APPROVED DRUG PRODUCTS

WITH THERAPEUTIC
EQUIVALENCE EVALUATIONS
( T H E O R AN G E B O O K )
1 / 43

Health Care Costs Continue to Increase upto 44% by 2006

So health cost of patient increases since branded drugs are costly

Clinicians are increasingly encouraged to prescribe GENERIC drugs for effective treatment

Before substituting a generic product, physicians and other decisions makers should consider the potential clinical and
pharmacoeconomic consequences like Over and Undertreatment, Adverse effects, Additional expenses and Cost savings

To help avoid complications arising from product substitution, the FDA established a list of generic drugs that can be safely and
appropriately substituted for brand products

The FDA has prepared a list of drugs that are bioequivalent they can be substituted for each other

These drugs are listed in a federal publication called Approved Drug Products With Therapeutic Equivalence Evaluations

known as the Orange Book

2 / 43

CONTENT . . .
A.

WHAT IS THE NEED OF THE ORANGE BOOK ?

B.

INTRODUCTION TO THE ORANGE BOOK ?

1.
2.
3.

Definition
History
Objectives

C.

CONTENTS OF THE ORANGE BOOK

D.

CUMMULATIVE SUPPLEMENT

E.

WHAT IS THE GREEN BOOK AND THE BLUE BOOK ?

F.

QUESTIONS

G.

REFERENCES
3 / 43

B. INTRODUCTION TO
THE ORANGE BOOK ?
1.
2.
3.

Definition
History
Objectives

4 / 43

1. Definition
It is the publication of Approved Drug Products With Therapeutic Equivalence Evaluations

by the Food and Drug Administration.

It is prepared by The Orange Book Staff, Center for Drug Evaluation and Research.
It identified drug products on the basis of safety and effectiveness by the Food and Drug

Administration under the Federal Food, Drug, and Cosmetics Act.

Drugs marketed only on the basis of safety or pre-1938 drugs.

The list is independent of any current regulatory action against a drug product.
The main criterion for the inclusion of any product is that the product is the subject of an

application with an effective approval that has not been withdrawn for safety or efficacy
reasons.

The FDA does not recommend substituting drugs that have not been determined to be

bioequivalent.

Drugs that are not listed as bioequivalent should not be substituted for each other.
5 / 43

2. History
YEAR

ACTION

May 31, 1978

The Commissioner of the Food and Drug Administration sent a letter to officials of
each state stating FDA's intent to provide a list of all prescription drug products
that are approved by FDA for safety and effectiveness, along with therapeutic
equivalence determinations for multisource prescription products.

January, 1979

The list was distributed (included only currently marketed prescription drug
products approved by FDA through NDAs and ANDAs under the provisions of
section 505 of the Act)

October 31, 1980

The final rule (includes FDAs response to the public comments on the proposal)
was published in the Federal Register (45 FR 72582).
The list incorporated appropriate corrections and additions.
6 / 43

3. Objectives
Objectives
3.

Toallow
allow
To
review of
of
review
patterns of
of
patterns
access
access
and usage
usage
and

Toallow
allow
To
discovery of
of
discovery
use of
of
use
unusual
unusual
privileges
privileges

Toallow
allow
To
discovery of
of
discovery
repeated
repeated
attempts
attempts
to bypass
bypass
to
protections
protections

Toserve
serve
To
as aa
as
deterrent
deterrent
by its
its
by
existence
existence

Tosupply
supply
To
an
an
additional
additional
form of
of user
user
form
assurance
assurance
7 / 43

C. CONTENTS OF THE
ORANGE BOOK
(PREFACE TO 27 EDITION)

8 / 43

1.

INTRODUCTION

1.1

Content and Exclusion

1.2

Therapeutic Equivalence-Related Terms

1.3

Statistical Criteria for Bioequivalence

1.4

Reference Listed Drug

1.5

General Policies and Legal Status

1.6

Practitioner/User Responsibilities

1.7

Therapeutic Equivalence Evaluations Codes

1.8

Description of Special Situations

1.9

Therapeutic Equivalence Code Change for a Drug Entity

1.10

Change of the Therapeutic Equivalence Evaluation for a Single Product

1.11

Discontinued Section

1.12

Changes to the Orange Book

1.13

Availability of the Edition

2.

HOW TO USE THE DRUG PRODUCTS LISTS

2.1

Key Sections for Using the Drug Product Lists

9 / 43

2.2

Drug Product Illustration

2.3

Therapeutic Equivalence Evaluations Illustration

DRUG PRODUCT LISTS
Prescription Drug Product List
OTC Drug Product List
Drug Products with Approval under Section 505 of the Act Administered by the Center for Biologics
Evaluation and Research List
Discontinued Drug Product List
Orphan Products Designations and Approvals List
Drug Products Which Must Demonstrate in vivo Bioavailability Only if Product Fails to Achieve
Adequate Dissolution
APPENDICES

A.

Product Name Index A-1

B.

Product Name Index Listed by

C.

Uniform Terms
PATENT AND EXCLUSIVITY INFORMATION ADDENDUM

A.

Patent and Exclusivity Lists

B.

Patent and Exclusivity Terms

10 / 43

CONTENTS OF THE
ORANGE BOOK

1. INTRODUCTION

11 / 43

1.1 Content and Exclusion

Approved OTC drug

products for those which are not marketed
Approved prescription drug with
therapeutic equivalence evaluations
Drug products with
Biologics Evaluation and Research
List of approved products
that have been discontinued from marketing

12 / 43

Cont
The List also includes:
Indices of prescription and OTC drug by trade or established
name (if no trade name exists) and by applicant name (holder
of the approved application).
The list includes applicants names in abbreviated form.
An Addendum contains drug patent and exclusivity

information for the Prescription.

It includes only full approval products and not tentative

approval products.

The List excludes:

Distributors or re-packagers of products
13 / 43

1.2 Therapeutic Equivalence-Related

Terms

Pharmaceutical
equivalents

Pharmaceutical
alternatives

Therapeutic
equivalents

Bioequivalence

Bioavailability

14 / 43

Pharmaceutical Equivalents
1. Contain the same active ingredient(s),
2. Have the same dosage form and route of

administration, and
3. Identical in strength or concentration
4. May differ in shape, release mechanisms, and

packaging
15 / 43

Pharmaceutical Alternatives
Contain the same therapeutic moiety but might

differ in ,

1. Salts, esters, or complexes form of the same

moiety,

2. Different dosage forms,

3. Different strengths

16 / 43

Therapeutic Equivalents

Therapeutic equivalents are expected to have the same clinical effect

and safety profile.

Drug products are considered therapeutic equivalents if they are all

of the following

1.

Pharmaceutical equivalents

2.

Bioequivalent

3.

Approved as safe and effective

4.

Adequately labeled

5.

Manufactured in compliance with current Good Manufacturing

Practice regulations
17 / 43

Bioequivalence
Drug products are considered

bioequivalent if they are

pharmaceutical equivalents
whose rate and extent of
absorption are not statistically
different when administered to
subjects at the same molar dose
under similar experimental
conditions
Bioequivalence use to

in vitro
test methods

comparative
clinical trials

Demonstrated by

in vivo
test methods

pharmacodynamic
studies

determine Therapeutic
Equivalents
18 / 43

1.3 Statistical Criteria for

Bioequivalence
In short Bioequivalence refers to equivalent release of the

same drug substance from two or more drug products.

The standard bioequivalence (PK) study is conducted in

24-36 adults using a two-treatment crossover study design.

Alternately, a four-period, replicate design crossover study

can also be used.

The statistical methodology for analyzing these

bioequivalence studies is called the two one-sided test

procedure.

Two situations are tested with this statistical methodology.

19 / 43

Cont

Pharmacokinetic parameters determine are AUC and Cmax.

1.

Two criteria includes,

Whether a generic product (test), when substituted for a brand-name
product (reference) is significantly less bioavailable. (A limit of test-product
average/reference-product average of 80%)

2.

Whether a brand-name product when substituted for a generic product is

significantly less bioavailable. (A limit of reference-product average/testproduct average 125%)

A difference of greater than 20% for each of the above tests was determined
to be significant

The confidence interval for both pharmacokinetic parameters, AUC and

Cmax, must be entirely within the 80% to 125% boundaries cited above
20 / 43

Example,
Product A is bioequivalent to

Pharmacokinetic
Reference Range

125%

100%

80
%

the reference drug; its

confidence interval of the AUC
falls within 80% to 125% of the
reference drug
Product B is not bioequivalent

to the reference drug; its

confidence interval of the AUC
falls outside of 80% to 125% of
the reference drug

Product A
Reference
Product B
Bioequivalent
Drug
Not Bioequivalent
21 / 43

1.4 Reference Listed Drug

A reference listed drug means the listed drug identified by FDA as the drug

product upon which an applicant relies in seeking approval of its ANDA.

Bioequivalence study carried out

Applicant's product

Compared with reference standard

In vivo & Invitro

The aim of FDA is to avoid possible significant variations among generic

drugs and their brand name counterpart.

The reference listed drug is identified by the symbol "+" in the

Prescription and Over-the-Counter (OTC) Drug Product Lists.

List is available for oral dosage forms, injectables, ophthalmics, otics, and

topical products.

22 / 43

1.5 General Policies and Legal Status

The List contains public information and advice.
It is not compulsory the drug products which may be

purchased, prescribed, dispensed, or substituted for one

another, nor does it, should be avoided.

Exclusion of a drug product from the List does not

necessarily mean that the drug product is not safe or

effective, or that such a product is not therapeutically
equivalent to other drug products.

Rather, FDA has not evaluated the safety, effectiveness,

and quality of the drug product.

23 / 43

1.6 Practitioner/User Responsibilities

Professional care and judgment should be exercised in using the list.

Practitioner should be aware of the multi-source and single-source drug

products.
Multisource Drug Product means those pharmaceutical equivalents
available from more than one manufacturer. For such products, a therapeutic
equivalence (TE) code is included and, in addition, product information is
highlighted in bold face and underlined.
Single-Source Drug Product means only one approved product is available
for particular active ingredient, dosage form, route of administration, and
strength. For such product no therapeutic equivalence code is included.

1.

2.

Products on the List are identified by the names of the holders of approved
applications (applicants) who may not necessarily be the manufacturer of
the product:

Applicants like Manufacture, Contract Manufacturer, Repackager,

Distributor or Marketer.
24 / 43

1.7 Therapeutic Equivalence

Evaluations Codes
The coding system for therapeutic equivalence evaluations
First letter : therapeutically equivalent to other pharmaceutically equivalent products
Second letter : provide additional information on the basis of FDA's evaluations

A CODES

B CODES

1.

TE rating is assigned to PE products as they

are manufactured in accordance with cGMP
regulations and meet the other requirements
of their approved applications or

1.

Documented
bioequivalence problems
and no adequate
bioequivalence have been
submitted to FDA

2.

For those DESI (Drug Efficacy Study

Implementation) drug products and for post1962 drug products in a dosage form
presenting a potential bioequivalence
problem, an evaluation of TE is assigned to
PE, if approved application contains
scientific evidence establishing through in
vivo and in vitro studies.

2.

The quality standards are

inadequate to determine
therapeutic equivalence

3.

The drug products are

under regulatory review
25 / 43

Code A: Drug product that FDA

considers to be therapeutically equivalent
Sr.

Codes

Description

1.

AA

Products in conventional dosage forms not presenting bio-equivalence

problems (All oral dosage forms)

2.

AB

Products meeting necessary bio-equivalence requirements (Multisource drug

(AB1,
AB2,
AB3 )

product )
(In certain instances, a number is added to end of the AB code to make a three character code, which is
assigned only in situations when more than one reference listed drug of the same strength has been
designated under the same heading.
Two or more reference listed drugs are generally selected only when there are at-least two potential
reference drug products which are not bio-equivalent to each other)

AN

Solutions and powder for aerosolization (Marketed for use in any of several delivery

3.

systems)

4.

AO

Injectable oil solutions

5.

AP

Injectable aqueous solutions and in certain cases, intra-venous non-aqueous

solutions (Different routes of administration, Different preservatives or no preservatives, Dry
powders for reconstitution, Concentrated sterile solutions for dilutions, Sterile solutions ready for
injection Should produce same concentration prior to injection)

6.

AT

Topical products
26 / 43

Code B: Drug product that are not to

be therapeutically equivalent
Sr

Codes

Description

1.

B*

Drug products requiring further FDA investigation and review to determine therapeutic
equivalence.

2.

BC

Extended release dosage forms (capsules, injectable and tablets bioequivalence data have not been
submitted).

3.

BD

Active ingredients and dosage forms with documented bio-equivalence problems (Adequate
studies have not been submitted to FDA since due to bio-equivalence problems).

4.

BE

Delayed release oral dosage forms (Significant differences in absorption).

5.

BN

Products in aerosol-nebulizer drug delivery systems (differences in the dose of drug and particle
size delivered by different products)

6.

BP

Active ingredients and dosage forms with potential bio-equivalence problems

7.

BR

Suppositories or enemas that delivers drug for systemic absorption

8.

BS

Products having drug standard deficiencies (variation in pharmacologically active components)

9.

BT

Topical product for which the data are in-sufficient to determine therapeutic equivalence

10

BX

Drug products for which the data are insufficient to determine therapeutic equivalence
27 / 43

1.8 Description of Special Situations

Drugs

Description of Special Situations

Amino-acid and Protein

Hydrolysate injections

These products differ in the amount and kinds of amino-acids they

contain, and therefore, are not considered pharmaceutical equivalents.
For this reasons, these products are not considered therapeutically
equivalent.

Follitropin alpha and beta

Physico-chemical tests and bio-assay, follitropin alpha and follitropin

beta are indistinguishable

Gaviscon tablets

Gaviscon is an OTC product which has been marketed since

September 1970. The active ingredients in this product, aluminum
hydroxide and magnesium trisilicate, were reviewed by the Agency's
OTC Antacid Panel . However, the tablet failed to pass the antacid test
which is required of all antacid products. The Agency, therefore, placed
the tablet in Category III for lack of effectiveness.

Patent certification (s)

Reference listed drug based
upon a suitability petition

ANDA that refers to a Reference Listed Drug (RLD) approved pursuant

to a suitability petition must demonstrate that the proposed product is
bioequivalent to the RLD

28 / 43

1.9 Therapeutic Equivalence Code

Change for a Drug Entity
Such change occur in response to a petition or on its own

initiative.
Changes will generally occur when new scientific
information affects the therapeutic equivalence of an entire
category of drug products in the List.
The change may be from the code,
AA
No Bioequivalence problem

BP
Bioequivalence problem

This procedure does not apply to a change of a particular

product code (e.g., a change from BP to AB or from AB to

BX).
29 / 43

1.11 Discontinued Section

1.

When the product have been discontinued from

marketing,

2.

Are for military use,

3.

Or have had their approvals withdrawn for other than

safety or efficacy reasons

4.

Drug Products for exportation

30 / 43

CONTENTS OF THE
ORANGE BOOK
2. HOW TO USE THE DRUG PRODUCT
LISTS

31 / 43

2.1 Key Sections for Using the Drug

Product Lists.

1.
2.

3.
4.
5.

This contains illustrations, along with Drug Product Lists, indices,

and lists of abbreviations and terms which facilitate their use.
Illustration: Depicts the format found in the Prescription Drug
Product List.
Drug Product Lists: The Prescription and OTC drug product lists,
arranged alphabetically by active ingredient (s), contains product
identification information (active ingredients, dosage forms, routes
of administration, product names, application holders, strengths) for
single and multiple ingredient drug products. Also shown are the
application number and drug product number.
Product Name Index.
Product Name Index Listed by Applicant.
Uniform terms.

32 / 43

2.2 Drug Product Illustration

SINGLE INGREDIENT
ACTIVE INGREDIENT
DOSAGE FORM : ROUTE OF ADMINISTRATION

MEPIRIDINE HYDROCHLORIDE
INJECTABLE : INJECTION

TRADE OR GENERIC NAME

HEXANON

REFERENCE LISTED DRUG

AP + METRO PHYS
AP +
AP +
AP +
MEPIRIDINE HCL

TE CODE FOR MULTISOURCE PRODUCT

FINAL APPROVAL DATE

SINGLE SOURCE PRODUCT (NO TE CODE)

AP DONHARE PHARM
AP
AP

25 mg / ml
50 mg / ml
75 mg / ml
100 mg /
ml
25 mg / ml
50 mg / ml
75 mg / ml

AP
AP

100 mg / ml

JOHONSON MED
AP HOLOVAC LLC
OBS PHARM

10 mg / ml
25 mg / ml
150 mg / ml

N13111 001
N13111 002
N13111 003
Aug 22, 1983
N13111 004
Jan 19, 1985
N11586 001
N12569 001
N14458 002
Aug 11, 1987
N22543 004
Aug 28, 1987
N11786 002
N24765 003
N03841 003

APPLICANT
AVAILABLE STRENGTH OF PRODUCT
APPLICANT NUMBER & PRODUCT NUMBER
PRODUCT NUMBER IS FOR FDA INTERNAL COMPUTER DATA USE ONLY

33 / 43

Example
ALBUTEROL : AEROSOL, METERED; INHALATION
VENTOLIN : AB + GLAXOSMITHKLINE 0.09MG/INH N18473 001
ALBUTEROL : AB ARMSTRONG PHARMS 0.09MG/INH N72273 001 Aug 14, 1996
AB GENPHARM
0.09MG/INH N73045 001 Aug 19, 1997
Albuterol :
Active Ingredient
Aerosol, Metered; Inhalation : Dosage Form / Route of Administration
Ventolin :
Proprietary Name
Albuterol :
Generic Name
GlaxoSmithKline, :
Manufacturer
+ sign :
Indicates Ventolin is Reference Listed Drug (RLD)
AB :
Therapeutic Equivalence (TE) Code
Amstrong Pharm, Genpharm : Applicant
0.09MG/INH :
Strength
N18473 001, N72273 001, : Application Number and Product Number of respective
products
Aug 14 1996, Aug 19 1997: Final Approval Date
34 / 43

2.3 Therapeutic Equivalence

Evaluations Illustration
SULFASALAZINE
TABLET : ORAL
FAZINE
AB

Product consider therapeutically equivalent to each other

500 mg

N4 2999 001

500 mg

N4 0222 001

500 mg

N4 1297 001

SULAZINE
AB

Product consider not therapeutically equivalent to any other

product listed

PARKLAND

URSA

SULFASALAZINE
BP

BROWN

SULFASALAZINE
TABLET : ORAL
FAZINE
AB

Product consider not therapeutically equivalent to each

other

PARKLAND

500 mg

N4 2999 001

SULFASALAZINE
BP

BROWN

500 mg

N4 1297 001

35 / 43

Cont
Drug Product reviewed through DESI are not included
It includes only full approval products and not tentative approval

products

Drug Product of Repackager/Distributor is considered to be

therapeutically equivalent to the Application Holders product

Even if the Application holders drug product is single source or

coded as nonequivalent, repackagers or distributors product is

TE to Application Holders product

The new approvals and required changes in data are included in

each subsequent edition. Even monthly cummulative supplements

are published
36 / 43

DRUG PRODUCT LISTS

1.

Prescription Drug Product List

2.

OTC Drug Product List

3.

Drug Products with Approval under Section 505 of the Act

Administered by the Center for Biologics Evaluation and Research
List

4.

Discontinued Drug Product List

5.

Orphan Products Designations and Approvals List

6.

Drug Products Which Must Demonstrate in vivo Bioavailability

Only if Product Fails to Achieve Adequate Dissolution
37 / 43

APPENDIX
A. Appendix A: Product Name Index, is an index of

Prescription and OTC Drug Products by established or

trade names.

B.

Appendix B: Product Name Index Listed by Applicant, is

an index of Prescription and OTC Drug Products that
cross references applicants to drug products.

C.

Appendix C: Uniform terms, To improve readability,

uniform terms are used to designate dosage forms, routes
of administration and abbreviations used to express
strengths.
38 / 43

F. CUMMULATIVE SUPPLEMENT

It is one of a series of monthly updates to the Approved Drug Products with Therapeutic Equivalence
Evaluations.

Provides information on :
Newly approved drugs
Revised therapeutic equivalence evaluations
Updated patent and exclusivity data
Applicant Name Changes

Products that have

Never been marketed,
Are for exportation, or for military use,
Have been discontinued from marketing
That have had their approvals withdrawn for other than safety or efficacy reasons will be flagged
in this. Cumulative Supplement with the "@" symbol to designate their non-marketed status. (will be
included in Discontinued Section)

New additions to the Prescription Drug Product List and OTC Drug Product List are indicated by the
symbol >A>.

The Patent and Exclusivity List new additions are indicated by the symbol >A>

New deletions to the Prescription Drug Product List and OTC Drug Product List are indicated by the
symbol >D> (DELETE)
39 / 43

G. THE GREEN BOOK & THE

BLUE BOOK
THE GREEN BOOK
It is a list of all animal drug products

approved for safety and effectiveness.

It consist of eight sections which are as

follow,
Section 1 - NADA Number, Trade Names and
Sponsors arranged by Tradename,
NADA Number
Section 2 - Active Ingredients
Section 3 - Patent Information
Section 4 - Exclusivity Periods
Section 5 - Products Subject to Notice of Hearing
Section 6 - Voluntary Withdrawals

THE BLUE BOOK

The FDA publication Requirement

of Laws and Regulations Enforced

by the U.S. Food and Drug
Administration

It has been discontinued as of

October 2002.

In its place there is a Wealth Of

Compliance Information on the

FDA Website. For links to this
information, please go to the
Websites
Industry
Portal<http://www.fda.gov/oc/indu
stry/default.htm>.

Section 7 - Suitability Petition Actions

Section 8 - 2006 Monthly Updates
40 / 43

H. QUESTIONS
1.

September 2005
Define: Pharmaceutical Equivalents, Pharmaceutical
Alternatives and Therapeutic equivalents. What are the
criteria for these equivalents? (Internals July 2006)

2.

What are the statistical criteria for Bio-equivalence

September 2006
What are Orange Book, Green Book and Blue Book?
Discuss the coding system for Therapeutic Equivalence
Evaluation and how it can be changed giving suitable
illustration? (Internals July 2006)

41 / 43

I. REFERENCE
http://www.fda.gov/cder/orange/obannual.pdf
http://www.fda.gov/cder/orange/obcs.pdf

42 / 43

THANK
YOU

43 / 43