# Presentation: 203810

## Factive®   (gemifloxacin)NDA 21-158

**March 4, 2003 **
**Anti Infective Drugs Advisory Committee Meeting**
**Edward Cox, M.D., M.P.H.**
**Deputy Director, Office of Drug Evaluation IV**
**Center for Drug Evaluation and Research**
**U.S. Food and Drug Administration**

## FDA Presentations

**Microbiology****	****	**
**	****     ****Peter Dionne, MS**
**Community-Acquired Pneumonia****	**
**	****    ****Regina Alivisatos, MD**
**Acute Bacterial Exacerbation of Chronic Bronchitis **
**	****    ****Eileen Navarro, MD**
**Safety **
**	****    ****Maureen Tierney, MD, MSc**
**Summary**
**	****    ****Edward Cox, MD, MPH**

## MICROBIOLOGY OF FACTIVE ®

**GEMIFLOXACIN MESYLATE**
**NDA 21-158**
**Peter A. Dionne**
**Microbiologist DSPIDP**

## OVERVIEW

**Activity compared to other Quinolones**
**Activity against Resistant *****S. pneumoniae***
**Activity against *****S. pneumoniae*****   Mutants**
**Efficacy against *****S. pneumoniae*****  in Rat Pneumonia model**

## In vitro  Activity of Gemifloxacin and Comparators {MIC90s}

## Comparative PK Data for Quinolones

**Gemi MICs are Lower against Gram positive       ****bacteria compared to other quinolones**
**Gemi MICs are about equal to other quinolones against Gram negative bacteria**
**Gemi PK parameters weaken the significance of lower MICs against Gram +**
**Gemi PK parameters may affect efficacy against Enterobacteriaceae**

## Activity Against PEN-R S. pneumoniae

## Activity Against Quinolone-RS. pneumoniae

## MICs of Selected S. pneumoniaeMutants

## Susceptibility of Cipro-RS. pneumoniae

## Activity Against 44 S. pneumoniaeSecond Step Mutants [# at each MIC]

***S. pneumoniae  *****MICs against Pen-R = MICs against Pen-S as with all quinolones**
**Gemi MICs against Quin-R *****S. pneumoniae  *****are in the range of 0.25-1 mcg/mL; Moxi MICs about           4 mcg/mL**
***S. pneumoniae*****  double-mutants have Gemi MICs 0.25 mcg/mL; Moxi ~ 2 mcg/mL; Levo ~32 mcg/mL**
**Gemi PK values about 6 times lower than Moxi PK **

## Efficacy of Gemifloxacin Compared to Levofloxacin in RTI in Rats (Gemi MIC < 0.03 mcg/mL]

**	**

## Efficacy of Gemifloxacin Compared to Levofloxacin in RTI in Rats [Gemi MICs > 0.125 mcg/mL]

## Efficacy of Gemifloxacin Compared to Moxifloxacin and Gatifloxacin in RTI in Rats

## In rat S. pneumoniae  RTI infection model 

**Isolates with Gemi MICs **_**<**_** 0.03 mcg/mL once daily dosing is effective and CFU/lung reaches close to level of detection (**_**<**_** 1.7 CFU/lung]**
**Isolates with Gemi MICs **_**>**_** 0.125 mcg/mL must be dosed BID for efficacy and CFU/lung is > level of detection**
**Gemi better than Levo; Gemi about same as Moxi and Gati**

## Summary

**GEMI ~ MOXI > LEVO**

## Community Acquired PneumoniaFactive (gemifloxacin)NDA 21-158

- Regina Alivisatos, MD

## Sponsor’s Proposed Indication

- Community-acquired pneumonia** caused by *****Streptococcus pneumoniae *****(including penicillin-, clarithromycin- and cefuroxime-resistant strains*****)*****, *****Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella catarrhalis; Mycoplasma pneumoniae; Chlamydia pneumoniae;***** *****Legionella pneumophila; Staphylococcus aureus ***
- Proposed Dose**: One 320 mg tablet daily for 7 days**

## Overview

**Efficacy in relation to**
**Duration of Treatment**
**Severity of disease**
***Streptococcus pneumoniae***
**      ****Penicillin-resistant**
**      ****Macrolide-resistant**
**      ****Cefuroxime-resistant**
**      ****Quinolone-resistant**

## Clinical Studies

## FDA Analyses - Duration of Treatment

**Statistical issues with the combining of all 7 day patients**
**because**
**1 controlled study (011) and 2 uncontrolled were of 7 days duration *****a priori***
**in studies 061, 049, and 185, the duration of treatment was determined at the on-therapy visit and was investigator-driven**
**FDA performed additional analyses based on a stricter division of studies into those with *****a priori***** duration of 7 days and those where duration could vary **

## Patient Disposition- CAP

## FDA Analysis of Clinical Response by Duration of Treatment

## Severity

**Severity was determined by retrospective application of Fine criteria with the exception of study 287 where the Fine criteria were applied prospectively**
**Patients assigned to a risk class (I - V) according to demographic, clinical and laboratory characteristics that stratified them by risk of mortality within 30 days **
**Based on assigned risk class, patients were classified as having mild (I, II), moderate (III) or severe (IV, V) disease**
**Patients in risk classes I, II and III can often be managed as outpatients, whereas those in classes IV and V are at higher risk of death and often require hospitalization***
***mortality risk class IV = 9 - 12%, class V = 30%**

## Severity DemographicsGemifloxacin ITT

## FDA Analysis of Clinical Response by Severity

## Clinical Response in Hospitalized Patients

**Hospitalization used as a criterion to assess the effectiveness of gemifloxacin in severe cases CAP**
**Questions regarding appropriateness of using hospitalization as a sole determinant of severity**
**Decision to hospitalize was investigator-driven and      may have varied according to geographic location**
**Only in study 185 were all patients hospitalized as per protocol for at least 24 hours**
**Comparable efficacy between treatment arms**

## FDA Analysis of Clinical Response in Bacteremic Patients

## Severity and Mortality

## Severity and Precedents

**Two quinolones, levofloxacin and moxifloxacin have a severe disease claim; both with PO and IV formulations**
**Criteria for determining severity differed but were applied at the time of randomization in both applications that received an approval.**
**Criteria were used to determine mode of treatment as well as duration.**
**Most of the severe patients in the levofloxacin NDA received IV treatment.**
**Moxifloxacin claim was granted after FDA review of the IV formulation.**** **

## Streptococcus pneumoniae

**Sponsor is requesting approval for penicillin, macrolide, and cefuroxime resistant *****S. pneumoniae***** Data also submitted on quinolone-resistant *****S. pneumoniae***
**Levofloxacin and moxifloxacin have the indication of PRSP **
**No antimicrobial currently has an MRSP indication**
**PRSP and MRSP discussed at January 2003 AIDAC**
**No previous claims for cefuroxime-resistant PRSP**
**What is the clinical relevance of Macrolide- and Cefuroxime-resistant  *****S. pneumoniae***** in the setting of penicillin resistance?**

## Penicillin Resistant Streptococcus pneumoniae

**Agency and sponsor in agreement that:**
**12 BPP gemifloxacin-treated patients had *****Streptococcus pneumoniae***** isolates with penicillin MICs of ******** 2mcg/mL (3 of these had MICs of **
**    ****4 mcg/mL)**
**Clinical success and bacteriological eradication rates in the PP  patients with PRSP were 100% **
**Four (4) comparator arm patients had PRSP with 100% clinical success and bacteriological eradication rates **

## Macrolide Resistant Streptococcus pneumoniae

**25 gemifloxacin-treated PP patients with *****Streptococcus***
***pneumoniae***** had macrolide resistant isolates**
**(clarithromycin MIC ******** 1mcg/mL)**
**Clinical success and bacteriologic eradication rates were 22/25 (88%) PP**
**10 isolates (40%) were also penicillin-resistant **
**12 comparator-treated PP patients had  macrolide resistant**
***Streptococcus pneumoniae***
**Clinical success and bacteriologic eradication rates were 11/12 (91.6%) PP**
**3 isolates (25%) were also penicillin-resistant**** **

## Cefuroxime-resistant Streptococcus pneumoniae

**18 patients had ****cefuroxime -resistant *****Streptococcus pneumoniae***** isolates ****(MIC ******** 4 mcg/mL)**** **
**Clinical success and bacteriological eradication rates at follow-up were 17/18  (94.4%) **
**12 out of the 18 cefuroxime-resistant isolates  were also PRSP (67%)**
**15 of the 18 ****cefuroxime-resistant isolates ****were also clarithromycin resistant (83%)**
**On the comparators arm there were 7 patients with *****Streptococcus pneumoniae***** isolates (PP) resistant to cefuroxime that were all successfully treated (ITT 8)**

## Quinolone-resistant Streptococcus pneumoniae

**In the gemifloxacin group of the combined studies population, there were no pathogens resistant to ofloxacin and levofloxacin **
**1 resistant isolate on the all comparators arm (failure)**
**In the gemifloxacin group there were 4 isolates of *****Streptococcus pneumoniae *****with an MIC against ciprofloxacin of 4 mcg/mL (clinical success and bacteriological eradication rate: 100%)****  **

## Acute Bacterial Exacerbation of Chronic BronchitisFactive (gemifloxacin) NDA 21-158

**Eileen Navarro, MD**

## ABECBApplicant’s Proposed Label Indication and Claim

** **“**FACTIVE is effective for the treatment of acute exacerbations of chronic bronchitis due to***** H. influenzae, M. catarrhalis, S. pneumoniae, H. parainfluenzae *****and***** S. aureus*****.”**
-  “**earlier eradication of *****H. influenzae *****from the sputum”**

## Issues in Applicant’s Additional Findings :

-  “**Superior clinical efficacy”**
** “****Prolonged exacerbation-free intervals”**
** “****Efficacy in hospitalized severe ABECB”**
** “****no requirement for an IV to oral switch”**
**results in earlier time to hospital discharge**
**reduces RTI related hospitalization**
- 					LIMITATIONS:
** ****Study design issues**
** ****Adjustments for multiple comparisons**
** ****Clinical relevance**

## Efficacy in Principal Studies

## Early Bacterial Eradication in ABECB

- Early Bacterial Eradication in ABECB

- Patients with *H. influenzae* represent only a small
-   proportion of patients with ABECB in the clinical
-   studies
-  In patients with *H. influenzae,* no clear correlation
-   of early eradication with clinical benefit
-  Early eradication related to pharmacokinetics
-  Eradication favored comparators in some pivotal
-   studies

## Clinical Success - ITT AnalysisSupportive Studies

- Clinical Success - ITT AnalysisSupportive Studies

## Applicant’s Finding: Superiority over Comparators ITT - Considerations

**A finding limited to the ITT population of Supportive Studies 069 and 207**
**Primary analysis of clinical efficacy (PP) - non-inferiority **
**Similar response rates in the secondary analyses of Bacterial Efficacy in the BPP and BITT **
**Pivotal ABECB studies do not show superiority for Clinical Efficacy in ITT and PP population.**

## Efficacy in Severe ABECBStudy 207- Considerations

**Non-inferior to parenteral therapy in hospitalized ABECB**
**open label, non-US study**
**hospitalized patients able to tolerate oral therapy limits applicability to ALL  hospitalised patients requiring parenteral therapy**
**Earlier time to discharge (mean difference of 0.5 days)**
**clinical significance of a 0.5 day difference**
**multiple secondary endpoints**
**no difference in primary outcome  **
**no difference in other related outcomes (time to resolution, indirect costs)**** **

## Prolonged Time to Next Exacerbation & Reduced Respiratory Tract Related Hospitalization - Considerations

_**Prolonged Time to Next Exacerbation**_** **
**3 studies - contradictory outcomes **
**one showed a trend favoring FACTIVE (Study 139), one favored the comparator (Study 105)**
**Study 112 -primary analysis showed no difference**
_**Reduced Respiratory Tract Related Hospitalization**_** **
**Analyses not adjusted for multiple comparisons**
**No difference in other related outcomes (e.g. indirect costs)**

## Partial List of Approved Products for ABECB

- Quinolone:
- 	levofloxacin
- 	ofloxacin
- 	moxifloxacin
- 	ciprofloxacin
- 	gatifloxacin
- Macrolide:
- 	clarithromycin
- 	azithromycin

- Beta lactam:
- 	amoxicillin/clavulanate
- 	cefaclor
- 	ceftibuten
- 	cefuroxime axetil
- 	cefdinir
- 	cefditoren pivoxil
- 	cefixime
- 	cefpodoxime
- 	loracarbef

## Anti-infective Use in ABECB- Considerations

## Summary

**FACTIVE clinical efficacy non-inferior to comparators in ABECB**
**Unresolved questions regarding clinical relevance or applicability of other findings**
**Limited evidence supporting other findings**
**Potential impact of broader use in the community**

## Safety of Factive(gemifloxacin)NDA 21-158

- Maureen R. Tierney, MD, MSc.
- Medical Officer
- FDA

## Safety Population

- Phase II and III clinical trials
- Gemifloxacin 320 mg po=6775
- All Comparators (beta lactams, macrolides, and quinolones)=5248
- ABECB~45%
- CAP~17.5%
- ABS,  uUTI, cUTI, SSSI, NGU
- Study 344 & other special Clin. Pharm.

## Demographics of Safety Population

## Demographics of Safety Population

## Demographics of Safety Population

## Adverse Events of Special Interest

- Withdrawals and Serious Adverse Events
- QT Prolongation
- Hepatic Safety Profile
- Rash

## Withdrawals Due to Adverse Events

## Serious Adverse Events with Suspected Relationship

## QT Effects

- Known side effect for quinolone class
- Some mild prolongation noted in database
- Serious event if occurred

## QT Effects

## Mean Change in QTc

- Clinical Pharmacology  4.9 msec
- Combined Clinical Population  2.6 msec

## Changes in QTc

## Gemifloxacin Dose and QTc

- <footer>

- <date/time>

## Drug Interactions and QTc

- No inhibition or induction of CYP450 enzymes
- Not dependent upon metabolism by CYP450 enzymes
- Dual route of elimination

## Hepatic Safety Profile of Gemifloxacin

- Pre-clinical Findings
- LFT increases with 480 and 640 mg doses
- LFT increases in those with hepatic impairment or more comorbidity
- ALT and/or  BR elevations

## Pre-clinical Hepatic Findings in Dogs

- Cholangitis/pericholangitis with hepatocellular degeneration and single cell necrosis at high doses
- crystalline deposits of drug in bile canaliculi
- elevated ALT and Alk Phos

## LFT Elevations at Higher Doses

- Uncomplicated UTI Study
- gemifloxacin 640 mg x 1
- ciprofloxacin 250 mg BID x 3 days
-  9/592 (1.6%) of gemifloxacin group ALT>2xULN with 4 >6xULN
- No ALT elevations >2xULN for comparator
- No bilirubin elevations >2xULN in either group
- Similar results seen in 480mg and 640mg dose clinical pharmacology studies
- Study 005 4/16 elderly withdrawn with high LFTs (ALT 121-333)

## AEs of the Liver and Biliary System in Patients with Baseline Liver Disease*

**** history of liver disease and elevated LFTs at screening***
***Source: Sponsor Safety Table 17.35***

## LFT Elevations in Patients with Higher Comorbidity

- Study 185
- 6 with LFT elevations to >3xULN with 4 withdrawals from Gemifloxacin arm
-  3 with LFT elevations >3xULN but no withdrawals from comparator arm
- Study 287
- 2 with ALT>3xULN + BR>1.5mg/dl

## Combined ALT and Bilirubin Elevations

- ALT>3xULN + BR >1.5 mg/dl
- 2 patients in Study 287 Non comparative CAP
-  1 in comparator in combined clin pop
- ALT>2xULN + BR>1.5 mg/dl in range
- additional 3 for gemifloxacin from comparative clinical trials
-  none for comparator

## Bilirubin Elevations

- One healthy male BR 0.8 to 7.5 mg/dl during clin pharm study (previously had an elevation of BR to 1.7mg/dl on oflox)
- 3 BR elevations >2xULN <4xULN in patients in range at screening (none for comparator) in the combined clinical population (all in comparative studies)

## ALT Elevations

- No patient in range at screening had ALT elevation >8xULN on 320 mg
- 1 patient in total safety population had  treatment emergent ALT elevations to >8xULN on therapy-ALT  110 to 501  IU
- 2 patients on 640 mg dose who were in range at screening had ALT elevations >8xULN**                                                                                                                            **

## RASH

- Higher incidence than all comparators
- Higher number of serious AEs and withdrawals than all comparators
- Markedly high incidence in an enriched population (31.7% Study 344)
- Large % BSA, more urticaria, 6% mucus membrane involvement
- Issues affecting clinical practice

## RASH-Incidence of Events

## Severity of Rash

****some rashes categorized twice because of multiple rash terms***

## Time and Rash

- Two-thirds of rash in gemifloxacin patients began after day 7 of therapy
- Two-thirds of rash in comparator patients began Day 7 or before
- days 8,9,10 most likely for gemifloxacin rash

## Risk Factors for Rash Development

- Gender (female)
- Age (<40)
- Planned duration of treatment (>7 days)
- Indication
- HRT in Women >40 years of age

## Rash by Age, Gender, and Duration of Therapy - Combined Population

- <footer>

- <date/time>

**Rash by Age, Gender, and Duration of Therapy - Combined Population**

- gemifloxacin

- comparators

## Rash by Indication

## Rash in ABECB by Gender, Age and Duration

## Rash in CAP by Age, Gender, and Duration

## HRT use and Risk of Rash

## Prior or Subsequent Quinolone Usage

- 3/181 (1.7%) patients who had received a prior quinolone developed a rash
- selection bias - no rash on prior exposure
- 0/12 patients developed a rash upon receiving a subsequent quinolone after experiencing a rash on gemifloxacin
- selection bias (?) - rash probably not severe** **

## Study 344

## Demographics Study 344

## Study 344 Part A

## Withdrawals and SAEs Due to Rash Study 344 Part A

- Withdrawals
- 26/819 from Gemifloxacin
- 0/164  from Ciprofloxacin
- Serious AEs
- No rash related serious AEs in either arm
- Severe cutaneous AE’s
- 20/260 for gemifloxacin
- 0/7 for ciprofloxacin

## Time and Rash-Part A

## Severity of Rash-Part A

## Extent of Gemifloxacin RashPart A (N=260)

****unknown for 5 cases***

## Characteristics of Gemifloxacin Rash-Part A

## Mucus Membrane InvolvementPart A

- None in Ciprofloxacin rash (n=7)
- Gemifloxacin - 16/260 (6.2% of rash)
- Eyes 3/260
- Genitalia 1/260
- Mouth 12/260

## Mouth Mucus Membrane Lesions in Gemifloxacin Rash Part A

- 5 with one to a few ulcerations, erosions, papules, or vesicles inside mouth or on lips
- 2 with erythema on lips or inside mouth
- 2 with petechiae on lips
- 3 unavailable description of mouth lesions
- no pictures taken

## Treatment of Gemifloxacin Associated Rash

- Antihistamines
- Topical steroid preparations
- Systemic Steroids
- 12/260 rashes in Study 344
- 27/241 rashes in combined clinical population

## Case 1   344-025-1471

- 24yo WF with no PMH
- Onset day 8 with fever
- Pruritic rash with erythematous macules and papules >60%BSA
- Lesions in mouth (?type)
- Treatment with Zyrtec and Medrol pack
- Duration of rash 6 days
- Quality of Life - very much affected

## 025-01471

## Case 2   344-020-00844

- 20 yo WF no PMH
- Onset day 8
- Pruritic rash with erythematous macules and papules >60%BSA with plaques and mild facial edema
- Erythematous macules on lips
- Treatment Benadryl and oral Prednisone
- Duration of rash 12 days
- Quality of Life - moderately affected

## 020-00844

## Case 3 -344-025-01318

- 21 yo WF with h/o child asthma
- Onset Day 6
- Pruritic urticarial rash with erythematous macules and papules >60% BSA
- Treatment Benadryl and oral Solumedrol
- Duration of rash 6 days
- Quality of Life - some aspects very much affected

## 025-01318

## Case 4 344-030-1420

- 21 yo WF no PMH
- Onset day 8
- Non pruritic rash with erythematous macules and papules >60%BSA with ulcers in mouth and pharyngitis
- Not withdrawn
- No systemic therapy
- Duration of rash 7 days
- Quality of Life-minimally affected

## 030-01420

## Case 5   344-028-1374

- 39 yo WF with a h/o hives to sulfa
- Onset day 9
- Morbilliform urticarial eruption 40-60% BSA with erythema on labial mucosa
- Acetaminophen only
- Duration of rash 30 days** **
- Quality of Life-no assessment made

## 028-01374

## Case 6  344-029-01399

- 20 yo WF no PMH
- Onset Day 6
- Pruritic rash with erythematous macules 20-40% BSA
- Duration of rash 4 days
- No photographs of rash taken
- Biopsy - Linear deposition of IgM along dermal basement membrane** **
- Quality of Life-moderately affected

## Slide 105

## Histopatholgy of Gemifloxacin Rash

- Most-mild superficial perivascular infiltrate
- Moderate or deep perivasular infiltrate in 10 specimens
- Eosinophils noted in 10 cases
- No pattern for CD-4 or CD-8 cells
- IF faint deposits of IgM and/or C3 in dermal vessel lumina with 1 along BM
- No evidence of vasculitis, bulla or necrosis

## Study 344 Part B

## Study 344 Part B Excluding Center 027

## Summary Study 344 - Part B

- Suggestion of minor cross-sensitization with ciprofloxacin (not conclusive)
- Cannot extrapolate about cross sensitization with other quinolones
- No evidence of subclinical sensitization with gemifloxacin

## Quinolones and Severe Cutaneous Reactions

- Roujeau et al NEJM 1995;333:1600-7.
- Multivariate Crude RR for SJS/TEN
- quinolones 10 (2.6-38)
- aminopenicillins 6.7 (2.5-18)
- sulfonamides  173 (75-396)
- Literature Review
- 13 case reports SJS/TEN with a variety of fluoroquinolones

## Summary of Safety

- Minor increase in Mean QTc
- Some LFT elevations particularly in those with liver disease or more comorbidity
- Rash
- Increased overall incidence
- Large %BSA involved
- Some severe rashes with mucus membrane involvement in Study 344

## Risk Benefit

## Risk Benefit Considerations - ABECB

- Efficacy
- Length of therapy
- Chronic condition often requiring recurrent therapy
- Rash rates in population prescribed drug
- Possible limitation of future quinolone availabilty in those who experience rash
- Small increases in LFTs
- Minor increase in mean QTC

## Risk Benefit Considerations - CAP

- Efficacy
- Oral therapy
- Prescriber compliance with 7 day regimens
- Possible limitation of future quinolone availability in those who experience rash
- Possibly more hepatic effects in those with more comorbidity
- Minor increase in mean QTc

## Slide 115

## Summary - 1

**Microbiology**
**in vitro and animal model data**
**pharmacokinetic parameters**
**Community Acquired Pneumonia**
**duration of treatment**
**severity of disease**
***Streptococcus pneumoniae***
**Acute Bacterial Exacerbation of Chronic Bronchitis**
**principal studies support efficacy**
**statistical and clinical considerations for other findings**
**population differences clinical trial vs. usage data**

## Summary - 2 

**Safety**
**rash - rates, risk factors, remaining questions**
**risk for more serious dermatologic manifestations?**
**likelihood of cross-sensitization to other fluoroquinolones?**
**practical considerations?**
**hepatic safety - findings at daily doses >320 mg**
**cardiac repolarization**
**risk benefit considerations for the proposed indications**
**CAP**
**ABECB**