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Ciprofloxacin
Anthrax post-exposure prophylaxis
Andrew S. Verderame
Associate Director, Regulatory Affairs
Bayer Corporation, Pharmaceutical Division
11/19/09 2
Agenda
11/19/09 3
Introduction
11/19/09 4
Proposed Labeling
11/19/09 5
Approved CIPRO® Formulations
11/19/09 6
Approved CIPRO®
Oral and I.V. Indications
• Lower Respiratory • Nosocomial Pneumonia*
Infections* • Chronic Bacterial Prostatitis
• Skin and Skin Structure • Acute Sinusitis
Infections*
• Acute Uncomplicated
• Bone and Joint Infections*
Cystitis
• Urinary Tract Infections*
• Typhoid Fever
• Infectious Diarrhea*
• Urethral and Cervical
• Complicated Intra- Gonococcal Infections
Abdominal Infections*
• Empirical Therapy in Febrile
Neutropenic Patients*
1990 - 1991
• Gulf War
− Bayer provided 30 million CIPRO 500 mg Tablets to
the US Government
− CIPRO Tablets distributed to air and ground troops
− Bayer commended for meeting urgent production and
delivery timelines
11/19/09 8
Events Leading to
Anthrax Submission
1998
• U.S. Army Medical Research Institute of
Infectious Diseases’ Medical Management of
Biological Casualties Handbook (3rd Ed.)
references ciprofloxacin 500 mg oral bid as a
preferred antibiotic therapy for anthrax
prophylaxis
11/19/09 9
Events Leading to
Anthrax Submission
1999
• The Centers for Disease Control’s Morbidity and
Mortality Weekly Report published the recommended
treatment guidelines for post-exposure prophylaxis
of anthrax, including ciprofloxacin use as a drug of
choice
• The Working Group on Civilian Biodefense published
their consensus statement in JAMA for Public Health
Management following the use of anthrax as a
biological weapon, also listing ciprofloxacin as a
preferred agent
11/19/09 10
Events Leading to
Anthrax Submission
1999
• Government agencies contacted Bayer regarding
ciprofloxacin to provide advice and to help facilitate
the Federal Government’s Emergency Preparedness
Plans in the event of a bioterrorist attack
• Internal Bayer discussions were held concerning
the published recommendations and heightened
awareness of potential bioterrorism and action plan
created
11/19/09 11
Events Leading to
Anthrax Submission
1999
• Bayer submitted a detailed briefing package to the
FDA to assess the regulatory position regarding the
feasibility of an anthrax prophylaxis indication and
the required content of a labeling supplement
• FDA agreed that the information available was
sufficient to file a supplemental application and
encouraged Bayer to do so
11/19/09 12
Concurrent Events
1998 -1999
• August 1998 Bayer proposed a pediatric
development program to FDA in complicated urinary
tract infections
• May 1999 FDA issued a Written Request Letter to
Bayer requesting the initiation of clinical trials with
ciprofloxacin in pediatric patients
• Large scale pediatric studies began prior to year end
1999
11/19/09 13
Final Events Leading
to Anthrax Submission
11/19/09 14
Rationale for the Use of Ciprofloxacin
• Ciprofloxacin Pharmacokinetics
11/19/09 15
Pharmacokinetics/Pharmacodynamics
11/19/09 16
Pharmacokinetics/Pharmacodynamics
11/19/09 17
Pharmacokinetics/Pharmacodynamics
11/19/09 18
Tissue Penetration
1
Gottfried et al Clin. Infect. Dis. 27(4): 968, 1998
2
Bergan et al Eur. J. Clin. Microbiol. Vol. 5 No. 4 pp. 458-461, 1986
* 3 hours
11/19/09 19
CIPRO® Clinical Database
11/19/09 20
Review of US Lower Respiratory
Tract Infection Clinical Database
11/19/09 21
Clinical Success Rates
in the LRTI Pooled Studies
100
86 85
80
Percent Success (%)
60
N = 1689
N = 1523
40
20
0
CIPRO COMPARATORS
11/19/09 22
Review of Overall Clinical
Trials Safety Database
11/19/09 23
Review of Global Clinical
Trials Safety Database
Cipro Pts from Control Cipro Pts Cipro Pts
Controlled Patients Treated 30 – 59 Treated ≥60
Studies N = 11,980 Days Days
N = 12,799 N = 1,420 N = 1,051
(%) (%) (%) (%)
Any Event 31.1 32.8 27.8 28.6
Nausea 5.5 5.0 8.9 3.8
Diarrhea 4.1 4.7 5.8 2.5
Vomiting 2.8 2.2 4.4 1.7
Headache 2.6 5.2 1.3 1.0
Rash 2.5 2.7 3.6 3.9
LFT
2.1 2.1 3.2 2.6
Abnormal
Abdominal
1.7 1.8 1.4 3.6
Pain
Pruritus 1.3 1.1 1.4 1.5
Dizziness 1.1 1.3 0.7 0.6
11/19/09 24
CIPRO® Pediatric Experience
11/19/09 25
Review of Controlled Pediatric
Clinical Trial Safety Database
CIPRO CONTROL
N = 167 N = 178
(%) (%)
Any Event 51 44
LFT Abnormal 12 12
Vomiting 10 4
Rash 7 4
Nausea 7 3
Arthralgia 5 7
Joint Disorder 5 6
Abdominal Pain 4 4
Headache 4 3
Diarrhea 2 3
Pruritus 2 1
Dizziness 0 2
11/19/09 26
Ciprofloxacin Global Clinical
Trials Pediatric Safety Database
Adverse Events* By Duration of Therapy
All Cipro All Cipro Pediatric Pts All Cipro Pediatric Pts
Pediatric Pts Treated 30 – 59 Days Treated ≥60 Days**
N = 2,327 N = 189 N = 104
(%) (%) (%)
Any Event 13 20 17
Nausea 2 4 2
LFT Abnormal 2 2 1
Arthralgia 1 4 5
Diarrhea 1 2 0
Rash 1 1 2
Pruritus 1 1 2
Arthritis <1 1 0
Photosensitivity Reaction <1 2 3
Injection Site Sensitivity <1 0 2
Nervousness <1 0 2
Abnormal Kidney Function <1 2 0
11/19/09 28
CIPRO® Pediatric Experience
* IMS Data
11/19/09 29
CIPRO® - Review of Global
Post-Marketing Safety Database
11/19/09 30
Ciprofloxacin Spontaneous ADE Reports1
Ten Most Frequently Reported Events
(All Formulations)
11/19/09 34
Conclusions
11/19/09 35
11/19/09 36