Phase One

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CiprofloxacinAnthrax post-exposure prophylaxis

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

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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

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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

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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 2811735-1745, 1999
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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
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Approved CIPRO Oral and I.V. Indications

• Lower Respiratory Infections
• Skin and Skin Structure Infections
• Bone and Joint Infections
• Urinary Tract Infections
• Infectious Diarrhea
• Complicated Intra-Abdominal Infections
• Empirical Therapy in Febrile Neutropenic Patients

• Nosocomial Pneumonia
• Chronic Bacterial Prostatitis
• Acute Sinusitis
• Acute Uncomplicated
• Cystitis
• Typhoid Fever
• Urethral and Cervical Gonococcal Infections

Includes Severe Infections
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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

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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

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Events Leading to Anthrax Submission

• 1999
• The Centers for Disease Controls 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

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Events Leading to Anthrax Submission

• 1999
• Government agencies contacted Bayer regarding
  ciprofloxacin to provide advice and to help
  facilitate the Federal Governments 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

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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

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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

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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

• The Cmin is approximately 0.2 ?g/mL
• The MIC90 of Bacillus anthracis is 0.06 µg/mL

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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

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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
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

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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

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Clinical Success Rates in the LRTI Pooled Studies
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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

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Review of Global Clinical Trials Safety Database
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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

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Review of Controlled Pediatric Clinical Trial
Safety Database
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Ciprofloxacin Global Clinical Trials Pediatric
Safety Database
Adverse Events By Duration of Therapy
Events reported in 2 or more patients treated
for 30-59 or ? 60 days None of these were
considered serious by the reporting investigator
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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

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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

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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 Reports1Ten 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)
1 Bayer Global Drug Safety Database
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Ciprofloxacin Spontaneous ADE Reports1Ten 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
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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

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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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