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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 l.jpg

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

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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

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NDA 21-158

Peter A. Dionne

Microbiologist DSPIDP

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  • Activity compared to other Quinolones

  • Activity against Resistant S. pneumoniae

  • Activity against S. pneumoniae Mutants

  • Efficacy against S. pneumoniae in Rat Pneumonia model

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In vitro Activity of Gemifloxacin and Comparators {MIC90s}

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  • 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

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ActivityAgainst PEN-R S. pneumoniae

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MICs of Selected S. pneumoniaeMutants

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

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  • 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

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

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In rat Gatifloxacin in RTI in RatsS. 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

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Summary Gatifloxacin in RTI in Rats


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Community Acquired Pneumonia Gatifloxacin in RTI in RatsFactive (gemifloxacin)NDA 21-158

Regina Alivisatos, MD

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Sponsor’s Proposed Indication Gatifloxacin in RTI in Rats

  • 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

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Overview Gatifloxacin in RTI in Rats

Efficacy in relation to

  • Duration of Treatment

  • Severity of disease

  • Streptococcus pneumoniae





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Clinical Studies Gatifloxacin in RTI in Rats

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FDA Analyses - Duration of Treatment Gatifloxacin in RTI in Rats

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

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Patient Disposition- CAP Gatifloxacin in RTI in Rats

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Severity Gatifloxacin in RTI in Rats

  • 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%

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Severity Demographics Gatifloxacin in RTI in RatsGemifloxacin ITT

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Clinical Response in Hospitalized Patients Gatifloxacin in RTI in Rats

  • 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

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Severity and Mortality Gatifloxacin in RTI in Rats

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Severity and Precedents Gatifloxacin in RTI in Rats

  • 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.

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Streptococcus pneumoniae Gatifloxacin in RTI in Rats

  • 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?

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Penicillin Resistant Gatifloxacin in RTI in RatsStreptococcus 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

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Macrolide Resistant Gatifloxacin in RTI in RatsStreptococcus 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

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Cefuroxime-resistant Gatifloxacin in RTI in RatsStreptococcus 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)

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Quinolone-resistant Gatifloxacin in RTI in RatsStreptococcus 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%)

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Acute Bacterial Exacerbation of Chronic Bronchitis Gatifloxacin in RTI in RatsFactive (gemifloxacin) NDA 21-158

Eileen Navarro, MD

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ABECB Gatifloxacin in RTI in RatsApplicant’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”

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Issues in Applicant’s Additional Findings : Gatifloxacin in RTI in Rats

  • “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

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Efficacy in Principal Studies Gatifloxacin in RTI in Rats

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Early Bacterial Gatifloxacin in RTI in RatsEradication 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

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Clinical Success - ITT Analysis Gatifloxacin in RTI in RatsSupportive Studies

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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.

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Efficacy in Severe ABECB ConsiderationsStudy 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)

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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)

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Quinolone: Tract Related Hospitalization - Considerations









Beta lactam:




cefuroxime axetil


cefditoren pivoxil




Partial List of Approved Products for ABECB

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Anti-infective Use in ABECB- Considerations Tract Related Hospitalization - Considerations

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Summary Tract Related Hospitalization - Considerations

  • 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

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Safety of Factive Tract Related Hospitalization - Considerations(gemifloxacin)NDA 21-158

Maureen R. Tierney, MD, MSc.

Medical Officer


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Safety Population Tract Related Hospitalization - Considerations

  • 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.

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Demographics of Safety Population Tract Related Hospitalization - Considerations

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Demographics of Safety Population Tract Related Hospitalization - Considerations

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Demographics of Safety Population Tract Related Hospitalization - Considerations

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Adverse Events of Special Interest Tract Related Hospitalization - Considerations

  • Withdrawals and Serious Adverse Events

  • QT Prolongation

  • Hepatic Safety Profile

  • Rash

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Withdrawals Due to Adverse Events Tract Related Hospitalization - Considerations

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Serious Adverse Events with Suspected Relationship Tract Related Hospitalization - Considerations

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QT Effects Tract Related Hospitalization - Considerations

  • Known side effect for quinolone class

  • Some mild prolongation noted in database

  • Serious event if occurred

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QT Effects Tract Related Hospitalization - Considerations

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Mean Change in QTc Tract Related Hospitalization - Considerations

  • Clinical Pharmacology 4.9 msec

  • Combined Clinical Population 2.6 msec

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Changes in QTc Tract Related Hospitalization - Considerations

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Gemifloxacin Dose and QTc Tract Related Hospitalization - Considerations

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Drug Interactions and QTc Tract Related Hospitalization - Considerations

  • No inhibition or induction of CYP450 enzymes

  • Not dependent upon metabolism by CYP450 enzymes

  • Dual route of elimination

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Hepatic Safety Profile of Gemifloxacin Tract Related Hospitalization - Considerations

  • 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

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Pre-clinical Hepatic Findings in Dogs Tract Related Hospitalization - Considerations

  • Cholangitis/pericholangitis with hepatocellular degeneration and single cell necrosis at high doses

  • crystalline deposits of drug in bile canaliculi

  • elevated ALT and Alk Phos

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LFT Elevations at Higher Doses Tract Related Hospitalization - Considerations

  • 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)

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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

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LFT Elevations in Patients with Higher Comorbidity Baseline Liver Disease*

  • 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

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Combined ALT and Bilirubin Elevations Baseline Liver Disease*

  • 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

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    Bilirubin Elevations Baseline Liver Disease*

    • 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)

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    ALT Elevations Baseline Liver Disease*

    • 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

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    RASH Baseline Liver Disease*

    • 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

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    RASH-Incidence of Events Baseline Liver Disease*

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    Severity of Rash Baseline Liver Disease*

    *some rashes categorized twice because of multiple rash terms

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    Time and Rash Baseline Liver Disease*

    • 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

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    Risk Factors for Rash Development Baseline Liver Disease*

    • Gender (female)

    • Age (<40)

    • Planned duration of treatment (>7 days)

    • Indication

    • HRT in Women >40 years of age

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



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    Rash by Indication Population

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    Rash in ABECB by Gender, Age Populationand Duration

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    Prior or Subsequent Quinolone Usage Population

    • 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

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    Study 344 Population

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    Study 344 Part A Population

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    Withdrawals and SAEs Due to Rash Study 344 Part A Population

    • 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

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    Extent of Gemifloxacin Rash PopulationPart A (N=260)

    *unknown for 5 cases

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    Mucus Membrane Involvement PopulationPart A

    • None in Ciprofloxacin rash (n=7)

    • Gemifloxacin - 16/260 (6.2% of rash)

      • Eyes 3/260

      • Genitalia 1/260

      • Mouth 12/260

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    Mouth Mucus Membrane Lesions in Gemifloxacin Rash Part A Population

    • 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

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    Treatment of Gemifloxacin Associated Rash Population

    • Antihistamines

    • Topical steroid preparations

    • Systemic Steroids

      • 12/260 rashes in Study 344

      • 27/241 rashes in combined clinical population

    Case 1 344 025 1471 l.jpg
    Case 1 344-025-1471 Population

    • 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

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    025-01471 Population

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    Case 2 344-020-00844 Population

    • 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 l.jpg
    020-00844 Population

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    Case 3 -344-025-01318 Population

    • 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

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    025-01318 Population

    Case 4 344 030 1420 l.jpg
    Case 4 344-030-1420 Population

    • 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

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    030-01420 Population

    Case 5 344 028 1374 l.jpg
    Case 5 344-028-1374 Population

    • 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

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    028-01374 Population

    Case 6 344 029 01399 l.jpg
    Case 6 344-029-01399 Population

    • 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

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    Histopatholgy of Gemifloxacin Rash Population

    • 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

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    Study 344 Part B Population

    Summary study 344 part b l.jpg
    Summary Study 344 - Part B Population

    • Suggestion of minor cross-sensitization with ciprofloxacin (not conclusive)

    • Cannot extrapolate about cross sensitization with other quinolones

    • No evidence of subclinical sensitization with gemifloxacin

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    Quinolones and Severe Cutaneous Reactions Population

    • 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

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    Summary of Safety Population

    • 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

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    Risk Benefit Population

    Risk benefit considerations abecb l.jpg
    Risk Benefit Considerations - ABECB Population

    • 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

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    Risk Benefit Considerations - CAP Population

    • 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

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    Summary - 1 Population

    • 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

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    Summary - 2 Population

    • 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