11/19/09 1

Ciprofloxacin
Anthrax post-exposure prophylaxis

Andrew S. Verderame
Associate Director, Regulatory Affairs
Bayer Corporation, Pharmaceutical Division

11/19/09 2
 Agenda

• Introduction and Proposed Labeling

• CIPRO Product Line
• Events Leading to the Submission
• Discussion of Indication and Submission
• Rationale for the use of Ciprofloxacin in this
indication
• Conclusion

11/19/09 3
 Introduction

• On February 29, 2000 Bayer submitted an sNDA

to FDA for all oral and I.V. CIPRO formulations
to provide labeling for an anthrax post-
inhalation exposure prophylaxis indication
• According to FDA, this is the first antimicrobial
drug application submitted for an indication
resulting from the intentional use of a biological
agent

11/19/09 4
 Proposed Labeling

• Proposed Indication for adults and pediatrics:

Anthrax (post-inhalation exposure prophylaxis)
caused by Bacillus anthracis

• Recommended Dosage* (BID)

Formulation Adults Pediatrics
Tablet/Suspension 500 mg 10-15 mg/kg
I.V. 400 mg 10-15 mg/kg

• Recommended Duration* - 60 Days

* Inglesby TV, Henderson DA, Bartlett JG et al. JAMA 281:1735-1745, 1999

11/19/09 5
 Approved CIPRO® Formulations

Five formulations of ciprofloxacin have been

approved in the US for a wide variety of indications:
• Tablets
• Oral Suspension*
• Intravenous Solution
• Otic Suspension with hydrocortisone
• Ophthalmic Solution

* Approved for all CIPRO Tablet indications, and is the only

fluoroquinolone with an approved oral liquid formulation

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*

* Includes Severe Infections

11/19/09 7
 Events Leading to
Anthrax Submission

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

• Department of Defense conducts anthrax

Rhesus monkey testing

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

• Centers for Disease Control (CDC) contacted

Bayer (Nov. 1999) to encourage submission of a
labeling supplement to FDA
• On February 29, 2000 Bayer submitted an sNDA
to FDA for the CIPRO oral and IV formulations

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Rationale for the Use of Ciprofloxacin

• Ciprofloxacin Pharmacokinetics

• Review of Lower Respiratory Tract Infection

Clinical Database
• Review of ciprofloxacin safety in adults and
pediatrics

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Pharmacokinetics/Pharmacodynamics

• Bacillus anthracis is highly susceptible to ciprofloxacin

(MIC90 = 0.06 µg/mL)

• Ciprofloxacin half-life is approximately 4 hours

• Protein binding is approximately 30%

• The absolute bioavailability of the oral formulations is

approximately 70%

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 Pharmacokinetics/Pharmacodynamics

• Plasma concentrations observed at the

recommended dosages:
Cmax AUC24h
Ciprofloxacin Dose (µg/mL) (µg•h/mL)

Adult 500 mg PO BID 3.0 27.4

Adult 400 mg I.V. BID (1 hr infusion) 4.6 25.4
Pediatric 15 mg/kg PO BID 3.5 26.6
Pediatric 10 mg/kg I.V. BID (30 min infusion) 8.5 27.6
Pediatric 10 mg/kg I.V. TID (1 hr infusion) 3.6 – 5.3 26.7- 37.4

• The Cmin is approximately 0.2 µ g/mL

• The MIC90 of Bacillus anthracis is 0.06 µg/mL

11/19/09 17
Pharmacokinetics/Pharmacodynamics

• For optimal antibiotic effect the target values for

Cmax/MIC and AUC/MIC should be at least 8-10 and
125, respectively
• Cmax/MIC ratio = 50 for Bacillus anthracis

• AUC0-12h/MIC ratio = 228 for Bacillus anthracis

11/19/09 18
 Tissue Penetration

Concentration of ciprofloxacin in bronchial epithelial lining

fluid, alveolar macrophages and peripheral lymph fluid
remain above the target pathogen MIC for the entire dosing
interval1,2
Tissue or Fluid Concentration Concentration
(4 hours) (12 hours)
Bronchial Epithelial 1.87 ±0.94 µg/mL 0.42 ±0.10 µg/mL
Lining Fluid
Alveolar Macrophages 34.6 ±22.2 µg/mL 5.1 ±7.1 µg/mL
Peripheral Lymph 1.0 µg/mL* 0.25 µg/mL
Fluid

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
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 CIPRO® Clinical Database

• The most widely studied fluoroquinolone

• Bayer has sponsored over 850 ciprofloxacin

clinical trials
• Over 140,000 adults and 3,400 children have
been treated in the ciprofloxacin protocols
• Clinical trials have well defined the safety and
efficacy of ciprofloxacin therapy

11/19/09 20
 Review of US Lower Respiratory
Tract Infection Clinical Database

• 34 controlled studies included diseases such as

Nosocomial Pneumonia, Community Acquired
Pneumonia, Acute Exacerbations of Chronic
Bronchitis, Pulmonary Exacerbations of Cystic
Fibrosis
• Comparators such as Ceftazidime, Ampicillin,
Clarithromycin, Imipenem, Ceftriaxone,
Amoxicillin/Clavulanic Acid, Cefaclor,
Tobramycin, Cefuroxime, Erythromycin,
Vancomycin

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

• Over 1000 patients (including 104 children) have

received ciprofloxacin for 60 days or longer in
Bayer sponsored clinical trials worldwide
• The most common indications included:
− osteomyelitis
− cystic fibrosis
− prostatitis
− pyelonephritis
− UTI prophylaxis
− tuberculosis

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

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 CIPRO® Pediatric Experience

• Bayer has completed several pediatric clinical

trials: Cystic Fibrosis, Meningococcal carriage,
Diarrheal Diseases, Pneumonia, Neutropenia,
etc.
• Data available on over 3,400 CIPRO treated
pediatric patients
• No serious adverse events reported in the
pediatric patients (n = 104) receiving at least 60
days of ciprofloxacin in clinical trials

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

* Events reported in 2 or more patients treated for 30-59 or ≥ 60 days

** None of these were considered serious by the reporting investigator 11/19/09 27
 CIPRO® Pediatric Experience

• After discussions with FDA on study design,

two ciprofloxacin pediatric trials are currently
ongoing
• Complicated Urinary Tract Infection -
Controlled, Randomized, Double-Blind
Comparative Trial
• Long-term (post-dosing) Observational Study in
ciprofloxacin-treated Pediatric Patients

11/19/09 28
 CIPRO® Pediatric Experience

• Despite prominent class labeling warnings and no

promotion to the pediatric community, it is estimated
that 14,000 prescriptions are written annually (0.1 %
of all US CIPRO scripts) for patients younger than 10
years old, an additional 28,000 (0.2 %) for patients
between 10-14, and 140,000 (1%) for patients between
15-17*
• Approximately 4.5 million ciprofloxacin pediatric
treatment courses worldwide over the last 13 years

* IMS Data

11/19/09 29
 CIPRO® - Review of Global
Post-Marketing Safety Database

• Ciprofloxacin has been available for prescription

use for 13 years
• Over 250 million prescriptions written worldwide
(over 5 billion individual doses) for all formulations

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 Ciprofloxacin Spontaneous ADE Reports1
Ten Most Frequently Reported Events
(All Formulations)

All Patient Exposures (N ≈ 250 million)

Number of Reports
1. Rash 1232 (4.9 per 1 million patients)
2. Tendon Disorder 537
3. Arthralgia 476
4. Pruritus 466
5. Urticaria 457
6. Nausea 409
7. Diarrhea 396
8. Convulsion 366
9. LFT Abnormal 365
10. Dizziness 344
1
Bayer Global Drug Safety Database
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 Most Frequently Reported Ciprofloxacin
Spontaneous ADE Reports1 By Age (When Known)
(All Formulations)

Age ≥ 18 Age < 18

N ≈ 245 million N ≈ 4.5 million
1. Rash 1026 1. Rash 32
2. Tendon 433 2. Arthralgia 24
Disorder
3. Pruritus 394 3. Urticaria 24
4. Urticaria 380 4. Convulsion 15
5. Arthralgia 373 5. Face Edema 15
6. Nausea 334 6. Pruritus 15
7. Diarrhea 329 7. Fever 14
8. Convulsion 310 8. Anaphylactoid 13
Reaction
9. LFT Abnormal 296 9. Nausea 13
10. Dizziness 277 10. Photosensitivity 13
Reaction
1
Bayer Global Drug Safety Database
11/19/09 32
 Ciprofloxacin Spontaneous ADE Reports1
Ten Most Frequently Reported Serious Events
(All Formulations)

All Patient Exposures

N ≈ 250 million
1. Convulsion 215 (0.86 per 1 million patients)
2. Anaphylactoid Reaction 167
3. Rash 166
4. Tendon Rupture 142
5. Acute Kidney Failure 140
6. Tendon Disorder 128
7. LFT Abnormal 119
8. Thrombocytopenia 103
9. Kidney Failure 97
10. Kidney Function 96
Abnormal
1
Bayer Global Drug Safety Database
11/19/09 33
 Summary

• 13 years of marketed clinical experience

• Over 250 million prescriptions written worldwide

• Ciprofloxacin pharmacokinetics supports expected

efficacy in this indication
• The extensive clinical trial and post-marketing
experience with ciprofloxacin has defined its
safety profile, including extended treatment
durations

11/19/09 34
 Conclusions

• Bayer Corporation, after discussions with

several government agencies, has filed this
supplement in response to a public health need
• Given the seriousness of the indication and the
extraordinary hazards that an anthrax release
would entail, the risk / benefit ratio supports
ciprofloxacin therapy for this proposed
indication

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