDAL needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.11)]. Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of RISPERDAL needs to be titrated accordingly when fluoxetine or paroxetine is co-administered [see Drug Interactions (7.10)]. 2.6 Administration of RISPERDAL Oral Solution RISPERDAL Oral Solution can be administered directly from the calibrated pipette, or can be mixed with a beverage prior to administration. RISPERDAL Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea. 2.7 Directions for Use of RISPERDAL M-TAB Orally Disintegrating Tablets Tablet Accessing RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each. Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet. RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistant pouch containing a blister with 1 tablet each. The child-resistant pouch should be torn open at the notch to access the blister. Do not open the blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push the tablet through the foil, because this could damage the tablet.

RISPERDAL (risperidone)

RISPERDAL (risperidone)

Tablet Administration Using dry hands, remove the tablet from the blister unit and immediately place the entire RISPERDAL M-TAB Orally Disintegrating Tablet on the tongue. The RISPERDAL M-TAB Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. RISPERDAL M-TAB Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet. 3 DOSAGE FORMS AND STRENGTHS RISPERDAL Tablets are available in the following strengths and colors: 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All are capsule shaped, and imprinted with JANSSEN on one side and either Ris 0.25, Ris 0.5, R1, R2, R3, or R4 on the other side according to their respective strengths. RISPERDAL Oral Solution is available in a 1 mg/mL strength. RISPERDAL M-TAB Orally Disintegrating Tablets are available in the following strengths, colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square), 3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with R0.5, R1, R2, R3, or R4 according to their respective strengths. 4 CONTRAINDICATIONS Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Therefore, RISPERDAL is contraindicated in patients with a known hypersensitivity to the product. 5 5.1 WARNINGS AND PRECAUTIONS Increased Mortality in Elderly Patients with DementiaRelated Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning]. Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL is not approved for the treatment of patients with dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)] 5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. 5.2

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both erious s medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of anti sychotic drugs p administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, RISPERDAL should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL despite the presence of the syndrome. 5

RISPERDAL (risperidone)

RISPERDAL (risperidone)

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including RISPERDAL . Assessment of the relationship between atypical anti sychotic use and glucose p abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including RISPERDAL, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including RISPERDAL, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RISPERDAL, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERDAL. Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 1a. Table 1a. Change in Random Glucose from Seven PlaceboControlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania RISPERDAL Placebo 1-8 mg/day >8-16 mg/day Mean change from baseline (mg/dL) n=555 n=748 n=164 Serum Glucose Serum Glucose (<140 mg/dL to 200 mg/dL) -1.4 0.8 0.6 Proportion of patients with shifts 0.6% (3/525) 0.4% (3/702) 0% (0/158) 6

In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50). Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13-17 years of age), bipolar mania (10-17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 1b. Table 1b. Change in Fasting Glucose from Three PlaceboControlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13-17 years of age), Bipolar Mania (10-17 years of age), or Autistic Disorder (5 to 17 years of age) RISPERDAL Placebo 0.5-6 mg/day Mean change from baseline (mg/dL) n=76 n=135 Serum Glucose -1.3 2.6 Proportion of patients with shifts Serum Glucose (<100 mg/dL to 0% 0.8% 126 mg/dL) (0/64) (1/120) In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 2a. Table 2a. Change in Random Lipids From Seven PlaceboControlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania RISPERDAL Placebo 1-8 mg/day >8-16 mg/day Mean change from baseline (mg/dL) Cholesterol n=559 n=742 n=156 Change from baseline 0.6 6.9 1.8 Triglycerides Change from baseline Cholesterol (<200 mg/dL to 240 mg/dL) Triglycerides (<500 mg/dL to 500 mg/dL) n=183 -17.4 n=307 -4.9 n=123 -8.3

Proportion of patients with shifts 2.7% (10/368) 1.1% (2/180) 4.3% (22/516) 2.7% (8/301) 6.3% (6/96) 2.5% (3/121)

In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).

RISPERDAL (risperidone)

RISPERDAL (risperidone)

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13-17 years of age), bipolar mania (10-17 years of age), or autistic disorder (5-17 years of age) are presented in Table 2b. Table 2b. Change in Fasting Lipids From Three PlaceboControlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13-17 Years of Age), Bipolar Mania (10-17 Years of Age), or Autistic Disorder (5 to 17 Years of Age) RISPERDAL Placebo 0.5-6 mg/day Cholesterol Change from baseline LDL Change from baseline HDL Change from baseline Triglycerides Change from baseline Cholesterol (<170 mg/dL to 200 mg/dL) LDL (<110 mg/dL to 130 mg/dL) HDL (40 mg/dL to <40 mg/dL) Triglycerides (<150 mg/dL to 200 mg/dL) Mean change from baseline (mg/dL) n=74 n=133 0.3 -0.3 n=22 3.7 n=22 1.6 n=77 -9.0 n=22 0.5 n=22 -1.9 n=138 -2.6

Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with 7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania RISPERDAL Placebo 1-8 mg/day >8-16 mg/day (n=597) (n=769) (n=158) Weight (kg) Change from -0.3 0.7 2.2 baseline Weight Gain 2.9% 8.7% 20.9% 7% increase from baseline In longer-term, controlled and uncontrolled studies, RISPERDAL was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203). Data on mean changes in body weight and the proportion of subjects meeting the criterion of 7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13-17 years of age), bipolar mania (10-17 years of age), autistic disorder (5-17 years of age), or other psychiatric disorders (5-17 years of age) are presented in Table 3b. Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects With 7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (1317 Years of Age), Bipolar Mania (10-17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5-17 Years of Age) RISPERDAL Placebo 0.5-6 mg/day (n=375) (n=448) Weight (kg) Change from 0.6 2.0 baseline Weight Gain 7% increase from baseline 6.9% 32.6% In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242). In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatmentemergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of RISPERDAL treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index. In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that 7

Proportion of patients with shifts 2.4% (1/42) 0% (0/16) 0% (0/19) 1.5% (1/65) 3.8% (3/80) 0% (0/16) 10% (2/20) 7.1% (8/113)

In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexibledose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 3a.

RISPERDAL (risperidone)

RISPERDAL (risperidone)

increase occurred within the first 6 months of exposure to RISPERDAL. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index. In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL 0.5-2.5 mg group, 1.44 kg in the RISPERDAL 3-6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index. When treating pediatric patients with RISPERDAL for any indication, weight gain should be assessed against that expected with normal growth. 5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, RISPERDAL elevates prolactin levels and the elevation persists during chronic administration. RISPERDAL is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, p ituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor e pidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. 5.7 Orthostatic Hypotension RISPERDAL may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of RISPERDAL-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. RISPERDAL should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of RISPERDAL and antihypertensive medication. 8

5.8 Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including RISPERDAL . Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of druginduced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/ neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERDAL should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERDAL and have their WBC followed until recovery. 5.9 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event associated with RISPERDAL treatment, especially when ascertained by direct questioning of patients. This adverse event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (RISPERDAL 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of RISPERDAL 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event. Since RISPERDAL has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that RISPERDAL therapy does not affect them adversely. 5.10 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of RISPERDAL-treated patients, two in association with hyponatremia. RISPERDAL should be used cautiously in patients with a history of seizures. 5.11 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimers dementia. RISPERDAL and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and Precautions (5.1)] 5.12 Priapism Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.8)]. Severe priapism may require surgical intervention. 5.13 Thrombotic Thrombocytopenic Purpura (TTP) A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to RISPERDAL therapy is unknown. 5.14 Body Temperature Regulation Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

RISPERDAL (risperidone)

RISPERDAL (risperidone)

5.15 Antiemetic Effect Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reyes syndrome, and brain tumor. 5.16 Suicide The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for RISPERDAL should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose. 5.17 Use in Patients with Concomitant Illness Clinical experience with RISPERDAL in patients with certain concomitant systemic illnesses is limited. Patients with Parkinsons Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome. Caution is advisable in using RISPERDAL in patients with diseases or conditions that could affect metabolism or hemodynamic responses. RISPERDAL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies uring the products premarket testing. d Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose should be used in such patients [see Dosage and Administration (2.4)]. 5.18 Monitoring: Laboratory Tests No specific laboratory tests are recommended. 6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: ncreased mortality in elderly patients with dementia-related I psychosis [see Boxed Warning and Warnings and Precautions (5.1)] erebrovascular adverse events, including stroke, in elderly C patients with dementia-related psychosis [see Warnings and Precautions (5.2)] euroleptic malignant syndrome [see Warnings and N Precautions (5.3)] Tardive dyskinesia [see Warnings and Precautions (5.4)] etabolic changes [see Warnings and Precautions (5.5)] M Hyperprolactinemia [see Warnings and Precautions (5.6)] rthostatic hypotension [see Warnings and Precautions O (5.7)] eukopenia, neutropenia, and agranulocytosis [see Warnings L and Precautions (5.8)] otential for cognitive and motor impairment [see Warnings P and Precautions (5.9)] Seizures [see Warnings and Precautions (5.10)] Dysphagia [see Warnings and Precautions (5.11)] Priapism [see Warnings and Precautions (5.12)] 9

hrombotic Thrombocytopenic Purpura (TTP) [see Warnings T and Precautions (5.13)] isruption of body temperature regulation [see Warnings D and Precautions (5.14)] Antiemetic effect [see Warnings and Precautions (5.15)] Suicide [see Warnings and Precautions (5.16)] ncreased sensitivity in patients with Parkinsons disease or I those with dementia with Lewy bodies [see Warnings and Precautions (5.17)] iseases or conditions that could affect metabolism or D hemodynamic responses [see Warnings and Precautions (5.17)] The most common adverse reactions in clinical trials ( 10%) were somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions (6.5)]. The data described in this section are derived from a clinical trial database consisting of 9712 adult and pediatric patients exposed to one or more doses of RISPERDAL for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9712 patients, 2626 were patients who received RISPERDAL while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with RISPERDAL varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of RISPERDAL (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for RISPERDAL often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of all adverse reactions were mild to moderate in severity. 6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia Adult Patients with Schizophrenia Table 4 lists the adverse reactions reported in 1% or more of RISPERDAL-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

RISPERDAL (risperidone)

RISPERDAL (risperidone)

Table 4. Adverse Reactions in 1% of RISPERDAL-Treated Adult Patients with Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event RISPERDAL 2-8 mg >8-16 mg per day per day Placebo (N=366) (N=198) (N=225) <1 1 <1 3 9 8 8 7 4 3 2 2 1 1 1 3 2 2 <1 3 2 1 1 1 1 <1 1 4 2 2 1 14 10 7 7 3 3 2 2 1 1 32 16 1 1 3 1 1 4 9 6 5 0 1 1 1 1 1 1 1 2 1 1 4 3 2 3 1 2 2 0 1 3 1 1 17 10 4 2 4 3 3 0 2 1 25 11 1 0 0 0 1 4 6 5 7 1 1 <1 1 0 0 1 0 1 <1 0 3 1 1 0 0 <1 0 <1 1 <1 1 0 8 3 2 1 2 1 1 0 2 0 27 11 <1 System/Organ Class Adverse Reaction Gastrointestinal Disorders Salivary hypersecretion Nervous System Disorders Parkinsonism* Sedation Somnolence Tremor Akathisia* Dizziness Dystonia* Psychiatric Disorders Anxiety System/Organ Class Adverse Reaction Renal and Urinary Disorders Urinary incontinence Reproductive System and Breast Disorders Ejaculation failure Respiratory, Thoracic and Mediastinal Disorders Nasal congestion Dyspnea Epistaxis Skin and Subcutaneous Tissue Disorders Rash Dry skin Dandruff Seborrheic dermatitis Hyperkeratosis Vascular Disorders Orthostatic hypotension Hypotension

Percentage of Patients Reporting Event RISPERDAL 2-8 mg >8-16 mg per day per day Placebo (N=366) (N=198) (N=225) 1 <1 4 1 <1 1 1 1 <1 0 2 1 1 1 6 2 2 4 3 1 1 1 1 1 0 0 2 0 0 1 0 0 0 1 0 0

System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders Anemia Cardiac Disorders Tachycardia Ear and Labyrinth Disorders Ear pain Eye Disorders Vision blurred Gastrointestinal Disorders Nausea Constipation Dyspepsia Vomiting Dry mouth Abdominal discomfort Salivary hypersecretion Diarrhea Abdominal pain Abdominal pain upper Stomach discomfort General Disorders Fatigue Chest pain Asthenia Immune System Disorders Hypersensitivity Infections and Infestations Nasopharyngitis Upper respiratory tract infection Sinusitis Urinary tract infection Investigations Weight increased lood creatine phosphokinase B increased Heart rate increased Metabolism and Nutrition Disorders Decreased appetite Musculoskeletal and Connective Tissue Disorders Back pain Arthralgia Pain in extremity Joint stiffness Nervous System Disorders Parkinsonism* Akathisia* Dizziness Somnolence Dystonia* Sedation Tremor* Dizziness postural Dyskinesia* Syncope Psychiatric Disorders Insomnia Anxiety Nervousness

*Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinsons disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor. Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis. Pediatric Patients with Schizophrenia Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial. Table 5. Adverse Reactions in 5% of RISPERDAL-Treated Pediatric Patients with Schizophrenia in a DoubleBlind Trial
Percentage of Patients Reporting Event RISPERDAL 4-6 mg 1-3 mg per day Placebo per day (N=51) (N=54) (N=55) 0 16 13 11 11 9 7 2 7 10 28 8 4 10 10 14 6 6 2 11 2 2 6 4 2 0 0

*Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. 10

RISPERDAL (risperidone)

RISPERDAL (risperidone)

6.2

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials Bipolar Mania Adult Patients with Bipolar Mania Table 6 lists the adverse reactions reported in 1% or more of RISPERDAL-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials. Table 6. Adverse Reactions in 1% of RISPERDAL-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials Percentage of Patients Reporting Event RISPERDAL 1-6 mg per day Placebo System/Organ Class (N=448) (N=424) Adverse Reaction Cardiac Disorders Tachycardia 1 <1 Eye Disorders Vision blurred 2 1 Gastrointestinal Disorders Nausea 5 2 Diarrhea 3 2 Salivary hypersecretion 3 1 Dyspepsia 2 2 Stomach discomfort 2 <1 General Disorders Fatigue 2 1 Asthenia 1 1 Pyrexia 1 1 Infections and Infestations Nasopharyngitis 1 1 Investigations Aspartate aminotransferase 1 <1 increased Nervous System Disorders Parkinsonism* 25 9 Akathisia* 9 3 Tremor* 6 3 Dizziness 6 5 Sedation 6 2 Somnolence 5 2 Dystonia* 5 1 Lethargy 2 1 Dyskinesia* 1 <1 Reproductive System and Breast Disorders Galactorrhea 1 0 Skin and Subcutaneous Tissue Disorders Acne 1 0 *Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. Dyskinesia includes muscle twitching and dyskinesia.

Table 7 lists the adverse reactions reported in 2% or more of RISPERDAL-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials. Table 7. Adverse Reactions in 2% of RISPERDAL-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials Percentage of Patients Reporting Event Placebo + RISPERDAL + Mood Stabilizer Mood Stabilizer System/Organ Class (N=127) (N=126) Adverse Reaction Cardiac Disorders Palpitations 2 0 Gastrointestinal Disorders Dyspepsia 9 8 Nausea 6 4 Diarrhea 6 4 Dry mouth 4 4 Vomiting 4 6 Constipation 3 3 Salivary hypersecretion 2 0 General Disorders Chest pain 2 1 Fatigue 2 2 Infections and Infestations Nasopharyngitis 2 3 Urinary tract infection 2 1 Investigations Weight increased 2 2 Nervous System Disorders Parkinsonism* 14 4 Headache 14 15 Akathisia* 8 0 Dizziness 7 2 Sedation 6 3 Tremor 6 2 Somnolence 3 1 Lethargy 2 1 Psychiatric Disorders Insomnia 4 8 Anxiety 3 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 5 2 Cough 2 0 *Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.

11

RISPERDAL (risperidone)

RISPERDAL (risperidone)

Pediatric Patients with Bipolar Mania Table 8 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial. Table 8. Adverse Reactions in 5% of RISPERDAL-Treated Pediatric Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Event RISPERDAL 0.5-2.5 mg 3-6 mg System/Organ Class per day per day Placebo Adverse Reaction (N=50) (N=61) (N=58) Eye Disorders 0 Vision blurred 4 7 Gastrointestinal Disorders 5 Abdominal pain upper 16 13 7 Nausea 16 13 5 Vomiting 10 10 2 Diarrhea 8 7 2 Dyspepsia 10 3 2 Stomach discomfort 6 0 General Disorders 3 Fatigue 18 30 Metabolism and Nutrition Disorders 2 Increased appetite 4 7 Nervous System Disorders 12 Somnolence 22 30 7 Sedation 20 23 5 Dizziness 16 13 3 Parkinsonism* 6 12 0 Dystonia* 6 5 2 Akathisia* 0 8 Psychiatric Disorders 3 Anxiety 0 8 Respiratory, Thoracic and Mediastinal Disorders 5 Pharyngolaryngeal pain 10 3 Skin and Subcutaneous Tissue Disorders 2 Rash 0 7 *Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. 6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder Table 9 lists the adverse reactions reported in 5% or more of RISPERDAL-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials.

Table 9. Adverse Reactions in 5% of RISPERDAL-Treated Pediatric Patients Treated for Irritability Associated with Autistic Disorder in Double-Blind, PlaceboControlled Trials Percentage of Patients Reporting Event RISPERDAL 0.5-4.0 mg per day Placebo System/Organ Class (N=76) (N=80) Adverse Reaction Cardiac Disorders Tachycardia 5 0 Gastrointestinal Disorders Vomiting 25 21 Constipation 21 8 Dry mouth 15 6 Salivary hypersecretion 9 0 Nausea 8 6 General Disorders Fatigue 42 13 Feeling abnormal 5 0 Infections and Infestations Nasopharyngitis 21 10 Rhinitis 13 10 Upper respiratory tract 8 3 infection Investigations Weight increased 5 0 Metabolism and Nutrition Disorders Increased appetite 47 19 Nervous System Disorders Somnolence 49 18 Sedation 29 3 Drooling 16 5 Tremor 12 1 Parkinsonism* 11 1 Dizziness 9 3 Dyskinesia 7 3 Lethargy 5 3 Respiratory, Thoracic and Mediastinal Disorders Cough 24 18 Rhinorrhea 16 13 Nasal congestion 13 5 Skin and Subcutaneous Tissue Disorders Rash 11 8 *Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. In another study with patients treated for irritability associated with autistic disorder, headache (6%), epistaxis (6%) and pyrexia (6%) were also observed in RISPERDAL-treated pediatric subjects.

12

RISPERDAL (risperidone)

RISPERDAL (risperidone)

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the pediatric patients treated with RISPERDAL in the above double-blind, placebo-controlled c linical trial data sets. In addition, the following also includes adverse reactions reported in RISPERDAL-treated patients who participated in other studies, including double-blind, activecontrolled and open-label studies in schizophrenia and bipolar mania studies in pediatric patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder, and studies in elderly patients with dementia. Blood and Lymphatic System Disorders: granulocytopenia, neutropenia Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders: tinnitus Endocrine Disorders: hyperprolactinemia Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness Immune System Disorders: drug hypersensitivity Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, onsillitis, bronchitis, eye infection, t localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia, anorexia Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep disorder, listlessness, libido decreased, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement 13

6.4

Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular Vascular Disorders: flushing Additional Adverse Reactions Reported with RISPERDAL CONSTA The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of RISPERDAL CONSTA, regardless of frequency of occurrence: Cardiac Disorders: bradycardia Ear and Labyrinth Disorders: vertigo Eye Disorders: blepharospasm Gastrointestinal Disorders: toothache, tongue spasm General Disorders and Administration Site Conditions: pain Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess Injury and Poisoning: fall Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain Nervous System Disorders: convulsion, paresthesia Psychiatric Disorders: depression Skin and Subcutaneous Tissue Disorders: eczema Vascular Disorders: hypertension 6.5 Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of RISPERDAL-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more RISPERDAL-treated patients were: Table 10. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Schizophrenia Trials RISPERDAL 2-8 mg/day >8-16 mg/day Placebo Adverse Reaction (N=366) (N=198) (N=225) Dizziness 1.4% 1.0% 0% Nausea 1.4% 0% 0% Vomiting 0.8% 0% 0% Parkinsonism 0.8% 0% 0% Somnolence 0.8% 0% 0% Dystonia 0.5% 0% 0% Agitation 0.5% 0% 0% Abdominal pain 0.5% 0% 0% Orthostatic hypotension 0.3% 0.5% 0% Akathisia 0.3% 2.0% 0%

RISPERDAL (risperidone)

RISPERDAL (risperidone)
Dose Groups Placebo Parkinsonism EPS Incidence 1.2 13% RISPERDAL RISPERDAL RISPERDAL RISPERDAL 2 mg 6 mg 10 mg 16 mg 0.9 17% 1.8 21% 2.4 21% 2.6 35%

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial. Schizophrenia - Pediatrics Approximately 7% (7/106), of RISPERDAL-treated patients discontinued treatment due to an adverse event in a doubleblind, placebo-controlled trial, compared with 4% (2/54) placebotreated patients. The adverse reactions associated with discontinuation for at least one RISPERDAL-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%). Bipolar Mania - Adults In double-blind, placebo-controlled trials with RISPERDAL as monotherapy, approximately 6% (25/448) of RISPERDAL-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in RISPERDAL-treated patients were: Table 11. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL-Treated Adult Patients in Bipolar Mania Clinical Trials RISPERDAL 1-6 mg/day Placebo Adverse Reaction (N=448) (N=424) Parkinsonism 0.4% 0% Lethargy 0.2% 0% Dizziness 0.2% 0% Alanine aminotransferase increased 0.2% 0.2% Aspartate aminotransferase increased 0.2% 0.2% Bipolar Mania - Pediatrics In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL-treated patients iscontinued due to an adverse d event, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one RISPERDAL-treated ediatric patient were nausea (3%), p somnolence (2%), sedation (2%), and vomiting (2%). Autistic Disorder - Pediatrics In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one RISPERDAL-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event. 6.6 Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with RISPERDAL treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of RISPERDAL (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of RISPERDAL (1, 4, 8, 12, and 16 mg/day):
RISPERDAL RISPERDAL RISPERDAL RISPERDAL RISPERDAL Dose Groups 1 mg 4 mg 8 mg 12 mg 16 mg Parkinsonism EPS Incidence 0.6 7% 1.7 12% 2.4 17% 2.9 18% 4.1 20%

Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Other Adverse Reactions Adverse event data elicited by a checklist for side effects from a large study comparing 5fixed doses of RISPERDAL (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration. 6.7 Changes in ECG Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups. In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the RISPERDAL groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes. In a placebo-controlled acute mania trial in children and adolescents (aged 10 17 years), there were no significant changes in ECG parameters, other than the effect of RISPERDAL to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 17 years), there were no clinically meaningful changes in ECG para eters including corrected QT intervals between m treatment groups or within treatment groups over time. 14

RISPERDAL (risperidone)

RISPERDAL (risperidone)

6.8 Postmarketing Experience The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water intoxication. Other adverse events reported since market introduction, which were temporally related to risperidone but not necessarily causally related, include the following: pituitary adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death. 7 DRUG INTERACTIONS 7.1 Centrally-Acting Drugs and Alcohol Given the primary CNS effects of risperidone, caution should be used when RISPERDAL is taken in combination with other centrally-acting drugs and alcohol. 7.2 Drugs with Hypotensive Effects Because of its potential for inducing hypotension, RISPERDAL may enhance the hypotensive effects of other therapeutic agents with this potential. 7.3 Levodopa and Dopamine Agonists RISPERDAL may antagonize the effects of levodopa and dopamine agonists. 7.4 Amitriptyline Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined. 7.5 Cimetidine and Ranitidine Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%. 7.6 Clozapine Chronic administration of clozapine with RISPERDAL may decrease the clearance of risperidone. 7.7 Lithium Repeated oral doses of RISPERDAL (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). 7.8 Valproate Repeated oral doses of RISPERDAL (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of RISPERDAL. 7.9 Digoxin RISPERDAL (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. 15

7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs [see Clinical Pharmacology (12.3)]. Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n70) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made. In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Fluoxetine and Paroxetine Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL . The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied. Erythromycin There were no significant interactions between RISPERDAL and erythromycin. 7.11 Carbamazepine and Other Enzyme Inducers Carbamazepine co-administration decreased the steady-state plasma concentrations of isperidone and 9-hydroxyrisperidone r by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. The dose of RISPERDAL may need to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with RISPERDAL may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL treatment. 7.12 Drugs Metabolized by CYP 2D6 In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, RISPERDAL did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits

RISPERDAL (risperidone)

RISPERDAL (risperidone)

given 0.4 to 6 times the MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as videnced by a decrease in the number of live pups e and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis. Placental transfer of risperidone occurs in rat pups. There are no adequate and well- ontrolled studies in pregnant women. c However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL therapy is unknown. Non-Teratogenic Effects Neonates exposed to antipsychotic drugs (including RISPERDAL) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. RISPERDAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.2 Labor and Delivery The effect of RISPERDAL on labor and delivery in humans is unknown. 8.3 Nursing Mothers In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving RISPERDAL should not breast-feed. 8.4 Pediatric Use The efficacy and safety of RISPERDAL in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical Studies (14.1)]. Additional safety and efficacy information was also assessed in one longterm (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia. Safety and effectiveness of RISPERDAL in children less than 13 years of age with schizophrenia have not been established. 16

The efficacy and safety of RISPERDAL in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)]. Safety and effectiveness of RISPERDAL in children less than 10 years of age with bipolar disorder have not been established. The efficacy and safety of RISPERDAL in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions (6.3) and Clinical Studies (14.4)]. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of RISPERDAL as patients treated for irritability associated with autistic disorder. The safety and effectiveness of RISPERDAL in pediatric patients less than 5 years of age with autistic disorder have not been established. Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with RISPERDAL, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL treatment [see also Warnings and Precautions (5.4)]. Somnolence Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these events were most often of early onset and transient in duration. [See also Adverse Reactions (6.1, 6.2, 6.3)] Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration (2.1, 2.2, 2.3)]. Hyperprolactinemia, Growth, and Sexual Maturation RISPERDAL has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6)]. In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received RISPERDAL had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 8287% of patients who received RISPERDAL had elevated levels of prolactin compared to 37% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications.

RISPERDAL (risperidone)

RISPERDAL (risperidone)

In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of RISPERDAL-treated patients and gynecomastia was reported in 2.3% of RISPERDAL-treated patients. Juvenile dogs were treated for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen, with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period. In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD. The long-term effects of RISPERDAL on growth and sexual maturation have not been fully evaluated in children and adolescents. 8.5 Geriatric Use Clinical studies of RISPERDAL in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4, 2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4)]. Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus RISPERDAL when compared to patients treated with RISPERDAL alone or with placebo plus furosemide. No pathological mechanism has 17

been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of RISPERDAL regardless of concomitant use with furosemide. RISPERDAL is not approved for the treatment of patients with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)] 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance RISPERDAL (risperidone) is not a controlled substance. 9.2 Abuse RISPERDAL has not been systematically studied in animals or humans for its potential for abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of RISPERDAL misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). 9.3 Dependence RISPERDAL has not been systematically studied in animals or humans for its potential for tolerance or physical dependence. 10 OVERDOSAGE 10.1 Human Experience Premarketing experience included eight reports of acute RISPERDAL overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drugs known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience includes reports of acute RISPERDAL overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drugs known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to RISPERDAL overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of RISPERDAL and paroxetine. 10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Because of the rapid disintegration of RISPERDAL M-TAB Orally Disintegrating Tablets, pill fragments may not appear in gastric contents obtained with lavage. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring

RISPERDAL (risperidone)

RISPERDAL (risperidone)

should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alphablocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to RISPERDAL . Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. 11 DESCRIPTION RISPERDAL contains risperidone, a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4Hpyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:

Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl. RISPERDAL Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. RISPERDAL tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn). The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide. The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake. RISPERDAL is also available as a 1 mg/mL oral solution. RISPERDAL Oral Solution contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and purified water. RISPERDAL M-TAB Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg (light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths. RISPERDAL M-TAB Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL M-TAB Orally Disintegrating Tablets contain xanthan gum.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of RISPERDAL, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drugs therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. RISPERDAL is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. RISPERDAL acts as an antagonist at other receptors, but with lower potency. RISPERDAL has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5 M) for cholinergic muscarinic or 1 and 2 adrenergic receptors. 12.2 Pharmacodynamics The clinical effect from RISPERDAL results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the other effects of RISPERDAL. 12.3 Pharmacokinetics Absorption Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution. Pharmacokinetic studies showed that RISPERDAL M-TAB Orally Disintegrating Tablets and RISPERDAL Oral Solution are bioequivalent to RISPERDAL Tablets. Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and isperidone plus 9-hydroxyrisperidone r are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in extensive metabolizers). Food Effect Food does not affect either the rate or extent of absorption of risperidone. Thus, RISPERDAL can be given with or without meals. Distribution Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and 1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxy isperidone r at 50 ng/mL, changes of unknown clinical significance. 18

RISPERDAL (risperidone)

RISPERDAL (risperidone)

Metabolism and Drug Interactions Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are poor metabolizers) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone r apidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers. Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions (7.12)]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperi one in patients receiving quinidine have not been d evaluated, but observations in a odest number (n70) of poor m metabolizers given RISPERDAL do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with RISPERDAL may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions (7.11)]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions 7.12)]. Excretion Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces. The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and m ultiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours. Renal Impairment In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL doses should be reduced in patients with renal disease [see Dosage and Administration (2.4) and Warnings and Precautions (5.17)]. 19

Hepatic Impairment While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and 1-acid glycoprotein. RISPERDAL doses should be reduced in patients with liver disease [see Dosage and Administration (2.4) and Warnings and Precautions (5.17)]. Elderly In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination halflives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [see Dosage and Administration (2.4)]. Pediatric The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight. Race and Gender Effects No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The following table summarizes the multiples of the human dose on a mg/m2 (mg/kg) basis at which these tumors occurred.
Multiples of Maximum Human Dose in mg/m2 (mg/kg) Lowest Highest Sex Effect Level No-Effect Level female 0.75 (9.4) 0.2 (2.4) male female female male male 1.5 (9.4) 0.2 (2.4) 0.4 (2.4) 6.0 (37.5) 1.5 (9.4) 0.4 (2.4) none none 1.5 (9.4) 0.4 (2.4)

Tumor Type Species Pituitary adenomas mouse Endocrine pancreas adenomas rat Mammary gland adenocarcinomas mouse rat rat Mammary gland neoplasm, Total rat

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; h owever, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine

RISPERDAL (risperidone)

RISPERDAL (risperidone)

pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be rolactin-mediated. The relevance for human risk of the p findings of prolactin-mediated endocrine tumors in rodents is unknown [see Warnings and Precautions (5.6)]. Mutagenesis No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test, mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in human lymphocytes or Chinese hamster cells. Impairment of Fertility Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. No no-effect doses were noted in either rat or dog. 14 CLINICAL STUDIES 14.1 Schizophrenia Adults Short-Term Efficacy The efficacy of RISPERDAL in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of g eneral psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed. The results of the trials follow: (1) In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL in doses up to 10 mg/day (twice-daily schedule), RISPERDAL was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS. (2) In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 RISPERDAL groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest 20

RISPERDAL dose groups were generally superior to lacebo on p the PANSS negative subscale. The most consistently positive responses on all easures were seen for the 6 mg dose group, m and there was no suggestion of increased benefit from larger doses. (3) In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest RISPERDAL dose groups were generally superior to the 1 mg RISPERDAL dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group. (4) In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of RISPERDAL (4 and 8 mg/day on a once-daily schedule), both RISPERDAL dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group. Long-Term Efficacy In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to RISPERDAL (2-8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving RISPERDAL experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator. Pediatrics The efficacy of RISPERDAL in the treatment of schizophrenia in adolescents aged 1317 years was demonstrated in two shortterm (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: RISPERDAL 1-3 mg/day (n = 55, mean modal dose = 2.6 mg), RISPERDAL 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the second trial (study #2), patients were randomized to either RISPERDAL 0.15-0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or RISPERDAL 1.56 mg/ day (n = 125, mean modal dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score. Results of the studies demonstrated efficacy of RISPERDAL in all dose groups from 1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the 4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.56 mg/day group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy.

RISPERDAL (risperidone)

RISPERDAL (risperidone)

14.2 Bipolar Mania - Monotherapy Adults The efficacy of RISPERDAL in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV riteria c for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The rimary outcome in p these trials was change from baseline in the YMRS total score. The results of the trials follow: (1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of RISPERDAL 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), RISPERDAL was superior to placebo in the reduction of YMRS total score. (2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), RISPERDAL was superior to placebo in the reduction of YMRS total score. Pediatrics The efficacy of RISPERDAL in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebocontrolled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: RISPERDAL 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg), RISPERDAL 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score. Results of this study demonstrated efficacy of RISPERDAL in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the p rimary parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy. 14.3 Bipolar Mania Combination Therapy The efficacy of RISPERDAL with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course. (1) In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL, placebo, or an active comparator, in 21

combination with their original therapy. RISPERDAL, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score. (2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL or placebo, in combination with their original therapy. RISPERDAL, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone. 14.4 Irritability Associated with Autistic Disorder Short-Term Efficacy The efficacy of RISPERDAL in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16-104.3 kg). Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate selfinjuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies. The results of these trials are as follows: (1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL 0.5-3.5 mg/day on a weight-adjusted basis. RISPERDAL, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo. (2) In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, RISPERDAL 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo. Long-Term Efficacy Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with RISPERDAL for 4 or 6 months (depending on

RISPERDAL (risperidone)

RISPERDAL (risperidone)

whether they received RISPERDAL or placebo in the doubleblind study). During this open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL of 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day). Patients who maintained their positive response to RISPERDAL (response was defined as 25% improvement on the ABC-I subscale and a CGI-C rating of much improved or very much improved) during the 4-6 month open-label treatment phase for about 140 days, on average, were randomized to receive RISPERDAL or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase). 16 HOW SUPPLIED/STORAGE AND HANDLING RISPERDAL (risperidone) Tablets RISPERDAL (risperidone) Tablets are imprinted JANSSEN on one side and either Ris 0.25, Ris 0.5, R1, R2, R3, or R4 according to their respective strengths. 0.25 mg dark yellow, capsule-shaped tablets: bottles of 60 NDC 50458-301-04, bottles of 500 NDC 50458-301-50, and hospital unit dose blister packs of 100 NDC 50458-301-01. 0.5 mg red-brown, capsule-shaped tablets: bottles of 60 NDC 50458-302-06, bottles of 500 NDC 50458-302-50, and hospital unit dose blister packs of 100 NDC 50458-302-01. 1 mg white, capsule-shaped tablets: bottles of 60 NDC 50458300-06, bottles of 500 NDC 50458-300-50, and hospital unit dose blister packs of 100 NDC 50458-300-01. 2 mg orange, capsule-shaped tablets: bottles of 60 NDC 50458320-06, bottles of 500 NDC 50458-320-50, and hospital unit dose blister packs of 100 NDC 50458-320-01. 3 mg yellow, capsule-shaped tablets: bottles of 60 NDC 50458330-06, bottles of 500 NDC 50458-330-50, and hospital unit dose blister packs of 100 NDC 50458-330-01. 4 mg green, capsule-shaped tablets: bottles of 60 NDC 50458-35006 and hospital unit dose blister packs of 100 NDC 50458-350-01. RISPERDAL (risperidone) Oral Solution RISPERDAL (risperidone) 1 mg/mL Oral Solution (NDC 50458305-03) is supplied in 30 mL bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL. RISPERDAL M-TAB (risperidone) Orally Disintegrating Tablets RISPERDAL M-TAB (risperidone) Orally Disintegrating Tablets are etched on one side with R0.5, R1, R2, R3, or R4 according to their respective strengths. RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are packaged in blister packs of 4 (2 X 2) tablets. Orally Disintegrating Tablets 3 mg and 4 mg are packaged in a childresistant pouch containing a blister with 1 tablet.

0.5 mg light coral, round, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-395-28, and long-term care blister packaging of 30 tablets NDC 50458-395-30. 1 mg light coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-315-28, and long-term care blister packaging of 30 tablets NDC 50458-315-30. 2 mg coral, square, biconvex tablets: 7 blister packages (4 tablets each) per box, NDC 50458-325-28. 3 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-335-28. 4 mg coral, round, biconvex tablets: 28 blisters per box, NDC 50458-355-28. Storage and Handling RISPERDAL Tablets should be stored at controlled room temperature 15- 25C (59-77F). Protect from light and moisture. RISPERDAL 1 mg/mL Oral Solution should be stored at controlled room temperature 15-25C (59-77F). Protect from light and freezing. RISPERDAL M-TAB Orally Disintegrating Tablets should be stored at controlled room temperature 15-25C (59-77F). Keep out of reach of children. 17 PATIENT COUNSELING INFORMATION Physicians are advised to discuss the following issues with patients for whom they prescribe RISPERDAL: 17.1 Orthostatic Hypotension Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration [see Warnings and Precautions (5.7)]. 17.2 Interference with Cognitive and Motor Performance Since RISPERDAL has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that RISPERDAL therapy does not affect them adversely [see Warnings and Precautions (5.9)]. 17.3 Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)]. 17.4 Nursing Patients should be advised not to breast-feed an infant if they are taking RISPERDAL [see Use in Specific Populations (8.3)]. 17.5 Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)]. 17.6 Alcohol Patients should be advised to avoid alcohol while taking RISPERDAL [see Drug Interactions (7.1)].

22

RISPERDAL (risperidone)

17.7 Phenylketonurics Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.14 mg phenylalanine. Revised September 2011 Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2007 RISPERDAL Tablets are manufactured by: Janssen Ortho LLC, Gurabo, Puerto Rico 00778 RISPERDAL Oral Solution is manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium RISPERDAL M-TAB Orally Disintegrating Tablets are manufactured by: Janssen Ortho LLC, Gurabo, Puerto Rico 00778 RISPERDAL Tablets, RISPERDAL M-TAB Orally Disintegrating Tablets, and RISPERDAL Oral Solution are manufactured for: Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

01RS11003

23

SPORANOX (itraconazole) Capsules


The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 185 liters. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.) Special Populations: Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. x 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this patient population. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.) Hepatic Insufficiency: Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100-mg capsule dose of itraconazole was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 17 hours vs. 16 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of itraconazole. (See BOX WARNING, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.) Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX Capsules, SPORANOX should be discontinued. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) MICROBIOLOGY Mechanism of Action: In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes. Activity In Vitro and In Vivo: Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei, and other Candida species. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum, Blastomyces dermatitidis, Zygomycete, Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents. Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum, and Trichophyton mentagrophytes. Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species. Resistance: Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14 C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown. INDICATIONS AND USAGE SPORANOX (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1. Blastomycosis, pulmonary and extrapulmonary 2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and 3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies: Blastomycosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Congestive Heart Failure: SPORANOX (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of SPORANOX Capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.) Drug Interactions: Coadministration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol (levomethadyl) with SPORANOX (itraconazole) Capsules, Injection or Oral Solution is contraindicated. SPORANOX, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine, concomitantly with SPORANOX and/or other CYP3A4 inhibitors. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information. DESCRIPTION SPORANOX is the brand name for itraconazole, a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature:

()-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy]phenyl]-1-piperazinyl]phenyl]- 2-1,2,4-triazolin-5-one mixture with ()-1-[(R*)-sec-butyl]-4-[p-[4-[p[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl] phenyl]-2-1,2,4-triazolin-5-one or ()-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy]phenyl]-1-piperazinyl]phenyl]-2-1,2,4-triazolin-5-one Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1. SPORANOX Capsules contain 100 mg of itraconazole coated on sugar spheres. Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, starch, sucrose, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.) The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%. The oral bioavailability of itraconazole is maximal when SPORANOX (itraconazole) Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below: 50 mg (fed) 45 16* 3.2 1.3 567 264 100 mg (fed) 132 67 4.0 1.1 1899 838 100 mg (fasted) 38 20 3.3 1.0 722 289 200 mg (fed) 289 100 4.7 1.4 5211 2116

Cmax (ng/mL) Tmax (hours) AUC0 - (ng.h/mL)

* mean standard deviation Doubling the SPORANOX dose results in approximately a three-fold increase in the itraconazole plasma concentrations. Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX Capsules with or without a full meal: Hydroxyitraconazole Fed Fasted Cmax (ng/mL) 397 103 286 101 Tmax (hours) 5.1 1.6 4.5 1.1 AUC0 - (ng.h/mL) 7978 2648 5191 2489 t1/2 (hours) 12 3 12 3 * mean standard deviation Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX Capsules were administered with a cola beverage. Eighteen men with AIDS received single 200-mg doses of SPORANOX Capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when SPORANOX Capsules were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% 121% and 95% 128%, respectively. Thirty healthy men received single 200-mg doses of SPORANOX Capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when SPORANOX Capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% 37% and 42% 39%, respectively. When SPORANOX Capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when SPORANOX Capsules were administered alone. (See PRECAUTIONS: Drug Interactions.) Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX Capsules b.i.d. (with a full meal) for 15 days: Cmax (ng/mL) Cmin (ng/mL) Tmax (hours) AUC0-12h (ng.h/mL) t1/2 (hours) Itraconazole 2282 514* 1855 535 4.6 1.8 22569 5375 64 32 Hydroxyitraconazole 3488 742 3349 761 3.4 3.4 38572 8450 56 24 * mean standard deviation Itraconazole Fed Fasted 239 85* 140 65 4.5 1.1 3.9 1.0 3423 1154 2094 905 21 5 21 7

SPORANOX (itraconazole) Capsules


Histoplasmosis: Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients: Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis: Analyses were conducted on data from an open-label, single-patient-use protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail: Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX Capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive). Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX Capsules b.i.d., followed by a 3-week period without SPORANOX, which was followed by a second 1-week pulse of 200 mg of SPORANOX Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed. CONTRAINDICATIONS Congestive Heart Failure: SPORANOX (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.) Drug Interactions: Concomitant administration of SPORANOX (itraconazole) Capsules, Injection, or Oral Solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with SPORANOX. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with SPORANOX. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with SPORANOX. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.) SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX to patients with hypersensitivity to other azoles. WARNINGS SPORANOX (itraconazole) Capsules and SPORANOX Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Hepatic Effects: SPORANOX has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX use or reinstitution of treatment with SPORANOX is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with SPORANOX and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: SPORANOX Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. SPORANOX Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of SPORANOX Capsules, discontinue administration. Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. SPORANOX has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX and nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.) PRECAUTIONS General: SPORANOX (itraconazole) Capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.) Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.)

SPORANOX (itraconazole) Capsules


Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with SPORANOX treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving SPORANOX. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy: If neuropathy occurs that may be attributable to SPORANOX Capsules, the treatment should be discontinued. Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions; CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients: The topical effects of mucosal exposure may be different between the SPORANOX Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX Capsules should not be used interchangeably with SPORANOX Oral Solution. Instruct patients to take SPORANOX Capsules with a full meal. Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX administration, they should discontinue SPORANOX and contact their healthcare provider immediately. Instruct patients to stop SPORANOX treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. Drug Interactions: Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (see Table 1 below and the following drug class subheadings that follow): 1. SPORANOX may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX . These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. 2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX may not be effective in patients concomitantly taking SPORANOX and one of these drugs. Therefore, administration of these drugs with SPORANOX is not recommended. 3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX. Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX 1 Drug plasma concentration increased by itraconazole Antiarrhythmics digoxin, dofetilide,2 quinidine,2 disopyramide Anticonvulsants carbamazepine Antimycobacterials rifabutin Antineoplastics busulfan, docetaxel, vinca alkaloids Antipsychotics pimozide2 Benzodiazepines alprazolam, diazepam, midazolam,2,3 triazolam2 Calcium Channel Blockers dihydropyridines (including nisoldipine 2 ), verapamil Gastrointestinal Motility Agents cisapride2 HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2 Immunosuppressants cyclosporine, tacrolimus, sirolimus Oral Hypoglycemics oral hypoglycemics Protease Inhibitors indinavir, ritonavir, saquinavir Other levacetylmethadol (levomethadyl),2 ergot alkaloids,2 halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl Decrease plasma concentration of itraconazole Anticonvulsants carbamazepine, phenobarbital, phenytoin Antimycobacterials isoniazid, rifabutin, rifampin Gastric Acid Suppressors/Neutralizers antacids, H2-receptor antagonists, proton pump inhibitors Non-nucleoside Reverse Transcriptase nevirapine Inhibitors Increase plasma concentration of itraconazole Macrolide Antibiotics clarithromycin, erythromycin Protease Inhibitors indinavir, ritonavir
1 This

list is not all-inclusive. with SPORANOX based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.) 3 For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.
2 Contraindicated

Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX and disopyramide are administered concomitantly. Concomitant administration of digoxin and SPORANOX has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein. Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant

SPORANOX (itraconazole) Capsules


administration of SPORANOX and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and carbamazepine may inhibit the metabolism of carbamazepine. Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended. Antineoplastics: SPORANOX may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) Benzodiazepines: Concomitant administration of SPORANOX and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged. Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary. Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction, therefore the concomitant administration of SPORANOX and nisoldipine is contraindicated. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information). Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX Capsules. In a clinical study, when SPORANOX Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced. Gastrointestinal Motility Agents: Coadministration of SPORANOX with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.) HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) Immunosuppressants: Concomitant administration of SPORANOX and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX and sirolimus could increase plasma concentrations of sirolimus. Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC0 - of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively. Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied. Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX and oral hypoglycemic agents are coadministered. Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined. Protease Inhibitors: Concomitant administration of SPORANOX and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX and protease inhibitors must be given concomitantly. Other: Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX and levacetylmethadol is contraindicated. Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX is contraindicated. Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX and halofantrine are administered concomitantly. In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX may increase plasma concentrations of alfentanil. Human pharmacokinetic data suggest that concomitant administration of SPORANOX and buspirone results in significant increases in plasma concentrations of buspirone. SPORANOX may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone. In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX and trimetrexate may inhibit the metabolism of trimetrexate. SPORANOX enhances the anticoagulant effect of coumarin-like drugs, such as warfarin. Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX. Fentanyl plasma concentrations could be increased or prolonged by concomitant use of SPORANOX and may cause potentially fatal respiratory depression. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.

SPORANOX (itraconazole) Capsules


Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T 1/2 C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats. Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD). Pregnancy: Teratogenic effects. Pregnancy Category C: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (5-20x MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout SPORANOX therapy and for 2 months following the end of treatment. During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-marketing Experience.) Nursing Mothers: Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants. Pediatric Use: The efficacy and safety of SPORANOX have not been established in pediatric patients. No pharmacokinetic data on SPORANOX Capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. SPORANOX Oral Solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported. The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients. Geriatric Use: Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). Itraconazole should be used with care in elderly patients (see PRECAUTIONS). HIV-Infected Patients: Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased. Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS SPORANOX has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients. Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% Body System/Adverse Event Gastrointestinal Nausea Vomiting Diarrhea Abdominal Pain Anorexia Body as a Whole Edema Fatigue Fever Malaise Skin and Appendages Rash* Pruritus Central/Peripheral Nervous System Headache Dizziness Psychiatric Libido Decreased Somnolence Cardiovascular Hypertension Metabolic/Nutritional Hypokalemia Urinary System Albuminuria Liver and Biliary System Hepatic Function Abnormal Reproductive System, Male Impotence Incidence (%) (N=602) 11 5 3 2 1 4 3 3 1 9 3 4 2 1 1 3 2 1 3 1

*Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications.

SPORANOX (itraconazole) Capsules


Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain. Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Elevated Liver Enzymes (greater than twice the upper limit of normal) Gastrointestinal Disorders Rash Hypertension Orthostatic Hypotension Headache Malaise Myalgia Vasculitis Vertigo Incidence (%) Itraconazole (N=112) 4 4 3 2 1 1 1 1 1 1

SPORANOX (itraconazole) Capsules


Treatment of Blastomycosis and Histoplasmosis: The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis: A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations: In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously. IV Injection: the recommended intravenous dose is 200 mg b.i.d. for four consecutive doses, followed by 200 mg once daily thereafter. Each intravenous dose should be infused over 1 hour. The safety and efficacy of SPORANOX Injection administered for greater than 14 days is not known. See complete prescribing information for SPORANOX (itraconazole) Injection. Capsules: although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX Capsules and SPORANOX Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis: Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis: Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS for further information.) Use in Patients with Hepatic Impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.) HOW SUPPLIED SPORANOX (itraconazole) Capsules are available containing 100 mg of itraconazole, with a blue opaque cap and pink transparent body, imprinted with JANSSEN and SPORANOX 100. The capsules are supplied in unit-dose blister packs of 3 x 10 capsules (NDC 50458-290-01), bottles of 30 capsules (NDC 50458-290-04) and in the PulsePak containing 7 blister packs x 4 capsules each (NDC 50458-290-28). Store at controlled room temperature 15-25C (59-77F). Protect from light and moisture. Keep out of reach of children. Janssen 2001 U.S. Patent Nos. 4,267,179; 5,633,015 Capsule contents manufactured by: Janssen Pharmaceutica N.V. Olen, Belgium Manufactured by: JOLLC, Gurabo, Puerto Rico 00778 Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 7501627 Revised March 2009

The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%. Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Rash/Pruritus Hypertriglyceridemia Incidence (%) Itraconazole (N=37) 3 3

The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%. Post-marketing Experience Adverse drug reactions that have been identified during post-approval use of SPORANOX (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Postmarketing Reports of Adverse Drug Reactions Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia Immune system disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Metabolism and nutrition disorders: Hypertriglyceridemia, hypokalemia Nervous system disorders: Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness Eye disorders: Visual disturbances, including vision blurred and diplopia Ear and labyrinth disorders: Transient or permanent hearing loss, tinnitus Cardiac disorders: Congestive heart failure Respiratory, thoracic and mediastinal disorders: Pulmonary edema Gastrointestinal disorders: Abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia Hepato-biliary disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus Musculoskeletal and connective tissue disorders: Myalgia, arthralgia Renal and urinary disorders: Urinary incontinence, pollakiuria Reproductive system and breast disorders: Menstrual disorders, erectile dysfunction General disorders and administration site conditions: Peripheral edema There is limited information on the use of SPORANOX during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.) OVERDOSAGE Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of SPORANOX (itraconazole) Oral Solution or up to 3000 mg of SPORANOX (itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses. DOSAGE AND ADMINISTRATION SPORANOX (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX Capsules is a different preparation than SPORANOX Oral Solution and should not be used interchangeably.

Replace with April 2012 version

V AGINAL CREAM

0.4% 0.8% 80mg

V AGINAL CREAM

INDICATIONS AND USAGE TERAZOL 7 (terconazole) Vaginal Cream 0.4%, TERAZOL 3 (terconazole) Vaginal Cream 0.8% and TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal candidiasis (moniliasis). As these products are effective only for vulvovaginitis caused by the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures. CONTRAINDICATIONS Patients known to be hypersensitive to terconazole or to any of the components of the cream or suppositories. WARNINGS None. PRECAUTIONS General: Discontinue use and do not retreat with terconazole if sensitization, irritation, fever, chills or flu-like symptoms are reported during use. The base contained in the suppository formulation may interact with certain rubber or latex products, such as those used in vaginal contraceptive diaphragms; therefore concurrent use is not recommended. Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic studies (standard KOH smear and/or cultures) should be repeated to confirm the diagnosis and rule out other pathogens. Drug Interactions: TERAZOL 7 (terconazole) Vaginal Cream 0.4% and TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg: The therapeutic effect of these products is not affected by oral contraceptive usage. TERAZOL 3 (terconazole) Vaginal Cream 0.8%: The levels of estradiol (E2) and progesterone did not differ significantly when 0.8% terconazole vaginal cream was administered to healthy female volunteers established on a low dose oral contraceptive. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not been performed. Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ cells. Impairment of Fertility: No impairment of fertility occurred when female rats were administered terconazole orally up to 40 mg/kg/day for a three month period. Pregnancy: Teratogenic Effects: Pregnancy Category C. There was no evidence of teratogenicity when terconazole was administered orally up to 40 mg/kg/day (25x the recommended intravaginal human dose of the suppository formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in rats. Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease in litter size and number of viable young and reduced fetal weight. There was also delay in ossification and an increased incidence of skeletal variants. The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level (0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole 0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after intravaginal administration of terconazole 80 mg vaginal suppository. This safety assessment does not account for possible exposure of the fetus through direct transfer to terconazole from the irritated vagina by diffusion across amniotic membranes. Since terconazole is absorbed from the human vagina, it should not be used in the first trimester of pregnancy unless the physician considers it essential to the welfare of the patient. Nursing Mothers: It is not known whether this drug is excreted in human milk. Animal studies have shown that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed decreased survival during the first few post-partum days, but overall pup weight and weight gain were comparable to or greater than controls throughout lactation. Because many drugs are excreted in human milk, and because of the potential for adverse reaction in nursing infants from terconazole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and efficacy in children have not been established.

V AGINAL SUPPOSITORIES

DESCRIPTION TERAZOL 7 (terconazole) Vaginal Cream 0.4% is a white to off-white, water washable cream for intravaginal administration containing 0.4% of the antifungal agent terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water. TERAZOL 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable cream for intravaginal administration containing 0.8% of the antifungal agent terconazole, cis-1-[p- [[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water. TERAZOL 3 (terconazole) Vaginal Suppositories are white to off-white suppositories for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole. The structural formula of terconazole is as follows:

TERCONAZOLE

Terconazole, a triazole derivative, is a white to almost white powder with a molecular weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in butanol. CLINICAL PHARMACOLOGY Following intravaginal administration of terconazole in humans, absorption ranged from 5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects with tubal ligations. Following daily intravaginal administration of 0.8% terconazole 40 mg (0.8% cream x 5 g) for seven days to normal humans, plasma concentrations were low and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours. Results from similar studies in patients with vulvovaginal candidiasis indicate that the slow rate of absorption, the lack of accumulation, and the mean peak plasma concentration of terconazole was not different from that observed in healthy women. The absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with vulvovaginal candidiasis were also similar to those found in normal volunteers. Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3). Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both by renal (32-56%) and fecal (47-52%) routes. In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is independent of drug concentration. Photosensitivity reactions were observed in some normal volunteers following repeated dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered artificial ultraviolet light. Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in patients who were treated with terconazole suppositories or vaginal cream (0.4% and 0.8%). Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida albicans. Antifungal activity has also been demonstrated against other fungi. The MIC values of terconazole against most Lactobacillus spp. typically found in the human vagina were >128 mcg/mL; therefore these beneficial bacteria are _ not affected by drug treatment. The exact pharmacologic mode of action of terconazole is uncertain; however, it may exert its antifungal activity by the disruption of normal fungal cell membrane permeability. No resistance to terconazole has developed during successive passages of C. albicans.

Geriatric Use: Clinical studies of TERAZOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ADVERSE REACTIONS TERAZOL 7 (terconazole) Vaginal Cream 0.4%: During controlled clinical studies conducted in the United States, 521 patients with vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on comparative analyses with placebo, the adverse experiences considered most likely related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo) and body pain (2.1% vs. 0% with placebo). Vulvovaginal burning (5.2%), itching (2.3%) or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0% with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The adverse drug experience on terconazole most frequently causing discontinuation was vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%). TERAZOL 3 (terconazole) Vaginal Cream 0.8%: During controlled clinical studies conducted in the United States, patients with vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three days. Based on comparative analyses with placebo and a standard agent, the adverse experiences considered most likely related to terconazole 0.8% vaginal cream were headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo). Genital complaints in general, and burning and itching in particular, occurred less frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% with placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. The adverse drug experience most frequently causing discontinuation of therapy was vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3% with the placebo group. TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg: During controlled clinical studies conducted in the United States, 284 patients with vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories. Based on comparative analyses with placebo (295 patients), the adverse experiences considered adverse reactions most likely related to terconazole 80 mg vaginal suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that were reported but were not statistically significantly different from placebo were burning (15.2% vs. 11.2% with placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% vs. 1.4% with placebo) and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The adverse drug experience on terconazole most frequently causing discontinuation was burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs. 1.4% with placebo). OVERDOSAGE Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD 50 values were found to be 1741 and 849 mg/kg for the male and female, respectively. The oral LD 50 values for the male and female dog were 1280 and 640 mg/kg, respectively. DOSAGE AND ADMINISTRATION TERAZOL 7 (terconazole) Vaginal Cream 0.4%: One full applicator (5 g) of TERAZOL 7 Vaginal Cream (20 mg terconazole) should be administered intravaginally once daily at bedtime for seven consecutive days. TERAZOL 3 (terconazole) Vaginal Cream 0.8%: One full applicator (5 g) of TERAZOL 3 Vaginal Cream (40 mg terconazole) should be administered intravaginally once daily at bedtime for three consecutive days. TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg: One TERAZOL 3 Vaginal Suppository (80 mg terconazole) should be administered intravaginally once daily at bedtime for three consecutive days. Before prescribing another course of therapy, the diagnosis should be reconfirmed by smears and/or cultures and other pathogens commonly associated with vulvovaginitis ruled out. The therapeutic effect of these products is not affected by menstruation. HOW SUPPLIED TERAZOL 7 (terconazole) Vaginal Cream 0.4% is available in 45g (NDC 0062-5350-01) tubes with an ORTHO* Measured-Dose Applicator. Store at Controlled Room Temperature 15-30C (59-86F). TERAZOL 3 (terconazole) Vaginal Cream 0.8% is available in 20g (NDC 0062-5356-01) tubes with an ORTHO* Measured-Dose Applicator. Store at Controlled Room Temperature 15-30C (59-86F). TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5g, elliptically-shaped white to off-white suppositories in packages of three (NDC 0062-5351-01) with a vaginal applicator. Store at Controlled Room Temperature 15-30C (59-86F). *Trademark

V AGINAL CREAM

0.4% 0.8%

V AGINAL CREAM

PATIENT INSTRUCTIONS
Filling the applicator: 1. Remove the cap from the tube. 2. Use the pointed tip on the top of the cap to puncture the seal on the tube. 3. Screw the applicator onto the tube. 4. Squeeze the tube from the bottom and fill the applicator until the plunger stops. 5. Unscrew the applicator from the tube. Using the applicator: 1. Lie on your back with your knees drawn up toward your chest. 2. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into the vagina as far as it will comfortably go. 3. Slowly press the plunger of the applicator to release the cream into the vagina. 4. Remove the applicator from the vagina. 5. Apply one applicatorful each night for as many days at bedtime, as directed by your doctor. Cleaning the applicator: (Does not apply to sample applicators, which are for one time use only) After each use, you should thoroughly clean the applicator by following the procedure below: 1. Pull the plunger out of the barrel. 2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly. 3. Put the applicator back together by gently pushing the plunger into the barrel as far as it will go.

NOTE: Store the cream at Controlled Room Temperature 15-30C (59-86F). See end flap for lot number and expiration date.

V AGINAL SUPPOSITORIES

80mg

Three oval suppositories, for use inside the vagina only. Designed to be inserted into the vagina.

HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or without the applicator. A. Insertion with the applicator 1. Filling the applicator Break off suppository from the plastic strip. Pull the plastic completely apart at the notched end. Place the flat end of the suppository into the open end of the applicator as shown. You are now ready to insert the suppository into the vagina. 2. Using the applicator Lie on your back with your knees drawn up toward your chest. Holding the applicator by the ribbed end of the barrel, gently insert it into the vagina as far as it will comfortably go. Press the plunger to release the suppository into the vagina. Remove the applicator from the vagina.

3. Cleaning the applicator (Does not apply to sample applicators, which are for one time use only) After each use, you should thoroughly clean the applicator by following the procedure below: Pull the plunger out of the barrel. Wash both pieces with lukewarm, soapy water, and dry them thoroughly. Put the applicator back together by gently pushing the plunger into the barrel as far as it will go. B. Insertion without the applicator Lie on your back with your knees drawn up toward your chest. Place the suppository on the tip of your finger as shown. Insert the suppository gently into the vagina as far as it will comfortably go. NOTE: Store the suppositories at Controlled Room Temperature 15-30C (59-86F). See end flap for lot number and expiration date.

9. Discuss with your physician any medication you are already taking. Certain types of medication can make your vagina more susceptible to infection. 10. Eat nutritious meals to promote your general health.

Manufactured by: Janssen Ortho, LLC Manati, Puerto Rico 00674 (for the Vaginal Cream) Draxis Specialty Pharmaceuticals Inc., Kirkland, Quebec, Canada H9H 4J4 (for the Vaginal Cream and Vaginal Suppositories) Manufactured for: Ortho Womens Health & Urology, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869

A WORD ABOUT YEAST INFECTIONS


Why do yeast infections occur? Yeast infections are caused by an organism called Candida (KAN di duh). It may be present in small and harmless amounts in the mouth, digestive tract, and vagina. Sometimes the natural balance of the vagina becomes upset. This may lead to rapid growth of Candida, which results in a yeast infection. Symptoms of a yeast infection include itching, burning, redness, and an abnormal discharge. Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms and looking at a sample of the discharge under the microscope. How can I prevent yeast infections? Certain factors may increase your chance of developing a yeast infection. These factors dont actually cause the problem, but they may create a situation that allows the yeast to grow rapidly. Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in heat and moisture (two conditions in which yeast organisms thrive). Looser pants or skirts, 100% cotton underwear, and stockings may help avoid this problem. Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce the risk of yeast infections. Antibiotics: Antibiotics work by eliminating disease-causing organisms. While they are helpful in curing other problems, antibiotics may lead to an overgrowth of Candida in the vagina. Pregnancy: Hormonal changes in the body during pregnancy encourage the growth of yeast. This is a very common time for an infection to occur. Until the baby is born, it may be hard to completely eliminate yeast infections. If you believe you are pregnant, tell your doctor. Menstruation: Sometimes monthly changes in hormone levels may lead to yeast infections. Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics often have sugar in their urine, their vaginas are rich in this substance. Careful control of diabetes may help prevent yeast infection. Controlling these factors can help eliminate yeast infections and may prevent them from coming back. Some other helpful tips: 1. For best results, be sure to use the medication as prescribed by your doctor, even if you feel better quickly. 2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository formulation (not the cream) may damage the diaphragm. Therefore, use of the diaphragm during therapy with the suppository is not recommended. Consult your physician. 3. If your partner has any penile itching, redness, or discomfort, he should consult his physician and mention that you are being treated for a yeast infection. 4. You can use the medication even if you are having your menstrual period. However, you should not use tampons because they may absorb the medication. Instead, use external pads or napkins until you have finished your medication. You may also wish to wear a sanitary napkin if the vaginal medication leaks. 5. Dry the genital area thoroughly after showering, bathing, or swimming. Change out of a wet bathing suit or damp exercise clothes as soon as possible. A dry environment is less likely to encourage the growth of yeast. 6. Wipe from front to rear (away from the vagina) after a bowel movement. 7. Dont douche unless your doctor specifically tells you to do so. Douching may disturb the vaginal balance. 8. Dont scratch if you can help it. Scratching can cause more irritation and spread the infection.
Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998 Revised July 2010 10194300

TYLENOL with Codeine


(acetaminophen and codeine phosphate) tablets
HEPATOTOXICITY Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product (see WARNINGS). DESCRIPTION TYLENOL with Codeine is supplied in tablet form for oral administration. Acetaminophen, 4-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

C
III

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue TYLENOL with Codeine immediately and seek medical care if they experience these symptoms. Do not prescribe TYLENOL with Codeine for patients with acetaminophen allergy. Head Injuries In the presence of head injury or other intracranial lesions, the respiratory-depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS-depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries. Acute Abdominal Conditions Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions. Abuse Potential Codeine is habit forming and potentially abusable. Consequently, the extended use of this product is not recommended.

C8 H9 NO2 M.W. 151.16 Codeine phosphate, 7,8-didehydro-4, 5-epoxy-3-methoxy-17-methylmorphinan-6-ol phosphate (1:1) (salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the following structural formula:

Sulfite Sensitivity TYLENOL with Codeine (acetaminophen and codeine phosphate) Tablets contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. PRECAUTIONS General TYLENOL with Codeine (acetaminophen and codeine phosphate) Tablets should be prescribed with caution in certain special-risk patients, such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addisons disease, or prostatic hypertrophy. Ultra-Rapid Metabolizers of Codeine Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5% to 1% in Chinese and Japanese, 0.5% to 1% in Hispanics, 1% to 10% in Caucasians, 3% in African Americans, and 16% to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and inform their patients about these risks and the signs of morphine overdose (see PRECAUTIONS Nursing Mothers). Information for Patients/Caregivers Do not take TYLENOL with Codeine if you are allergic to any of its ingredients. If you develop signs of allergy such as a rash or difficulty breathing, stop taking TYLENOL with Codeine and contact your healthcare provider immediately. Do not take more than 4,000 milligrams of acetaminophen per day. Call your healthcare provider if you took more than the recommended dose. Codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Avoid such tasks while taking this product. Alcohol and other CNS depressants may produce an additive CNS depression when taken with this combination product. Avoid drinking alcohol or taking other CNS depressants when you are taking Tylenol with Codeine. Codeine may be habit forming. Take this drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed. Some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine, which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to lifethreatening or fatal side effects in nursing babies. If you are a nursing mother, watch for signs of morphine toxicity in your infant, including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Talk to your babys doctor immediately if you notice these signs. If you cannot reach the doctor right away, take your baby to an emergency room or call 911 (or local emergency services). Laboratory Tests In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests. Drug Interactions This drug may enhance the effects of other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression. Drug/Laboratory Test Interactions Codeine may increase serum amylase levels. Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid. Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether acetaminophen and codeine have a potential for carcinogenesis or mutagenesis. No adequate studies have been conducted in animals to determine whether acetaminophen has a potential for impairment of fertility.

C18H21NO3H3PO41/2 H2O M.W. 406.37 Each tablet contains: Acetaminophen ................................................................................................. 300 mg No. 3 Codeine Phosphate.......................................................................................30 mg (Warning: May be habit forming) Acetaminophen ................................................................................................. 300 mg No. 4 Codeine Phosphate.......................................................................................60 mg (Warning: May be habit forming) In addition, each tablet contains the following inactive ingredients: TYLENOL with Codeine No. 3 contains powdered cellulose, magnesium stearate, sodium metabisulfite*, pregelatinized starch (corn), and modified starch (corn). TYLENOL with Codeine No. 4 contains powdered cellulose, magnesium stearate, sodium metabisulfite*, pregelatinized starch (corn), and corn starch. * See WARNINGS CLINICAL PHARMACOLOGY This product combines the analgesic effects of a centrally acting analgesic, codeine, with a peripherally acting analgesic, acetaminophen. Pharmacokinetics The behavior of the individual components is described below. Codeine Codeine is rapidly absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues. The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Acetaminophen Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. INDICATIONS AND USAGE TYLENOL with Codeine (acetaminophen and codeine phosphate) Tablets are indicated for the relief of mild to moderately severe pain. CONTRAINDICATIONS This product should not be administered to patients who have previously exhibited hypersensitivity to codeine or acetaminophen. WARNINGS Hepatotoxicity Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products (see Boxed Warning).

Acetaminophen and codeine have been found to have no mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow. Pregnancy Teratogenic Effects: Pregnancy Category C. Codeine A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100 mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring. There are no adequate and well-controlled studies in pregnant women. TYLENOL with Codeine (acetaminophen and codeine phosphate) Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. These signs usually appear during the first few days of life. Labor and Delivery Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). The effect of codeine, if any, on the later growth, development, and functional maturation of the child is unknown. Nursing Mothers Acetaminophen is excreted in breast milk in small amounts, but the significance of its effect on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from acetaminophen, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeines active metabolite, morphine, leading to higherthan-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5% to 1% in Chinese and Japanese, 0.5% to 1% in Hispanics, 1% to 10% in Caucasians, 3% in African Americans, and 16% to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine-containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding (see PRECAUTIONS General, Ultra-Rapid Metabolizers of Codeine). ADVERSE REACTIONS The most frequently observed adverse reactions include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis. At higher doses, codeine has most of the disadvantages of morphine including respiratory depression. DRUG ABUSE AND DEPENDENCE Controlled Substance TYLENOL with Codeine (acetaminophen and codeine phosphate) Tablets are classified as a Schedule III controlled substance. Abuse and Dependence Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications. OVERDOSAGE Following an acute overdosage, toxicity may result from codeine or acetaminophen. Signs and Symptoms Toxicity from codeine poisoning includes the opioid triad of pinpoint pupils, depression of respiration, and loss of consciousness. Convulsions may occur. In acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment A single or multiple drug overdose with acetaminophen and codeine is a potentially lethal polydrug overdose and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 or more hours after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to severity of pain and response of the patient. The usual adult dosage is: Single Doses Maximum (Range) 24-Hour Dose ______________ ____________ Codeine Phosphate 15 mg to 60 mg 360 mg Acetaminophen 300 mg to 1,000 mg 4,000 mg Doses may be repeated up to every 4 hours. The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours, based upon the above dosage guidance. This information should be conveyed in the prescription. It should be kept in mind, however, that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects. HOW SUPPLIED TYLENOL with Codeine (acetaminophen and codeine phosphate) Tablets are white, round, flatfaced, beveled-edged tablet, imprinted McNEIL on one side and TYLENOL CODEINE and either 3 or 4 on the other side and are supplied as follows: TYLENOL with Codeine No. 3 bottle of 100 tablets NDC 50458-513-60 TYLENOL with Codeine No. 3 bottle of 1000 tablets NDC 50458-513-80 TYLENOL with Codeine No. 4 bottle of 100 tablets NDC 50458-515-60 TYLENOL with Codeine No. 4 bottle of 500 tablets NDC 50458-515-70 Store TYLENOL with Codeine Tablets at 20 to 25C (68 to 77F). (See USP Controlled Room Temperature.) Dispense in tight, light-resistant container as defined in the official compendium. Manufactured by: Janssen Ortho, LLC Gurabo, Puerto Rico 00778

Manufactured for: PriCara Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869 Revised September 2011 Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2000 10186601

(oxycodone and acetaminophen capsules USP) analgesic


For Oral Use

TYLOX

II C

HEPATOTOXICITY Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophencontaining product (see WARNINGS). DESCRIPTION Each capsule of TYLOX (oxycodone and acetaminophen capsules USP) contains: Oxycodone Hydrochloride USP .....................5 mg* Warning May be habit forming. Acetaminophen USP.....................................500 mg Inactive ingredients: docusate sodium, gelatin, magnesium stearate, sodium benzoate, sodium metabisulfite*, corn starch, FD&C Blue No. 1, FD&C Red No. 3, FD&C Red No. 40, and titanium dioxide. Acetaminophen occurs as a white, odorless crystalline powder, possessing a slightly bitter taste. The oxycodone component is 14-hydroxy-dihydrocodeinone, a white, odorless crystalline powder having a saline, bitter taste. It is derived from the opium alkaloid thebaine, and may be represented by the following structural formula:

Do not take more than 4,000 milligrams of acetaminophen per day. Call your healthcare provider if you took more than the recommended dose. Oxycodone may impair the mental and/or hysical abilities required for the performance of potentially p hazardous tasks such as driving a car or operating machinery. Exercise caution until you are reasonably certain that TYLOX does not adversely affect your ability to engage in such activities. Drug Interactions Patients receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedativehypnotics, or other CNS depressants (including alcohol) concomitantly with TYLOX may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. The concurrent use of anticholinergics with narcotics may produce paralytic ileus. Usage in Pregnancy Pregnancy Category C. Animal reproductive studies have not been conducted with TYLOX. It is also not known whether TYLOX can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. TYLOX should not be given to a pregnant woman, unless in the judgment of the physician, the potential benefits outweigh the possible hazards. Nonteratogenic Effects Use of narcotics during pregnancy may produce physical dependence in theneonate. Labor and Delivery As with all narcotics, administration of TYLOX to the mother shortly before delivery may result in some degree of respiratory depression in the newborn and the mother, especially if higher doses are used. Nursing Mothers It is not known whether the components of TYLOX are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TYLOX is administered to a nursing woman. Pediatric Use Safety and effectiveness in children have not been established. ADVERSE REACTIONS The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, and vomiting. These effects seem to be more prominent in ambulatory than in non-ambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, skin rash, and pruritus. At higher doses, oxycodone has most of the disadvantages of morphine including respiratory depression. DRUG ABUSE AND DEPENDENCE TYLOX capsules are a Schedule II controlled substance. Oxycodone can produce drug dependence and has the potential for being abused (see WARNINGS). OVERDOSAGE Following an acute overdosage, toxicity may result from the oxycodone or the acetaminophen. Signs and Symptoms Toxicity from oxycodone poisoning includes the opioid triad of: pinpoint pupils, depression of respiration, and loss of consciousness. Serious overdosage with oxycodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme som olence progressing to n stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest, and death may occur. In acetaminophen overdosage: dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment A single or multiple drug overdose with oxycodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. Oxycodone Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The narcotic antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including oxycodone. Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance, and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Acetaminophen Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication. DOSAGE AND ADMINISTRATION Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to oxycodone can develop with continued use and that the incidence of untoward effects is dose related. This product is inappropriate even in high doses for severe or intractable pain. TYLOX (oxycodone and acetaminophen capsules) are given orally. The usual adult dosage is one TYLOX capsule every 6 hours as needed for pain. HOW SUPPLIED TYLOX (oxycodone and acetaminophen capsules USP) contains 5 mg oxycodone and 500 mg acetaminophen. The capsules are red and imprinted with TYLOX McNEIL. TYLOX is available as follows: Bottles of 100 capsules - NDC 50458-526-60 Hospital Unit Dose 100 capsules NDC 50458-526-79 Dispense in tight, light-resistant container as defined in the official compendium. Store at controlled room temperature (15-30C, 59-86F). Protect from moisture. Manufactured by: Janssen Ortho, LLC Gurabo, Puerto Rico 00778

*5 mg oxycodone hydrochloride is equivalent to 4.4815 mg oxycodone *See WARNINGS CLINICAL PHARMACOLOGY The principal ingredient, oxycodone, is a semi-synthetic narcotic analgesic with multiple actions qualitatively similar to those of morphine; the most prominent of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value of the oxycodone in TYLOX (oxycodone and acetaminophen capsules) are analgesia and sedation. Oxycodone is similar to codeine and methadone in that it retains at least one-half of its analgesic activity when administered orally. Acetaminophen is a nonopiate, nonsalicylate analgesic and antipyretic. INDICATIONS AND USAGE TYLOX (oxycodone and acetaminophen capsules) are indicated for the relief of moderate to moderately severe pain. CONTRAINDICATIONS TYLOX (oxycodone and acetaminophen capsules) should not be administered to patients who are hypersensitive to any component. WARNINGS Hepatotoxicity Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products (see Boxed Warning). The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue TYLOX immediately and seek medical care if they experience these symptoms. Do not prescribe TYLOX for patients with acetaminophen allergy. TYLOX contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Drug Dependence Oxycodone can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of TYLOX (oxycodone and acetaminophen capsules), and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic-containing medications. Like other narcoticcontaining medications, TYLOX is subject to the Federal Control Substances Act (Schedule II). PRECAUTIONS General Head Injury and Increased Intracranial Pressure The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Acute Abdominal Conditions The administration of TYLOX (oxycodone and acetaminophen capsules) or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Special Risk Patients TYLOX should be given with caution to certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addisons disease, and prostatic hypertrophy or urethral stricture. Information for Patients Do not take TYLOX if you are allergic to any of its ingredients. If you develop signs of allergy such as a rash or difficulty breathing, stop taking TYLOX and contact your healthcare provider immediately.

Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, NJ 08869 Revised October 2011 Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2000 10187201

(tramadol hydrochloride/ acetaminophen) Tablets


Full Prescribing Information
HEPATOTOXICITY ULTRACET contains tramadol HCl and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product (see WARNINGS). DESCRIPTION ULTRACET (tramadol hydrochloride/acetaminophen) Tablets combines two analgesics, tramadol 37.5 mg and acetaminophen 325 mg. The chemical name for tramadol hydrochloride is ()cis-2-[(dimethylamino)methyl]-1-(3methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

ULTRACET

The molecular weight of tramadol hydrochloride is 299.84. Tramadol hydrochloride is a white, bitter, crystalline, and odorless powder. The chemical name for acetaminophen is N-acetyl-p-aminophenol. Its structural formula is:

The molecular weight of acetaminophen is 151.17. Acetaminophen is an analgesic and antipyretic agent which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste. ULTRACET tablets contain 37.5 mg tramadol hydrochloride and 325 mg acetaminophen and are light yellow in color. Inactive ingredients in the tablet are powdered cellulose, pregelatinized corn starch, sodium starch glycolate, corn starch, magnesium stearate, hypromellose, polyethylene glycol, polysorbate 80, titanium dioxide, iron oxide, and carnauba wax. CLINICAL PHARMACOLOGY The following information is based on studies of tramadol alone or acetaminophen alone, except where otherwise noted: Pharmacodynamics ULTRACET contains tramadol and acetaminophen. Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to -opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to -opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in -opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. Apart from analgesia, tramadol administration may produce aconstellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating, and pruritus) similar to that of other opioids. Acetaminophen is a non-opiate, non-salicylate analgesic. Pharmacokinetics Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and acetaminophen following oral administration of one ULTRACET tablet are shown in Table 1. Tramadol has a slower absorption and longer half-life when compared to acetaminophen. Table 1: Summary of Mean (SD) Pharmacokinetic Parameters of the (+)- and (-) Enantiomers of Tramadol and M1 and Acetaminophen Following A Single Oral Dose Of One Tramadol/Acetaminophen Combination Tablet (37.5 mg/325 mg) in Volunteers Parametera (+)-Tramadol (-)-Tramadol (+)-M1 (-)-M1 acetaminophen Cmax (ng/mL) 64.3 (9.3) 55.5 (8.1) 10.9 (5.7) 12.8 (4.2) 4.2 (0.8) tmax (h) 1.8 (0.6) 1.8 (0.7) 2.1 (0.7) 2.2 (0.7) 0.9 (0.7) CL/F (mL/min) 588 (226) 736 (244) 365 (84) t1/2 (h) 5.1 (1.4) 4.7 (1.2) 7.8 (3.0) 6.2 (1.6) 2.5 (0.6) a For acetaminophen, C max was measured as g/mL. A single-dose pharmacokinetic study of ULTRACET in volunteers showed no drug interactions between tramadol and acetaminophen. Upon multiple oral dosing to steady state, however, the bioavailability of tramadol and metabolite M1 was lower for the combination tablets compared to tramadol administered alone. The decrease in AUC was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-M1, and 24.2% for

(-)-M1. The cause of this reduced bioavailability is not clear. Following single- or multipledose administration of ULTRACET, no significant change in acetaminophen pharmacokinetics was observed when compared to acetaminophen given alone. Absorption The absolute bioavailability of tramadol from ULTRACET tablets has not been determined. Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of ULTRAM tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two ULTRACET tablets occurs at approximately two and three hours, respectively, post-dose. Peak plasma concentrations of acetaminophen occur within one hour and are not affected by co-administration with tramadol. Oral absorption of acetaminophen following administration of ULTRACET occurs primarily in the small intestine. Food Effects When ULTRACET was administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen. However, peak plasma concentrations, and the extents of absorption, of tramadol and acetaminophen were not affected. The clinical significance of this difference is unknown. Distribution The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 g/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of acetaminophen is bound to plasma protein. Metabolism Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interactions). Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are poor metabolizers of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in poor metabolizers versus extensive metabolizers, while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline, and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome. Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: a) conjugation with glucuronide; b) conjugation with sulfate; and c) oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates. Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5-6 and 7 hours, respectively, after administration of ULTRACET. The apparent plasma elimination half-life of racemic tramadol increased to 7-9 hours upon multiple dosing of ULTRACET. The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen is excreted unchanged in the urine. Special Populations Renal The pharmacokinetics of ULTRACET in patients with renal impairment has not been studied. Based on studies using tramadol alone, excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min. Adjustment of dosing regimen in this patient population is recommended (see DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose based on studies using tramadol alone. Hepatic The pharmacokinetics and tolerability of ULTRACET in patients with impaired hepatic function have not been studied. Since tramadol and acetaminophen are both extensively metabolized by the liver, the use of ULTRACET in patients with hepatic impairment is not recommended (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Geriatric A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with ULTRACET, which included 55 patients between 65 and 75years of age and 19 patients over 75 years of age, showed no significant changes in the pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and hepatic function (see PRECAUTIONS, Geriatric Use).

Gender Tramadol clearance was 20% higher in female subjects compared to males on four phase I studies of ULTRACET in 50male and 34 female healthy subjects. The clinical significance of this difference is unknown. Pediatric The pharmacokinetics of ULTRACET tablets has not been studied in pediatric patients below 16 years of age. CLINICAL STUDIES Single-Dose Studies for Treatment of Acute Pain In pivotal single-dose studies in acute pain, two tablets of ULTRACET administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. The onset of pain relief after ULTRACET was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after ULTRACET was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen. INDICATIONS AND USAGE ULTRACET is indicated for the short-term (five days or less) management of acute pain. CONTRAINDICATIONS ULTRACET should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, acetaminophen, any other component of this product, or opioids. ULTRACET is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids, or psychotropic drugs. ULTRACET may worsen central nervous system and respiratory depression in these patients. WARNINGS Hepatotoxicity ULTRACET contains tramadol HCl and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophencontaining products (see Boxed Warning). The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. Seizure Risk Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking:  electiveserotoninreuptakeinhibitors(SSRIanti epressantsoranorectics), S d  ricyclic antidepressants (TCAs), and other  ricyclic compounds (e.g., T t cyclobenzaprine, promethazine, etc.), or  theropioids. O Administration of tramadol may enhance the seizure risk in patients taking:  AO inhibitors (see also WARNINGS, Use with MAO Inhibitors and Serotonin M Re-uptake Inhibitors),  euroleptics,or N  therdrugsthatreducetheseizurethreshold. O Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, or CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure. Suicide Risk  onotprescribeULTRACET for patients who are suicidal or addiction-prone. D  rescribe ULTRACET with caution for patients taking tranquilizers or P antidepressant drugs and patients who use alcohol in excess and who suffer from emotional disturbance or depression. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of nonnarcotic analgesics. Tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs (see WARNINGS, Risk of Overdosage). Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including ULTRACET, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/ or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Hypersensitivity/Anaphylaxis Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive ULTRACET (see CONTRAINDICATIONS).

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue ULTRACET immediately and seek medical care if they experience these symptoms. Do not prescribe ULTRACET for patients with acetaminophen allergy. Respiratory Depression Administer ULTRACET cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE). Interaction With Central Nervous System (CNS) Depressants ULTRACET should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers, or sedative hypnotics. Tramadol increases the risk of CNS and respiratory depression in these patients. Interactions With Alcohol and Drugs of Abuse Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Increased Intracranial Pressure or Head Trauma ULTRACET should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status in these patients if they are receiving ULTRACET (see WARNINGS, Respiratory Depression). Use in Ambulatory Patients Tramadol may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly. Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors Use ULTRACET with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of tramadol with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome. Use With Alcohol ULTRACET should not be used concomitantly with alcohol consumption. The use of ULTRACET in patients with liver disease is not recommended. Use With Other Acetaminophen-containing Products Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, ULTRACET should not be used concomitantly with other acetaminophen-containing products. Misuse, Abuse and Diversion Tramadol has mu-opioid agonist activity. ULTRACET, atramadol-containing product, can be sought by drug abusers and people with addiction disorders and may be subject to criminal diversion. The possibility of illegal or illicit use should be considered when prescribing or dispensing ULTRACET in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses a significant risk to the abuser that could result in overdose and death (see DRUG ABUSE AND DEPENDENCE and OVERDOSAGE). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Risk of Overdosage Patients taking tramadol should be warned not to exceed the dose recommended by their physician. Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a cause of drug-related deaths. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, tricyclic antidepressants, or other CNS depressant drugs. Patients should be advised of the additive depressant effects of these combinations. Serious potential consequences of overdosage with tramadol are central nervous system depression, respiratory depression, and death. Some deaths have occurred as aconsequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE). A serious potential consequence of overdosage with acetaminophen is hepatic (centrilobular) necrosis, leading to hepatic failure and death. Emergency help should be sought immediately and treatment initiated immediately if overdose is suspected, even if symptoms are not apparent. Withdrawal Withdrawal symptoms may occur if ULTRACET is discontinued abruptly (see also DRUG ABUSE AND DEPENDENCE). Reported symptoms have included anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been reported less frequently with ULTRACET discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering ULTRACET at the time of discontinuation.

PRECAUTIONS General The recommended dose of ULTRACET should not be exceeded. Do not co-administer ULTRACET with other tramadol or acetaminophen-containing products (see WARNINGS, Use With Other Acetaminophen-containing Products and Risk of Overdosage). Pediatric Use The safety and effectiveness of ULTRACET has not been studied in the pediatric population. Geriatric Use In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function; of concomitant disease; and multiple drug therapy. Acute Abdominal Conditions The administration of ULTRACET may complicate the clinical assessment of patients with acute abdominal conditions. Use in Renal Disease ULTRACET has not been studied in patients with impaired renal function. Experience with tramadol suggests that impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosing interval of ULTRACET be increased, not to exceed 2 tablets every 12 hours. Use in Hepatic Disease ULTRACET has not been studied in patients with impaired hepatic function. The use of ULTRACET in patients with hepatic impairment is not recommended (see WARNINGS, Use With Alcohol). Information for Patients Do not take ULTRACET if you are allergic to any of its ingredients. If you develop signs of allergy such as a rash or difficulty breathing, stop taking ULTRACET and contact your healthcare provider immediately. Do not take more than 4,000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose. Do not take ULTRACET in combination with other tramadol or acetaminophencontaining products, including over-the-counter preparations. ULTRACET may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. ULTRACET may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. ULTRACET should not be taken concomitantly with alcohol-containing beverages during the course of treatment with ULTRACET. ULTRACET should be used with caution when taking medications such as tranquilizers, hypnotics, or other opiate-containing analgesics. Inform the physician if you are pregnant, think you might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery). Understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures, hepatic toxicity, and death. Drug Interactions CYP2D6 and CYP3A4 Inhibitors Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine, and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome. Serotonergic Drugs There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and 2-adrenergic blockers. Caution is advised when ULTRACET is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is areversible non-selective MAOI), lithium, or St. Johns Wort. If concomitant treatment of ULTRACET with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Triptans Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRACET is coadministered with a triptan. If concomitant treatment of ULTRACET with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Use With Carbamazepine Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRACET and carbamazepine is not recommended. Use With Quinidine Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Potential for Other Drugs to Affect Tramadol In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. Johns Wort, with ULTRACET may affect the metabolism of tramadol, leading to altered tramadol exposure.

Potential for Tramadol to Affect Other Drugs In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals. Use With Cimetidine Concomitant administration of ULTRACET and cimetidine has not been studied. Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRACET dosage regimen is recommended. Use With Digoxin Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. Use With Warfarin-Like Compounds Post-marketing surveillance of both tramadol and acetaminophen individual products have revealed rare alterations of warfarin effect, including elevation of prothrombin times. While such changes have been generally of limited clinical significance for the individual products, periodic evaluation of prothrombin time should be performed when ULTRACET and warfarin-like compounds are administered concurrently. Carcinogenesis, Mutagenesis, Impairment of Fertility There are no animal or laboratory studies on the combination product (tramadol and acetaminophen) to evaluate carcinogenesis, mutagenesis, or impairment of fertility. A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in amouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human tramadol dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or 1 time the maximum daily human tramadol dosage). Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans. No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (350 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.6and 2.4 times the maximum daily human tramadol dosage of 185 mg/m2. Pregnancy Teratogenic Effects: Pregnancy Category C No drug-related teratogenic effects were observed in the progeny of rats treated orally with tramadol and acetaminophen. The tramadol/acetaminophen combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose, 50/434 mg/kg tramadol/acetaminophen (300/2604 mg/m2 or 1.6 times the maximum daily human tramadol/acetaminophen dosage of 185/1591 mg/m2), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Non-teratogenic Effects: Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.6 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 2.6 times the maximum daily human tramadol dosage). There are no adequate and well-controlled studies in pregnant women. ULTRACET should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during post-marketing. Labor and Delivery ULTRACET should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. The effect of ULTRACET, if any, on the later growth, development, and functional maturation of the child is unknown. Nursing Mothers ULTRACET is not recommended for obstetrical preoperative medication or for postdelivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 g of tramadol (0.1% of the maternal dose) and 27 g of M1. ADVERSE REACTIONS Table 2 reports the incidence rate of treatment-emergent adverse events over five days of ULTRACET use in clinical trials (subjects took an average of at least 6 tablets per day).

Table 2: Incidence of Treatment-Emergent Adverse Events (2.0%) Body System Preferred Term Gastrointestinal System Disorders Constipation Diarrhea Nausea Dry Mouth Psychiatric Disorders Somnolence Anorexia Insomnia Central & Peripheral Nervous System Dizziness Skin and Appendages Sweating Increased Pruritus Reproductive Disorders, Male* Prostatic Disorder ULTRACET (N=142) (%) 6 3 3 2 6 3 2 3 4 2 2

*Number of males = 62 Incidence at least 1%, causal relationship at least possible or greater: the following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of ULTRACET. Body as a Whole Asthenia, fatigue, hot flushes Central and Peripheral Nervous System Dizziness, headache, tremor Gastrointestinal System Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting Psychiatric Disorders Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence Skin and Appendages Pruritus, rash, increased sweating Selected Adverse events occurring at less than 1%: the following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in ULTRACET clinical trials. Body as a Whole Chest pain, rigors, syncope, withdrawal syndrome Cardiovascular Disorders Hypertension, aggravated hypertension, hypotension Central and Peripheral Nervous System Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo Gastrointestinal System Dysphagia, melena, tongue edema Hearing and Vestibular Disorders Tinnitus Heart Rate and Rhythm Disorders Arrhythmia, palpitation, tachycardia Liver and Biliary System Hepatic function abnormal Metabolic and Nutritional Disorders Weight decrease Psychiatric Disorders Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking Red Blood Cell Disorders Anemia Respiratory System Dyspnea Urinary System Albuminuria, micturition disorder, oliguria, urinary retention Vision Disorders Abnormal vision Other clinically significant adverse experiences previously reported with tramadol hydrochloride: Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure, and gastrointestinal bleeding. Reported laboratory abnormalities included elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures, and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs. Other clinically significant adverse experiences previously reported with acetaminophen: Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally controlled by discontinuation of the drug and, when necessary, symptomatic treatment. DRUG ABUSE AND DEPENDENCE Abuse Tramadol has mu-opioid agonist activity. ULTRACET, a tramadol-containing product, can be abused and may be subject to criminal diversion. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, continued use despite harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Drug-seeking behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated loss of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating physician(s). Doctor shopping to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of ULTRACET can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that help to limit the potential abuse of this product. ULTRACET is intended for oral use only. Dependence Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist (see also WARNINGS, Withdrawal). The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with ULTRACET. OVERDOSAGE ULTRACET is a combination product. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, acetaminophen toxicity or both. The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. The initial symptoms seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea, vomiting, malaise, pallor and diaphoresis. An overdosage of ULTRACET may be a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Tramadol Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death. Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS, Misuse, Abuse, and Diversion). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of ULTRACET could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Acetaminophen In acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects also may occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. In the treatment of acetaminophen overdosage, gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 or more hours after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication. DOSAGE AND ADMINISTRATION For the short-term (five days or less) management of acute pain, the recommended dose of ULTRACET is 2tablets every 4 to 6 hours as needed for pain relief, up to a maximum of 8 tablets per day. Individualization of Dose In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosing interval of ULTRACET be increased not to exceed 2 tablets every 12 hours. Dose selection for an elderly patient should be cautious, in view of the potential for greater sensitivity to adverse events. HOW SUPPLIED ULTRACET (tramadol hydrochloride/acetaminophen) Tablets with tramadol 37.5 mg and acetaminophen 325 mg are light yellow, coated, capsule-shaped tablets imprinted O-M on one side and 650 on the other and are available as follows: 100s: NDC 50458-650-60 Bottles of 100 tablets HUD 100s: NDC 50458-650-10 Packages of 100 unit doses in blister packs, 10cards of 10 tablets each Dispense in a tight container. Store at 25C (77F); excursions permitted to 15 - 30C (59 - 86F). Manufactured by: Janssen Ortho, LLC Gurabo, Puerto Rico 00778 Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869 Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2003 Revised June 2011 10179302

ULTRAM
(tramadol hydrochloride) Tablets
Full Prescribing Information
DESCRIPTION ULTRAM (tramadol hydrochloride) tablets is a centrally acting analgesic. The chemical name for tramadol hydrochloride is ()cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

Table 1: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite Population/ Dosage Regimena Healthy Adults, 100 mg qid, MD p.o. Healthy Adults, 100 mg SD p.o. Geriatric, (>75 yrs) 50 mg SD p.o. Hepatic Impaired, 50 mg SD p.o. Renal Impaired, CLcr10-30 mL/min 100 mg SD i.v. Renal Impaired, CLcr<5 mL/min 100 mg SD i.v. a b c d Parent Drug/ Metabolite Tramadol M1 Tramadol M1 Tramadol M1 Tramadol M1 Tramadol M1 Tramadol M1 Peak Conc. (ng/mL) 592 (30) 110 (29) 308 (25) 55.0 (36) 208 (31) d 217 (11) 19.4 (12) c c c c Time to Peak (hrs) 2.3 (61) 2.4 (46) 1.6 (63) 3.0 (51) 2.1 (19) d 1.9 (16) 9.8 (20) c c c c Clearance/F b (mL/min/Kg) 5.90 (25) c 8.50 (31) c 6.89 (25) c 4.23 (56) c 4.23 (54) c 3.73 (17) c t1/2 (hrs) 6.7 (15) 7.0 (14) 5.6 (20) 6.7 (16) 7.0 (23) d 13.3 (11) 18.5 (15) 10.6 (31) 11.5 (40) 11.0 (29) 16.9 (18)

The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. ULTRAM tablets contain 50 mg of tramadol hydrochloride and are white in color. Inactive ingredients in the tablet are pregelatinized corn starch, modified starch (corn), hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and carnauba wax. CLINICAL PHARMACOLOGY Pharmacodynamics ULTRAMcontains tramadol, a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to -opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to -opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in -opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of ULTRAM. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours. Apart from analgesia, ULTRAM administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, ULTRAM has no effect on heart rate, leftventricular function or cardiac index. Orthostatic hypotension has been observed. Pharmacokinetics The analgesic activity of ULTRAM is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY, Pharmacodynamics). Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state. Absorption The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with four times per day dosing. There is no evidence of self-induction (see Figure 1 and Table 1 below). Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given four times per day.
1000 600 400 200 100 60 40 20 10 0 12 24 Time (h) 36 48 Tramadol (Multiple Dose) Tramadol (Single Dose) M1 (Multiple Dose) M1 (Single Dose)

SD = Single dose, MD = Multiple dose, p.o. = Oral administration, i.v. = Intravenous administration, q.i.d. = Four times daily F represents the oral bioavailability of tramadol Not applicable Not measured

Food Effects Oral administration of ULTRAM with food does not significantly affect its rate or extent of absorption, therefore, ULTRAM can be administered without regard to food. Distribution The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 g/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Metabolism Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interaction). Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These individuals are poor metabolizers of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in poor metabolizers versus extensive metabolizers, while M1 concentrations were 40% lower. Concomitant therapy with inhibitors of CYP2D6 such as fluoxetine, paroxetine and quinidine could result in significant drug interactions. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome. Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 1.4 and 7.4 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing. Special Populations Renal Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose. Hepatic Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION). Geriatric Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION).

Conc. (ng/mL)

Gender The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg IV dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown. CLINICAL STUDIES ULTRAM has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars). In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg ULTRAM tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg. ULTRAM has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving ULTRAM. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of ULTRAM in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX) daily. Titration Trials In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily ULTRAM dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration. In a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate ULTRAM therapy using slower titration rates. A 16-day titration schedule, starting with 25 mg qAM and using additional doses in 25 mg increments every third day to 100 mg/day (25 mg four times per day), followed by 50 mg increments in the total daily dose every third day to 200 mg/day (50 mg four times per day), resulted in fewer discontinuations due to nausea or vomiting and fewer discontinuations due to any cause than did a 10-day titration schedule. Figure 2:

INDICATIONS AND USAGE ULTRAM is indicated for the management of moderate to moderately severe pain in adults. CONTRAINDICATIONS ULTRAM should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. ULTRAM is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. ULTRAM may worsen central nervous system and respiratory depression in these patients. WARNINGS Seizure Risk Seizures have been reported in patients receiving ULTRAM within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of ULTRAM above the recommended range. Concomitant use of ULTRAM increases the seizure risk in patients taking: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or Other opioids. Administration of ULTRAM may enhance the seizure risk in patients taking: MAO inhibitors (see also WARNINGS, Use with MAO Inhibitors and Serotonin Re-Uptake Inhibitors), Neuroleptics, or Other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In ULTRAM overdose, naloxone administration may increase the risk of seizure.

Suicide Risk Do not prescribe ULTRAM for patients who are suicidal or addiction-prone. Prescribe ULTRAM Tablets with caution for patients who are taking tranquilizers or antidepressant drug and patients who use alcohol in excess and who suffer from emotional disturbance or depression. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of nonnarcotic analgesics. Tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs (see WARNINGS, Risk of Overdosage). Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including ULTRAM, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Anaphylactoid Reactions Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with ULTRAM. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive ULTRAM (see CONTRAINDICATIONS). Respiratory Depression Administer ULTRAM cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of ULTRAM are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE). Interaction With Central Nervous System (CNS) Depressants ULTRAM should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ULTRAM increases the risk of CNS and respiratory depression in these patients. Interactions With Alcohol and Drugs of Abuse Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Increased Intracranial Pressure or Head Trauma ULTRAM should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ULTRAM (see WARNINGS, Respiratory Depression). Use in Ambulatory Patients ULTRAM may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly. Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors Use ULTRAM with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of ULTRAM with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome. Misuse, Abuse and Diversion Tramadol has mu-opioid agonist activity. ULTRAM can be sought by drug abusers and people with addiction disorders and may be subject to criminal diversion. The possibility of illegal or illicit use should be considered when prescribing or dispensing ULTRAM in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses a significant risk to the abuser that could result in overdose and death (see DRUG ABUSE AND DEPENDENCE and OVERDOSAGE). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Risk of Overdosage Patients taking tramadol should be warned not to exceed the dose recommended by their physician. Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a cause of drug-related deaths. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS depressant drugs. Patients should be advised of the additive depressant effects of these combinations. Serious potential consequences of overdosage with ULTRAM (tramadol hydrochloride) tablets are central nervous system depression, respiratory depression and death. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).

Withdrawal Withdrawal symptoms may occur if ULTRAM is discontinued abruptly (see also DRUG ABUSE AND DEPENDENCE). Reported symptoms have included anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been reported less frequently with ULTRAM discontinuation include panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering ULTRAM at the time of discontinuation. PRECAUTIONS Acute Abdominal Conditions The administration of ULTRAM may complicate the clinical assessment of patients with acute abdominal conditions. Use in Renal and Hepatic Disease Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION). With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. Information for Patients Patients should be informed that ULTRAM may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. ULTRAM may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. ULTRAM should not be taken with alcohol containing beverages. ULTRAM should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics. The patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery). The patient should understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death. Drug Interactions CYP2D6 and CYP3A4 Inhibitors Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome. Serotonergic Drugs There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and 2-adrenergic blockers. Caution is advised when ULTRAM is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. Johns Wort. If concomitant treatment of ULTRAM with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Triptans Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRAM is coadministered with a triptan. If concomitant treatment of ULTRAM with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Use With Carbamazepine Patients taking carbamazepine may have a significantly reduced analgesic effect of ULTRAM. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRAM and carbamazepine is not recommended. Use With Quinidine Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and ULTRAM results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Potential for Other Drugs to Affect Tramadol In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. Johns Wort, with ULTRAM may affect the metabolism of tramadol leading to altered tramadol exposure. Potential for Tramadol to Affect Other Drugs In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals. Use With Cimetidine Concomitant administration of ULTRAM with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM dosage regimen is recommended. Use With Digoxin and Warfarin Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

Carcinogenesis, Mutagenesis, Impairment of Fertility A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.36 times the maximum daily human dosage of 246 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or 0.73 times the maximum daily human dosage). Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans. No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m2, respectively. Pregnancy, Teratogenic Effects: Pregnancy Category CTramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m2), rats ( 25 mg/kg or 150 mg/m2) and rabbits ( 75 mg/kg or 900 mg/m2) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m2 basis are 1.4, 0.6, and 3.6 times the maximum daily human dosage (246 mg/m2) for mouse, rat and rabbit, respectively.No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg or 420 mg/m2), rats (up to 80 mg/kg or 480 mg/m2) or rabbits (up to 300 mg/kg or 3600 mg/m2) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg (3600 mg/m2), a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/m2), respectively. Non-teratogenic Effects Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 1.9 and higher the maximum daily human dose). There are no adequate and well-controlled studies in pregnant women. ULTRAM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing. Labor and Delivery ULTRAM should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. The effect of ULTRAM, if any, on the later growth, development, and functional maturation of the child is unknown. Nursing Mothers ULTRAM is not recommended for obstetrical preoperative medication or for postdelivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 g of tramadol (0.1% of the maternal dose) and 27 g of M1. Pediatric Use The safety and efficacy of ULTRAM in patients under 16 years of age have not been established. The use of ULTRAM in the pediatric population is not recommended. Geriatric Use In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). A total of 455 elderly (65 years of age or older) subjects were exposed to ULTRAM in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75. ADVERSE REACTIONS ULTRAM was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. Table 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to ULTRAM administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for ULTRAM and the active control groups, TYLENOL with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the ULTRAM groups.

Table 2: Cumulative Incidence of Adverse Reactions for ULTRAM in Chronic Trials of Nonmalignant Pain (N = 427) Up to 7 Days 26% 24% 24% 18% 16% 9% 8% 7% 6% 6% 5% 5% 5% Up to 30 Days 31% 34% 38% 26% 23% 13% 10% 11% 11% 7% 9% 9% 6% Up to 90 Days 33% 40% 46% 32% 25% 17% 11% 14% 12% 9% 13% 10% 10%

Dizziness/Vertigo Nausea Constipation Headache Somnolence Vomiting Pruritus CNS Stimulation1 Asthenia Sweating Dyspepsia Dry Mouth Diarrhea
1

CNS Stimulation is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations

Incidence 1% to less than 5% possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with ULTRAM exists. Body as a Whole: Malaise. Cardiovascular: Vasodilation. Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder. Gastrointestinal: Abdominal pain, Anorexia, Flatulence. Musculoskeletal: Hypertonia. Skin: Rash. Special Senses: Visual disturbance. Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention. Incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in postmarketing experience. Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma). Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia. Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS), Tremor. Respiratory: Dyspnea. Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles. Special Senses: Dysgeusia. Urogenital: Dysuria, Menstrual disorder. Other adverse experiences, causal relationship unknown: A variety of other adverse events were reported infrequently in patients taking ULTRAM during clinical trials and/or reported in post-marketing experience. A causal relationship between ULTRAM and these events has not been determined. However, the most significant events are listed below as alerting information to the physician. Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism. Central Nervous System: Migraine, Speech disorders. Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure. Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria. Sensory: Cataracts, Deafness, Tinnitus. DRUG ABUSE AND DEPENDENCE Abuse Tramadol has mu-opioid agonist activity. ULTRAM can be abused and may be subject to criminal diversion. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Drug-seeking behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). Doctor shopping to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of ULTRAM can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that help to limit the potential abuse of this product. ULTRAM is intended for oral use only.

Dependence Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist (see also WARNINGS, Withdrawal). The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with ULTRAM. OVERDOSAGE Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death. Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS, Misuse, Abuse, and Diversion).Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of ULTRAM could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. DOSAGE AND ADMINISTRATION Adults (17 years of age and over) For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of ULTRAM can be improved by initiating therapy with the following titration regimen: ULTRAM should be started at 25 mg/day qAM and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg q.i.d.). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.). After titration, ULTRAM 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day. For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, ULTRAM 50 mg to 100 mg can be administered as needed for pain relief every four to six hours, not to exceed 400 mg per day. Individualization of Dose Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability. In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of ULTRAM be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis. The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours. In general, dose selection for an elderly patient over 65 years old should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. For elderly patients over 75 years old, total dose should not exceed 300 mg/day. HOW SUPPLIED ULTRAM (tramadol hydrochloride) Tablets - 50 mg are white, capsule-shaped, coated tablet imprinted ULTRAM on one side and 06 59 on the scored side. Bottles of 100 tablets: NDC 50458-659-60 Dispense in a tight container. Store at 25C (77F); excursions permitted to 15 30C (59 86F).

Manufactured by: Janssen Ortho, LLC Gurabo, Puerto Rico 00778 Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. Raritan, New Jersey 08869

OMJPI 2003 Revised September 2009 10179001

(tramadol HCI) Extended-Release Tablets


Rx only Prescribing Information DESCRIPTION ULTRAM ER (tramadol hydrochloride) is a centrally acting synthetic analgesic in an extended-release formulation. The chemical name is () cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: Figure 1

ULTRAM ER

The molecular weight of tramadol HCl is 299.8. It is a white, bitter, crystalline and odorless powder that is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. ULTRAM ER tablets contain 100, 200 or 300 mg of tramadol HCl in an extended-release formulation. The tablets are white to off-white in color and contain the inactive ingredients ethylcellulose, dibutyl sebacate, polyvinyl pyrrolidone, sodium stearyl fumarate, colloidal silicon dioxide, and polyvinyl alcohol. CLINICAL PHARMACOLOGY Mechanism of Action ULTRAM ER is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to -opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to -opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in -opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the ULTRAM ER clinical studies. Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Pharmacokinetics The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. ULTRAM ER is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of ULTRAM ER are approximately dose-proportional over a 100-400 mg dose range in healthy subjects. The observed tramadol AUC values for the 400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg dose. The clinical significance of this finding has not been studied and is not known.

b. M1

Food Effects After a single dose administration of 200 mg ULTRAM ER tablet with a high fat meal, the Cmax and AUC0- of tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions). While ULTRAM ER may be taken without regard to food, it is recommended that it be taken in a consistent manner. Distribution The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100-mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 g/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Metabolism Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N (mediated by CYP3A4 and CYP2B6) and O (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interactions). Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of ULTRAM ER are approximately 7.9 and 8.8 hours, respectively.
Special Populations Renal Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of ULTRAM ER 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). ULTRAM ER has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of ULTRAM ER does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ULTRAM ER should not be used in patients with severe renal impairment (see PRECAUTIONS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

Absorption In healthy subjects, the bioavailability of a ULTRAM ER 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (ULTRAM) was approximately 85-90%. Consistent with the extendedrelease nature of the formulation, there is a lag time in drug absorption following ULTRAM ER administration. The mean peak plasma concentrations of tramadol and M1 after administration of ULTRAM ER tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing (see Table 1 and Figure 2). Following administration of the ULTRAM ER, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing. The mean (%CV) pharmacokinetic parameter values for ULTRAM ER 200 mg administered once daily and tramadol HCl immediate-release (ULTRAM) 50 mg administered every six hours are provided in Table 1.
Table 1. Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=32) Tramadol M1 Metabolite ULTRAM ER ULTRAM ULTRAM ER ULTRAM 200-mg 50-mg 200-mg 50-mg Tablet Tablet Every Tablet Tablet Every Once-Daily 6 Hours Once-Daily 6 Hours 5975 (34) 335 (35) 187 (37) 12 (27) 61 (57) 6613 (27) 383 (21) 228 (32) 1.5 (42) 59 (35) 1890 (25) 95 (24) 69 (30) 15 (27) 34 (72) 2095 (26) 104 (24) 82 (27) 1.9 (57) 26 (47)

Pharmacokinetic Parameter AUC0-24 (ng h/mL) Cmax (ng/mL) Cmin (ng/mL) Tmax (h) % Fluctuation

Hepatic Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of ULTRAM ER 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate). The pharmacokinetics of tramadol after the administration of ULTRAM ER has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of ULTRAM ER does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ULTRAM ER should not be used in patients with severe hepatic impairment (see PRECAUTIONS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION). Geriatric The effect of age on the absorption of tramadol from ULTRAM ER in patients over the age of 65 years has not been studied and is unknown (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Gender Based on pooled multiple-dose pharmacokinetics studies for ULTRAM ER in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.
Drug Interactions The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. Based on a population PK analysis of Phase I studies with immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in poor metabolizers versus extensive metabolizers, while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 (fluoxetine, norfluoxetine, amitriptyline, and quinidine) inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. Johns Wort, with ULTRAM ER may affect the metabolism of tramadol leading to altered tramadol exposure (see PRECAUTIONS, Drug Interactions).

AUC0-24: Area Under the Curve in a 24-hour dosing interval; Cmax: Peak Concentration in a 24-hour dosing interval; Cmin: Trough Concentration in a 24-hour dosing interval; Tmax: Time to Peak Concentration Figure 2: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg ULTRAM ER Once-Daily and 50 mg ULTRAM Every 6 Hours.

Quinidine Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg quinidine two hours before the administration of ULTRAM ER 100 mg. The results demonstrated that the exposure of tramadol increased 50-60% and the exposure of M1 decreased 50-60% (see PRECAUTIONS, Drug Interactions). In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Carbamazepine Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of ULTRAM ER and carbamazepine is not recommended (see PRECAUTIONS, Drug Interactions).
a. Tramadol

Cimetidine Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the ULTRAM ER dosage regimen with cimetidine is recommended.

CLINICAL STUDIES ULTRAM ER was studied in patients with chronic, moderate to moderately severe pain due to osteoarthritis and/or low back pain in four 12-week, randomized, double-blind, placebo-controlled trials. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of 40 mm, off previous medications, on a 0 100 mm visual analog scale (VAS). Adequate evidence of efficacy was demonstrated in the following two studies: In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment was initiated at 100 mg QD for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in the ULTRAM ER treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the ULTRAM ER 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with ULTRAM ER 100 mg and 20% of patients treated with placebo. Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 3). Figure 3

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations. Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician. Anaphylactoid Reactions Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive ULTRAM ER (see CONTRAINDICATIONS). Respiratory Depression Administer ULTRAM ER cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE). Interaction With Central Nervous System (CNS) Depressants ULTRAM ER should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. ULTRAM ER increases the risk of CNS and respiratory depression in these patients. Increased Intracranial Pressure or Head Trauma ULTRAM ER should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving ULTRAM ER (see WARNINGS, Respiratory Depression). Use in Ambulatory Patients ULTRAM ER may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly. Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors Use ULTRAM ER with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of ULTRAM ER with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome. Withdrawal Withdrawal symptoms may occur if ULTRAM ER is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be reduced by tapering ULTRAM ER. Misuse, Abuse and Diversion of Opioids Tramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing ULTRAM ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. ULTRAM ER could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with Alcohol and Drugs of Abuse Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. DRUG ABUSE AND ADDICTION ULTRAM ER is a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. Drug-seeking behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). Doctor shopping to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. ULTRAM ER, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. ULTRAM ER is intended for oral use only. The crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Risk of Overdosage Serious potential consequences of overdosage with ULTRAM ER are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE). PRECAUTIONS Acute Abdominal Condition The administration of ULTRAM ER may complicate the clinical assessment of patients with acute abdominal conditions. Use in Renal and Hepatic Disease Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. ULTRAM ER has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths and once daily dosing of ULTRAM ER do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ULTRAM ER should not be used in patients with severe renal

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of ULTRAM ER in patients with osteoarthritis of the knee, patients titrated to an average daily ULTRAM ER dose of approximately 270 mg/day. Fortynine percent of patients randomized to ULTRAM ER completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the ULTRAM ER treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-four percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of ULTRAM ER-treated patients. The ULTRAM ER group demonstrated a statistically significant decrease in the mean VAS score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving ULTRAM ER and placebo (see Figure 4). Figure 4

INDICATIONS AND USAGE ULTRAM ER is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time. CONTRAINDICATIONS ULTRAM ER should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids. ULTRAM ER is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. ULTRAM ER may worsen central nervous system and respiratory depression in these patients. WARNINGS Seizure Risk Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or Other opioids. Administration of tramadol may enhance the seizure risk in patients taking: MAO inhibitors (see also WARNINGS, Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors), Neuroleptics, or Other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure. Suicide Risk Do not prescribe ULTRAM ER for patients who are suicidal or addiction-prone. Prescribe ULTRAM ER with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess. Tell your patients not to exceed the recommended dose and to limit their intake of alcohol. Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including ULTRAM ER, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. The pharmacokinetics of ULTRAM ER has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of ULTRAM ER do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, ULTRAM ER should not be used in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). INFORMATION FOR PATIENTS Patients should be informed that ULTRAM ER is for oral use only and should be swallowed whole. The tablets should not be chewed, crushed, or split. Patients should be informed that ULTRAM ER may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. Patients should be informed that ULTRAM ER may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients should be informed that ULTRAM ER should not be taken with alcohol containing beverages. Patients should be informed that ULTRAM ER should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics. Female patients should be instructed to inform the prescriber if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery). Patients should be educated regarding the single-dose and 24-hour dosing regimen, as exceeding these recommendations can result in respiratory depression, seizures or death. Use in Drug and Alcohol Addiction ULTRAM ER is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia. Drug Interactions CYP2D6 and CYP3A4 Inhibitors: Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome. Serotonergic Drugs: There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and 2-adrenergic blockers. Caution is advised when ULTRAM ER is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. Johns Wort. If concomitant treatment of ULTRAM ER with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Triptans: Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRAM ER is coadministered with a triptan. If concomitant treatment of ULTRAM ER with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Geriatric Use Nine-hundred one elderly (65 years of age or older) subjects were exposed to ULTRAM ER in clinical trials. Of those subjects, 156 were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: constipation, fatigue, weakness, postural hypotension and dyspepsia. For this reason, ULTRAM ER should be used with great caution in patients older than 75 years of age (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ADVERSE REACTIONS ULTRAM ER was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain. A total of 901 patients were 65 years or older. The frequency of adverse events generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 2). Table 2: Incidence (%) of patients with adverse event rates 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811). ULTRAM ER MedDRA Preferred Term Dizziness (not vertigo) Nausea Constipation Headache Somnolence Flushing Pruritus Vomiting Insomnia Dry Mouth Diarrhea Asthenia Postural hypotension Sweating increased Anorexia 100 mg (N=403) n (%) 64 (15.9) 61 (15.1) 49 (12.2) 49 (12.2) 33 (8.2) 31 (7.7) 25 (6.2) 20 (5.0) 26 (6.5) 20 (5.0) 15 (3.7) 14 (3.5) 7 (1.7) 6 (1.5) 3 (0.7) 200 mg (N=400) n (%) 81 (20.3) 90 (22.5) 68 (17.0) 62 (15.5) 45 (11.3) 40 (10.0) 34 (8.5) 29 (7.3) 32 (8.0) 29 (7.3) 27 (6.8) 24 (6.0) 17 (4.3) 8 (2.0) 7 (1.8) 300 mg (N=400) n (%) 90 (22.5) 102 (25.5) 85 (21.3) 46 (11.5) 29 (7.3) 35 (8.8) 30 (7.5) 34 (8.5) 36 (9.0) 39 (9.8) 37 (8.5) 26 (6.5) 8 (2.0) 15 (3.8) 21 (5.3) 400 mg (N=202) n (%) 57 (28.2) 53 (26.2) 60 (29.7) 32 (15.8) 41 (20.3) 32 (15.8) 24 (11.9) 19 (9.4) 22 (10.9) 18 (8.9) 10 (5.0) 13 (6.4) 11 (5.4) 13 (6.4) 12 (5.9) Placebo (N=406) n (%) 28 (6.9) 32 (7.9) 17 (4.2) 43 (10.6) 7 (1.7) 18 (4.4) 4 (1.0) 11 (2.7) 13 (3.2) 6 (1.5) 17 (4.2) 7 (1.7) 9 (2.2) 1 (0.2) 1 (0.2)

Use With Carbamazepine Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRAM ER and carbamazepine is not recommended. Use With Quinidine Coadministration of quinidine with ULTRAM ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure (see CLINICAL PHARMACOLOGY, Drug Interactions). The clinical consequences of these findings are unknown. Use With Digoxin and Warfarin Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times. Potential for Other Drugs to Affect Tramadol In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. Johns Wort, with ULTRAM ER may affect the metabolism of tramadol leading to altered tramadol exposure. Potential for Tramadol to Affect Other Drugs In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY No carcinogenic effect of tramadol was observed in p53(+/)-heterozygous mice at oral doses up to 150 mg/kg/day (approximately 2-fold maximum daily human dose [MDHD] of 400 mg/day for a 60 kg adult based on body surface conversion) for 26 weeks and in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold MDHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug. Tramadol was not mutagenic in the following assays: a bacterial reverse mutation assay using Salmonella and E. coli, a mouse lymphoma assay (in the absence of metabolic activation), and a bone marrow micronucleus test in mice. Mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans. No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg/day in male and female rats (approximately equivalent to MDHD). Pregnancy Teratogenic Effects: Pregnancy Category C Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (approximately equivalent to MDHD) in rats and 100 mg/kg (approximately 5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2-fold MDHD), 80 mg/kg in rats (2-fold MDHD) or 300 mg/kg in rabbits (approximately 15-fold MDHD). Non-teratogenic Effects Tramadol caused a reduction in neonatal body weight and survival at an oral dose of 80 mg/kg (approximately 2-fold MDHD) when rats were treated during late gestation throughout lactation period. There are no adequate and well-controlled studies in pregnant women. ULTRAM ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products. Labor and Delivery ULTRAM ER should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND ADDICTION). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol HCl during labor. The effect of ULTRAM ER, if any, on the later growth, development, and functional maturation of the child is unknown. Nursing Mothers ULTRAM ER is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100-mg dose of tramadol, the cumulative excretion in breast milk within sixteen hours postdose was 100 g of tramadol (0.1% of the maternal dose) and 27 g of M1. Pediatric Use The safety and efficacy of ULTRAM ER in patients under 18 years of age have not been established. The use of ULTRAM ER in the pediatric population is not recommended.

The following adverse events were reported from all the chronic pain studies (N=3108). The lists below include adverse events not otherwise noted in Table 2. Adverse events with incidence rates of 1.0% to <5.0% Eye disorders: vision blurred Gastrointestinal disorders: abdominal pain upper, dyspepsia, abdominal pain, sore throat General disorders: weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain Infections and infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis Investigations: blood creatine phosphokinase increased, weight decreased Metabolism and nutrition disorders: appetite decreased Musculoskeletal, connective tissue and bone disorders: arthralgia, back pain, pain in limb, neck pain Nervous system disorders: tremor, paresthesia, hypoesthesia Psychiatric disorders: nervousness, anxiety, depression, restlessness Respiratory, thoracic and mediastinal disorders: sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion Skin and subcutaneous tissue disorders: sweating increased, dermatitis Vascular disorders: hot flushes, vasodilatation Adverse events with incidence rates of 0.5% to <1.0% and serious adverse events reported in at least 2 patients. Cardiac disorders: palpitations, myocardial infarction Ear and labyrinth disorders: tinnitus, vertigo Gastrointestinal disorders: flatulence, toothache, constipation aggravated, appendicitis, pancreatitis General disorders: feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling Hepato-biliary disorders: cholelithiasis, cholecystitis Infections and infestations: cellulitis, ear infection, gastroenteritis, pneumonia, viral infection Injury and poisoning: joint sprain, muscle injury Investigations: alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal Musculoskeletal, connective tissue and bone disorders: muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated Nervous system disorders: migraine, sedation, syncope, disturbance in attention, dizziness aggravated Psychiatric disorders: euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams Renal and urinary disorders: difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention Respiratory, thoracic and mediastinal disorders: yawning Skin and subcutaneous tissue disorders: contusion, piloerection, clamminess, night sweats, urticaria Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia OVERDOSAGE Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death. Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. In the treatment of tramadol overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals convulsions following the administration of toxic doses of ULTRAM ER could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. DOSAGE AND ADMINISTRATION ULTRAM ER should not be used in patients with: creatinine clearance less than 30 mL/min, severe hepatic impairment (Child-Pugh Class C) (See PRECAUTIONS, Use in Renal and Hepatic Disease.) ULTRAM ER must be swallowed whole and must not be chewed, crushed, or split (see WARNINGS, Misuse, Abuse and Diversion of Opioids and DRUG ABUSE AND ADDICTION).

Adults (18 years of age and over) Patients Not Currently on Tramadol Immediate-Release Products For patients not currently treated with tramadol immediate-release (IR) products, ULTRAM ER should be initiated at a dose of 100 mg once daily and titrated up as necessary by 100-mg increments every five days to relief of pain and depending upon tolerability. ULTRAM ER should not be administered at a dose exceeding 300 mg per day. Patients Currently on Tramadol Immediate-Release Products For patients maintained on tramadol IR products, calculate the 24-hour tramadol IR dose and initiate a total daily dose of ULTRAM ER rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with ULTRAM ER, some patients maintained on tramadol IR products may not be able to convert to ULTRAM ER. ULTRAM ER should not be administered at a dose exceeding 300 mg per day. The concomitant use of ULTRAM ER with other tramadol products is not recommended (see WARNINGS). Individualization of Dose Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate upward as tolerated to achieve an adequate effect. Clinical studies of ULTRAM ER have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg. In general, dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. ULTRAM ER should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population. HOW SUPPLIED ULTRAM ER (tramadol hydrochloride) Extended-release tablets are supplied in the following package and dose strength forms: 100 mg: Round, convex, white to off-white tablets imprinted with 100 over ER on one side in black ink Bottle of 30 tablets NDC 50458-653-30 200 mg: Round, convex, white to off-white tablets imprinted with 200 over ER on one side in black ink Bottle of 30 tablets NDC 50458-655-30 300 mg: Round, convex, white to off-white tablets imprinted with 300 over ER on one side in black ink Bottle of 30 tablets NDC 50458-657-30 Store at 25C (77F); excursions permitted to 15-30C (59 - 86F). Manufactured by: Biovail Corporation, Mississauga, ON L5N 8M5, Canada Made in Canada Manufactured for: PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ 08869

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replace with June 2011

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AB CDE FGH IJKLMN O PQ RST UV WX YZ

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A
Adverse event an unwanted effect caused by the administration of a drug; onset may be sudden or develop over time; also known as a side effect Back to Top

B
BID Latin for bis in die (meaning "twice a day"); used in writing dosing directions for prescriptions Bioavailability the degree and rate at which a substance, such as a drug, is absorbed into a living system or is made available at the site of physiological activity Bioequivalence the property wherein two drugs with identical active ingredients, such as a brand-name drug and its generic equivalent, or two different dosage forms, such as tablet and oral suspension, of the same drug possess similar bioavailability and produce the same effect at the site of physiological activity Black box a warning placed at the beginning of an FDA-approved label; it is the strongest warning to prescribing physicians, healthcare professionals and patients that severe adverse reactions have been experienced from use of the product Back to Top

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Expiration date date after which a medicine must be sold or removed from availability because it is no longer expected to be fresh or effective Back to Top

the specific use for a drug product that has been approved by the FDA

F
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G
Generic not protected by trademark registration Back to Top

H
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I
Indication symptom or particular circumstance that indicates the advisability or necessity of a specific medical treatment or procedure Intravenous (IV) situated, performed or occurring within, or administered by entering a vein Back to Top

J, K, L
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M
Medication error any preventable event that can cause or lead to inappropriate medication use or patient harm while the medication is in the control of a healthcare professional, patient or consumer Morbidity incidence of disease; rate of sickness, as in a specified community or group Mortality number of deaths in a given time or place; proportion of deaths to population Back to Top

N
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O
OTC over-the-counter; a medication or device sold legally without a prescription Back to Top

P
Package insert a document, approved by the FDA and furnished by the drug manufacturer for use when dispensing the drug. The document indicates the drug's approved uses, contraindications and potential side effects Pharmacodynamics the study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure Pharmacoeconomics the study of economic factors regarding the cost of drug therapy, including their impact on healthcare systems and society Pharmacokinetics the activity of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation and excretion Back to Top

Q
QD Latin for quaque die (meaning "every day"); used in writing dosing instructions for prescriptions Back to Top

R
Resistance ability of a virus, bacterium or other pathogen to become less responsive to the effects of a drug Back to Top

S
Side effect sometimes referred to as adverse event; a secondary, and usually adverse effect, as of a drug or device Subcutaneous under the skin Back to Top

T
Tolerance the body capacity to endure or become less responsive to a substance, such as a drug, or a physiological injury, especially with repeated use or exposure Transdermal relating to, being or supplying a medication in a form for absorption through the skin into the bloodstream Back to Top

U
U.S. Food and Drug Administration (FDA) U.S. Department of Health and Human Services agency responsible for ensuring the safety and effectiveness of all drugs, biologics, vaccines and medical devices Back to Top

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Privacy Policy
Welcome
Welcome to www.JanssenPharmaceuticalsInc.com! This site is owned by Janssen Pharmaceuticals, Inc. This Privacy Policy is designed to tell you about our practices regarding collection, use, and disclosure of information that you may provide via this site. Please be sure to read this entire Privacy Policy before using or submitting information to this site. This site is governed by the applicable U.S. laws and governmental regulations and is intended for use by our customers, patients, and healthcare professionals in the United States.

Your Consent
By using this site, you agree to the terms of this Privacy Policy. Whenever you submit information via this site, you consent to the collection, use, and disclosure of that information in accordance with this Privacy Policy.

About Children
This site is not intended for children under the age of 13. We will not knowingly collect personally identifiable information via this site from visitors in this age group. We encourage parents to talk to their children about their use of the Internet and the information they disclose to Web sites.

Information You Provide


Some areas of this site may ask you to submit personally identifiable information in order for you to benefit from the specified features (such as newsletter subscriptions, tips/pointers, order processing, or resume submission) or to participate in a particular activity (such as sweepstakes or other promotions). You will be informed what information is required and what information is optional.

Passive Information Collection


As you navigate through this site, certain anonymous information can be passively collected (that is, gathered without your actively providing the information) using various technologies, such as cookies, Internet tags or web beacons, and navigational data collection (log files, server logs, clickstream). Your Internet browser automatically transmits to this site some of this anonymous information, such as the URL of the Web site you just came from and the Internet Protocol (IP) address and the browser version your computer is currently using. This site may also collect anonymous information from your computer through cookies and Internet tags or web beacons. You may set your browser to notify you when a cookie is sent or to refuse cookies altogether, but certain features of this site might not work without cookies. This site may use and combine such passively collected anonymous information to provide better service to site visitors, customize the site based on your preferences, compile and analyze statistics and trends, and otherwise administer and improve the site for your use. Such information is not combined with personally identifiable information collected elsewhere on the site unless you have consented. A "cookie" is a bit of information that a Web site sends to your Web browser that helps the site remember information about you and your preferences. "Session" cookies are temporary bits of information that are used to improve navigation, block visitors from providing information where inappropriate (the site remembers previous entries of age or country of origin that were outside the specified parameters and blocks subsequent changes), and collect aggregate statistical information on the site. They are erased once you exit your Web browser or otherwise turn off your computer. "Persistent" cookies are more permanent bits of information that are placed on the hard drive of your computer and stay there unless you delete the cookie. Persistent cookies store information on your computer for a number of purposes, such as retrieving certain information you have previously provided (such as passwords), helping to determine what areas of the Web site visitors find most valuable, and customizing the Web site based on your preferences on an ongoing basis. Persistent cookies placed by this site on your computer may hold personally identifiable information, but only if you have registered or have otherwise consented to the retention of personally identifiable information you have provided at the site. Otherwise, our sites server only knows that an unidentified visitor with your cookie has returned to the site. You can set your browser to accept all cookies, to reject all cookies, or to notify you whenever a cookie is offered so that you can decide each time whether to accept it. To learn more about cookies and how to specify your preferences, please search for "cookie" in the "Help" portion of your browser. A site may use Internet Protocol (IP) addresses. An IP address is a number assigned to your computer by your Internet service provider so you can access the Internet and is generally considered to be non-personally identifiable information, because in most cases an IP address is dynamic (changing each time you connect to the Internet), rather than static (unique to a particular users computer). The IP address can be used to diagnose problems with a server, report aggregate information, determine the fastest route for your computer to use in connecting to a site, and administer and improve the site. "Internet tags" (also known as single-pixel GIFs, clear GIFs, invisible GIFs, and 1-by-1 GIFs) are smaller than cookies and tell the Web site server information such as the IP address and browser type related to the visitors computer. Tags may be placed both on online advertisements that bring people to the site and on different pages of the site. Such tags indicate how many times a page is opened and which information is consulted. "Navigational data" (log files, server logs, and clickstream data) are used for system management, to improve the content of the site, market research purposes, and to communicate information to visitors.

Use and Disclosure of Information


Except as otherwise stated, we may use information collected via this site to improve the content of our site, to customize the site to your preferences, to communicate information to you (if you have requested it), for our marketing and research purposes, and for any other purpose specified. In addition, we may make full use of all information acquired through this site that is not in personally identifiable form. If you provide personally identifiable information to this site, we may combine such information with other actively collected information unless we specify otherwise at the point of collection. We may disclose personally identifiable information you provide via this site to other Johnson & Johnson affiliates worldwide that agree to treat it in accordance with this Privacy Policy and use it for the same purposes. We also may disclose personally identifiable information you provide via this site to third parties that are not Johnson & Johnson affiliates, but only: I. to contractors we use to support our business (such as fulfillment services, technical support, delivery services, and financial institutions), in which case we will require such third parties to agree to treat it in accordance with this Privacy Policy and use it for the same purposes; II. in connection with the sale, assignment, or other transfer of the business of this site to which the information relates, in which case we will require any such buyer to agree to treat it in accordance with this Privacy Policy and use it for the same purposes; or III. to respond to law enforcement requests or where required by applicable laws, court orders, or government regulations. The collection, use, and disclosure of information contemplated in this Privacy Policy may involve a transfer of the information to jurisdictions located outside your country of residence that may not have equivalent laws and rules regarding personally identifiable information. In these cases, you will be asked to consent to such transfers and disclosures in accordance with this Privacy Policy.

Access and Correction


To keep personally identifiable information that you provide via this site accurate, current, and complete, please contact us as specified below and we will take appropriate steps to update or correct such information in our possession, or to delete your information from our contact list.

Security
This site takes reasonable steps to protect personally identifiable information as you transmit it to our site and to protect such information from loss, misuse, and unauthorized access, disclosure, alteration, or destruction. You should keep in mind that no Internet transmission is ever completely secure or error-free. In particular, e-mail sent to or from this site may not be secure.

Links to Other Web Sites


This site may contain links or references to other Web sites to which this Privacy Policy does not apply. We encourage you to read the Privacy Policy of every Web site you visit.

How to Contact Us
If you have any questions, comments, requests, or concerns related to this Privacy Policy or the information practices of this site, or if you would like to opt out of future communications, please contact us as follows: Janssen Healthcare Learning Center PO Box 200 Titusville, New Jersey 08560 1-800- JANSSEN (1-800-526-7736)

Changes to This Privacy Policy


If this Privacy Policy changes, the revised policy will be posted on this site. Please check back periodically, and especially before you provide any personally identifiable information. This Privacy Policy was last updated on June 10th, 2011.

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Janssen Pharmaceuticals, Inc. Legal Notice Privacy Policy Safe Harbor

Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

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Safe Harbor

Safe Harbor Privacy Policy


Janssen Pharmaceuticals, Inc., and its affiliates are members of the Johnson & Johnson family of companies and are strongly committed to protecting the privacy of those who entrust us with their personal information. Our employees, and all those who do business with us, trust and expect that we will protect their personal information in accordance with the promises we make. In furtherance of our commitment, Janssen Pharmaceuticals, Inc., has certified to the US-EU Safe Harbor Framework and the US-Swiss Safe Harbor Framework with respect to personal data processed as part of our human resources activities and healthcare provider information management. Janssen Pharmaceutical, Inc.s affiliates have certified to the US-EU Safe Harbor Framework and the US-Swiss Safe Harbor Framework with respect to personal data processed as part of our human resources activities and clinical research activities. Accordingly, Janssen Pharmaceuticals, Inc., and its affiliates adhereto the Safe Harbor privacy principles and frequently asked questions, as separately agreed to by the US Department of Commerce and the European Commission, and the Federal Data Protection and Information Commissioner of Switzerland.

Scope
This Safe Harbor Privacy Policy sets forth how Janssen Pharmaceuticals, Inc., handles personal data transferred to the United States from countries in the European Economic Area (EEA) and Switzerland that are collected or received in managing our workforce and managing healthcare provider information; and how Janssen Pharmaceutical, Inc.s affiliates handle personal data transferred to the United States from countries in the EEA and Switzerland that are collected or received in managing our workforce and clinical research activities.

Definitions
The following terms are used throughout this document and are defined here for clarification.

Agent
"Agent" means a third party that processes personal data solely on behalf of and under the instructions of Janssen Pharmaceuticals, Inc., and its affiliates.

Personal Data
"Personal data" means any information or set of information that identifies or can reasonably be used to identify an individual. Personal data do not include information that is encoded or anonymized, or publicly available information that has not been combined with nonpublic personal information.

Sensitive Personal Data


"Sensitive personal data" means personal information that reveals race, ethnic origin, political opinions, religious or philosophical beliefs, or trade union membership, or that concerns health or sex life. Information will be treated as sensitive personal data where it is received from a third party that treats and identifies it as sensitive.

Privacy Principles
The following privacy principles apply to the collection, use, and disclosure of personal data by Janssen Pharmaceuticals, Inc., and its affiliates in conducting human resources and clinical activities.

Notice
Janssen Pharmaceuticals, Inc., and its affiliates will inform individuals about the purposes for which we collect and use personal data about them, how to contact us, the types of nonagent third parties with whom we may share personal data, and any ways that individuals may limit the use and sharing of such data. This notice will be provided when individuals are first asked to provide personal data or as soon thereafter as is practicable.

Choice
Janssen Pharmaceuticals, Inc., and its affiliates will offer an individual the opportunity to choose (opt out) whether personal data are (a) shared with a nonagent third party or (b) used for a purpose other than that for which the data were originally collected or subsequently authorized by the individual. Janssen Pharmaceuticals, Inc., and its affiliates will give an individual an affirmative or explicit (opt in) choice if the information is to be disclosed to a third party or used for a purpose other than those for which it was originally collected or subsequently authorized by the individual.

Access
Janssen Pharmaceuticals, Inc., and its affiliates will provide individuals with reasonable access to personal data about them and they may request the correction or amendment of personal data that they demonstrate to be incorrect or incomplete.

Transfers to Agents
Janssen Pharmaceuticals, Inc., and its affiliates will only transfer personal data to an agent where the agent has provided assurances that the agent provides at least the same level of privacy protection as is required by these privacy principles. Where we have knowledge that an agent is using or sharing personal data in a way that is contrary to these principles, Janssen Pharmaceuticals, Inc., and its affiliates will take reasonable steps to prevent or stop such processing.

Onward Transfer
Janssen Pharmaceuticals, Inc., and its affiliates will only transfer personal data to a nonagent third party where consistent with the notice provided to the individuals who are the subject of the data and any consent that those individuals have given.

Information Integrity
Janssen Pharmaceuticals, Inc., and its affiliates will only use and share personal data about individuals in a way that is consistent with the purposes for which the data were collected or subsequently authorized by those individuals. To the extent necessary for those purposes, Janssen Pharmaceuticals, Inc., and its affiliates will take reasonable steps to ensure that the data are accurate, complete, and current.

Information Security
Janssen Pharmaceuticals, Inc., and its affiliates will take reasonable precautions to protect personal data from loss, misuse, and unauthorized access, disclosure, alteration, and destruction.

Enforcement
Janssen Pharmaceuticals, Inc., and its affiliates have put in place mechanisms to verify our ongoing adherence to these privacy principles. We encourage individuals covered by this Policy to raise any concerns that they have about the way that we process their personal data by contacting us at the address below, and we will do our best to resolve them. We have also agreed to participate in the dispute resolution program provided by the European Data Protection Authorities Panel and to cooperate and comply with the Federal Data Protection and Information Commissioner of Switzerland.

Limitation on Scope of Principles


Adherence by Janssen Pharmaceuticals, Inc., and its affiliates to these privacy principles may be limited to the extent required to meet a legal, governmental, national security, or public interest.

How to Contact Us
Please contact us with any questions about our Safe Harbor certification practice. Johnson & Johnson Health Care Compliance & Privacy 1125 Trenton-Harbourton Road Titusville, New Jersey 08560 Phone: 1-609-730-7966 Attn: Senior Manager, Privacy Compliance Pharmaceuticals Group privacy5@its.jnj.com

Changes to this Policy


This Policy may be amended from time to time, consistent with the requirements of the Safe Harbor. When we do, we will also revise the "last updated" date at the bottom of this Policy. For material changes to this Policy, we will notify individuals by placing a notice on the following Web site: http://www.janssenpharmaceuticalsinc.com. This Safe Harbor privacy policy was last updated on December 5, 2011.

Contact Us

Global Resources

State Compliance

Site Map

Janssen Pharmaceuticals, Inc. Legal Notice Privacy Policy Safe Harbor

Janssen Pharmaceuticals, Inc. 2011. All Rights Reserved. The use of the information on this site is subject to the terms of our Legal Notice. Please see our Privacy Policy , Safe Harbor Privacy Policy . This site is published by Janssen Pharmaceuticals, Inc., which is solely responsible for its contents. Capitalized product names are trademarks of Janssen Pharmaceuticals, Inc. This information is intended for use by our customers, patients, and healthcare professionals in the United States only. Janssen Pharmaceuticals, Inc., recognizes that the internet is a global communications medium; however, laws, regulatory requirements, and medical practices for pharmaceutical products vary from country to country. The prescribing information included here may not be appropriate for use outside the United States. This page was last modified on: Feb 14 2012 at 14:14:22 EDT

Personal Medical History


for

Safety
Prescribing Healthcare Professional Dosage
(strength of pill/ times per day)

Medication Record
Include prescription, non-prescription and nutritional supplements.
Prescription Date Purpose How Taken
(with/without food)

Medication Name
(brand and/or generic)

Times Per Day

Side Effects

Surgeries Vaccinations Allergies

Family Medical History


for

Safety
Mapping your family medical history can help you identify some health risks you may face in the years ahead and help you plan for them. A complete family medical history includes information from three generations of relatives, including grandparents, parents, aunts and uncles, brothers and sisters, cousins, children, and nieces and nephews.
Relation to Self Health Conditions Date of Birth Date of Death

Blood Relatives Name

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