# Presentation: 658002

## Slide 1

## CiprofloxacinAnthrax post-exposure prophylaxis

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

## 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**

## 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**

## 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**** **

## 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**

## 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**

## 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**

## 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**

## 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**

## 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 **

## 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**

## 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**

## 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**

## Rationale for the Use of Ciprofloxacin

**Ciprofloxacin Pharmacokinetics**
**Review of Lower Respiratory Tract Infection Clinical Database**
**Review of ciprofloxacin safety in adults and pediatrics**

## Pharmacokinetics/Pharmacodynamics

***Bacillus anthracis *****is highly susceptible to ciprofloxacin (MIC****90**** = 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%**

## Pharmacokinetics/Pharmacodynamics

**  ****Plasma concentrations observed at the **
**   ****recommended dosages:**** **

**  ****The C****min**** is approximately 0.2 ********g/mL**
-   **The MIC****90**** of *****Bacillus anthracis *****is 0.06 μg/mL**

**Pharmacokinetics/Pharmacodynamics**

## Pharmacokinetics/Pharmacodynamics

**For optimal antibiotic effect the target values for C****max****/MIC and AUC/MIC should be at least 8-10 and 125, respectively**
**C****max****/MIC ratio = 50 for *****Bacillus anthracis***
**AUC****0-12h****/MIC ratio = 228 for *****Bacillus anthracis***

## 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   **
** ****interval****1,2**

**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**

## 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**

## 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**

## Clinical Success Rates in the LRTI Pooled Studies

## 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**

## Review of Global Clinical Trials Safety Database

## 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**

## Review of Controlled Pediatric Clinical Trial Safety Database

## 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**

## 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**

## 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**

## 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**

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

**                                     **_**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 **

**All Patient Exposures (N ******** 250 million)**

**1**** ****Bayer Global Drug Safety Database**

## Most Frequently Reported Ciprofloxacin Spontaneous ADE Reports1 By Age (When Known) (All Formulations)

**1**** ****Bayer Global Drug Safety Database**

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

**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                              **

_**All Patient Exposures**_
**N ******** ****250 million **

**1**** ****Bayer Global Drug Safety Database**

## 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**

## 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**

## Slide 36