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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

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factive gemifloxacin nda 21 158

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
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



NDA 21-158

Peter A. Dionne

Microbiologist DSPIDP

  • Activity compared to other Quinolones
  • Activity against Resistant S. pneumoniae
  • Activity against S. pneumoniae Mutants
  • Efficacy against S. pneumoniae in Rat Pneumonia model
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
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
in rat s pneumoniae rti infection model
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


sponsor s proposed indication
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

Efficacy in relation to

  • Duration of Treatment
  • Severity of disease
  • Streptococcus pneumoniae





fda analyses duration of treatment
FDA Analyses - Duration of Treatment

Statistical issues with the combining of all 7 day patients


  • 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
  • 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%

clinical response in hospitalized patients
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
severity and precedents
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
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
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
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
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
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

Acute Bacterial Exacerbation of Chronic BronchitisFactive (gemifloxacin) NDA 21-158

Eileen Navarro, MD

abecb applicant s proposed label indication and claim

ABECBApplicant’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
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


  • Study design issues
  • Adjustments for multiple comparisons
  • Clinical relevance
early bacterial eradication in abecb
Early BacterialEradication 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
applicant s finding superiority over comparators itt considerations
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
Efficacy in Severe ABECBStudy 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









Beta lactam:




cefuroxime axetil


cefditoren pivoxil




Partial List of Approved Products for ABECB
  • 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

Safety of Factive(gemifloxacin)NDA 21-158

Maureen R. Tierney, MD, MSc.

Medical Officer


safety population
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%
  • Study 344 & other special Clin. Pharm.
adverse events of special interest
Adverse Events of Special Interest
  • Withdrawals and Serious Adverse Events
  • QT Prolongation
  • Hepatic Safety Profile
  • Rash
qt effects
QT Effects
  • Known side effect for quinolone class
  • Some mild prolongation noted in database
  • Serious event if occurred
mean change in qtc
Mean Change in QTc
  • Clinical Pharmacology 4.9 msec
  • Combined Clinical Population 2.6 msec
drug interactions and qtc
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
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
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
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
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
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
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
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
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
  • 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
severity of rash
Severity of Rash

*some rashes categorized twice because of multiple rash terms

time and rash
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
Risk Factors for Rash Development
  • Gender (female)
  • Age (<40)
  • Planned duration of treatment (>7 days)
  • Indication
  • HRT in Women >40 years of age
prior or subsequent quinolone usage
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
withdrawals and saes due to rash 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
mucus membrane involvement part a
Mucus Membrane InvolvementPart 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
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
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
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
case 2 344 020 00844
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
case 3 344 025 01318
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
case 4 344 030 1420
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
case 5 344 028 1374
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
case 6 344 029 01399
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
histopatholgy of gemifloxacin rash
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
summary study 344 part b
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
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
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 considerations abecb
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
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
summary 1
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
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