# Presentation: 665080

## ZyvoxTM (linezolid)Tablets, injection, suspension

**NDAs 21-130, 21-131, 21-132**
**FDA presentation**
**Anti-Infective Drugs Advisory Committee**
**March 24, 2000**

## Overview

**Clinical pharmacology**
**Clinical/statistical analyses of efficacy**
**Clinical/statistical analyses of safety**
**Development of resistance**

## Clinical pharmacology:Pharmacokinetics

## Clinical pharmacology:Pharmacokinetics

**With 600 mg bid dosing:**
**AUC (PO) = 68 - 209 μg·h/mL**
**After normalization for body weight,****	****	****AUC = 11.2 - 23.8 μg·h/mL**

## Clinical pharmacology:Metabolism and excretion

**Metabolism**
**two major metabolites; toxicity not characterized**
**Excretion**
**35% in urine as parent drug**
**50% in urine as metabolites**
**10% in feces as metabolites**
**Metabolites accumulate in patients with renal impairment**

## Efficacy Analyses

## Clinical studies

**Community-acquired pneumonia**
**Study 33 (CAP in inpatients)**
**Study 51 (CAP in outpatients)**
**Hospital-acquired pneumonia (Study 48A)**
**Skin/skin structure infections**
**Studies 39A/39 (uncomplicated SSSI)**
**Study 55 (complicated SSSI)**
**MRSS infections (Study 31)**
**VRE infections (Studies 54A/54)**

## Differences in outcome assessment

***failure under certain pre-specified circumstances**

## Analytic populations

**Analytic populations**

**Randomized patients**
**   **
**ITT ****(all treated patients)**
** **
**MITT ****(pathogen isolated)**

**ITT ****(all treated patients)**
**CE ****(meet baseline and post-baseline criteria)**
**ME**
**(susceptible pathogen isolated within baseline window)**

## Community-acquired pneumonia

## Community-acquired pneumonia (Study 33)

**Population:  747 inpatients with CAP**
**Design:  Multi-center, multi-national, randomized, comparative, open-label**
**Treatment arms (7-14 d treatment duration)**
**Linezolid 600 mg IV q12h /600 mg po q12h**
**Ceftriaxone 1 g IV q12h /Cefpodoxime 200 mg po bid**
**Aztreonam allowed for Gram-negative infections**
**1o endpoint:  Microbiologic outcome**

## Study 33 (Inpatient CAP)Demographics

## Study 33 (inpatient CAP) Patient populations

## Study 33 (inpatient CAP) Clinical efficacy results

**   ****N =    330   313          109   117          285   274           92   99**

**Excludes patients with missing outcomes**

## Study 33 (inpatient CAP) 95% confidence intervals

**CE**

**ME**

**ITT**

**MITT**

**Difference in response rate between linezolid and ceftriaxone/cefpodoxime **

**FDA**

**Sponsor**

## Study 33 (inpatient CAP)Results by pathogen (ME patients)

## Study 33 (inpatient CAP)Subgroup analyses (CE patients)

## Study 33 (inpatient CAP)Effect of missing data

***Missing outcomes scored as failures**

**   ****N =    330   313          381   366          109   117          128   126**

## Community-acquired pneumonia (Study 51)

**Study population:  540 outpatients with CAP**
**Design:  Multi-center, multi-national, randomized, comparative, evaluator-blind**
**Treatment arms ( 10-14 d treatment duration)**
**Linezolid 600 mg po q12h**
**Cefpodoxime 200 mg po q12h**
**1o endpoint:  Clinical outcome**

## Study 51 (Outpatient CAP) Demographics

## Study 51 (outpatient CAP) Patient populations

## Study 51 (outpatient CAP) Clinical efficacy results

**   ****N =   227   222           54  52             213   208           50   48**

**Excludes patients with missing outcomes**

## Study 51 (outpatient CAP) 95% confidence intervals

**CE**

**ME**

**ITT**

**MITT**

**Difference in response rate between linezolid and cefpodoxime **

**FDA**

**Sponsor**

## Study 51 (outpatient CAP)Results by pathogen (ME patients)

## Study 51 (outpatient CAP)Subgroup analyses (CE patients)

## Study 51 (outpatient CAP)Effect of missing data

***Missing outcomes scored as failures**

**   ****N =    227   222          272   268          54   52            60   60**

## Hospital-acquired pneumonia

## Hospital-acquired pneumonia (Study 48A)

**Study population:  396 patients with HAP**
**Design:  Multi-center, multi-national, randomized, comparative, double-blind**
**Treatment arms (7-21 d treatment duration)**
**Linezolid 600 mg IV q12h ± Aztreonam 1-2 g IV q8h**
**Vancomycin 1 g IV q12h ± Aztreonam 1-2 g IV q8h**
**1° endpoints:  Clinical/microbiologic outcomes**

## Study 48A (HAP) Demographics

## Study 48A (HAP) Patient populations

## Study 48A (HAP) Clinical efficacy results

**   ****N = 174  164       82   72        122  103       54   41          22  20**

**Excludes patients with missing outcomes**

## Study 48A (HAP) 95% confidence intervals

**CE**

**ME**

**ITT**

**MITT**

**Difference in response rate between linezolid and vancomycin **

**FDA**

**Sponsor**

## Study 48A (HAP)Results by pathogen (ME patients)

## Study 48A (HAP)Subgroup analyses (ME patients)

## Study 48A (HAP)Subgroup analyses (MITT patients)

## Study 48A (HAP)Effect of missing data

***Missing outcomes scored as failures**

**   ****N =    174   164          203   193           82   72             94   83**

## Study 48A (HAP) Mortality rates

**   ****N =          203            193                           203          193**

## Uncomplicated skin and skin structure infections (uSSSI)

## Study 39A/39 (uSSSI)Description

**Population: 753 North American (39A),**
**	****	****332 Non-North American patients (39)**
**Design:  Multi-center, randomized, comparative, double-blind**
**Treatment arms (7-14 d treatment duration)**
**Linezolid 400 mg po q12h **
**Clarithromycin 250 mg po q12h**
**1o endpoints:  Clinical/microbiologic outcomes**

## Study 39A (uSSSI)  Demographics

## Study 39A (uSSSI) Patient populations

## Study 39A (uSSSI) Clinical efficacy results

**   ****N =      341   322                 320   307                  97   113**

**Excludes patients with missing outcomes**

## Study 39A (uSSSI)95% confidence intervals

**CE**

**ME**

**ITT**

**Difference in response rate between linezolid and clarithromycin **

**FDA**

**Sponsor**

## Study 39A (uSSSI) Results by pathogen

## Study 39A (uSSSI)Effect of missing data

***Missing outcomes scored as failures**

**   ****N =           341         322                         382         371**

## Study 39 (uSSSI)  Demographics

## Study 39 (uSSSI) Patient populations

## Study 39 (uSSSI) Clinical efficacy results

**   ****N =      148   149                127    127                43     58**

**Excludes patients with missing outcomes**

## Study 39 (uSSSI)95% confidence intervals

**CE**

**ME**

**ITT**

**Difference in response rate between linezolid and clarithromycin **

**FDA**

**Sponsor**

## Study 39 (uSSSI) Results by pathogen

## Complicated skin and skin structure infections (cSSSI)

## Complicated skin/skin structure infections (Study 55)

**Population:  819 patients with cSSSI**
**Study design:  Multi-center, multi-national, randomized, comparative, double-blind**
**Treatment arms (10-21 d treatment duration)**
**Linezolid 600 mg IV q12h / Linezolid 600 mg po bid**
**Oxacillin 2 g IV q6h / Dicloxacillin 500 mg po q6h**
**1° endpoints:  Clinical/microbiological outcomes**

## Study 55 (cSSSI)  Demographics

## Study 55 (cSSSI)Patient populations

## Study 55 (cSSSI) Clinical efficacy results

**   ****N =    327   348          269   267           245   242           101   108**

**Excludes patients with missing outcomes**

## Study 55 (cSSSI) 95% confidence intervals

**CE**

**ME**

**ITT**

**ITT-prime**

**Difference in response rate between linezolid and oxacillin/dicloxacillin **

- FDA

- Sponsor

## Study 55 (cSSSI) Results by pathogen

## Study 55 (cSSSI)Subgroup analyses

## Study 55 (cSSSI)Effect of missing data

***Missing outcomes scored as failures**

**   ****N =    327   348           400   419            269   267           316   313**

## Methicillin-resistant staphylococcal species (MRSS) infections

## MRSS infections(Study 31)

**Population:  460 patients with MRSS infection (Pneumonia, SSSI, UTI, BUO) **
**Design:  Multi-center, multi-national, randomized, comparative, open-label**
**Treatment arms (7-28 treatment duration)**
**Linezolid 600 mg IV q12h**
**Vancomycin 1 g IV q12h**
**Concomitant aztreonam/gentamicin allowed **
**1° endpoints:  Clinical/microbiologic outcomes**

## Study 31 (MRSS) Demographics

## Study 31 (MRSS)Patient populations

## Study 31 (MRSS) Clinical efficacy results

**   ****N =   181   160          128   112          116   125           59    67**

**Excludes patients with missing outcomes**

## Study 31 (MRSS)95% confidence intervals

**CE**

**ME**

**ITT**

**MITT**

**Difference in response rate between linezolid and vancomycin **

**FDA**

**Sponsor**

## Study 31 (MRSS)Results by pathogen (ME patients)

## Study 31 (MRSS)Results by pathogen (MITT patients)

## Study 31 (MRSS)Outcome by site of MRSA infection (ME)

## Study 31 (MRSS)Outcome by site of MRSA infection (MITT)

## Study 31 (MRSS)Effect of missing data

***Missing outcomes scored as failures**

**   ****N =   181   160          240   220          128   112         157   144**

## Vancomycin-resistant enterococcal (VRE) infections

## VRE infections (Study 54A)

**Population:  145 adult patients with known or suspected VRE infection (SST, UTI, BUO, IABD)**
**Design:  Multi-center, randomized, dose-comparison, double-blind, superiority**
**Treatment arms**
**Linezolid 600 mg IV q12h**
**Linezolid 200 mg IV q12h**
**Concomitant aztreonam or aminoglycosides allowed**
**1o endpoint:  Clinical outcome**

## Study 54A (VRE) Demographics

## Study 54A (VRE)Patient populations

## Study 54A (VRE) Efficacy results

- p=0.16

- p=0.15

**   ****N =****	****     58****	****  46****	****	****  17****	****14**

**Excludes patients with missing outcomes**

## Study 54A (VRE)Results by pathogen

## Study 54A (VRE)Outcome by site of VRE infection

***predominantly complicated IABD infection**

## Covariate analyses

**Covariate analyses were not prespecified**
**Multivariate analysis performed by FDA using:**
**Risk of mortality at baseline**
**1o diagnosis**
**Age, sex, weight**
**Bacteremia **
**Adjusted and unadjusted results consistent**

## Study 54A (VRE)Effect of missing data

***Missing outcomes scored as failures**

**   ****N =    58     46               65   52               17   14              18   16**

## Study 54A (VRE)All-cause mortality rates

**   ****N =****	****     65****	****  52****	****	****  18****	****16**

**4/18**

**9/16**

**18/52**

**16/65**

## Causes of death in patients with VRE bacteremia

**High dose**
**VRE infection (1)**
**Sepsis (2)**
**Respiratory failure (1)**

**Low dose**
**VRE infection (3)**
**Sepsis (1)**
**Pneumonia (1)**
**GVHD (1)**
**AIDS (1)**
**Gastric cancer (1)**
**Liver rejection (1)**

## Covariate analysis of mortality in  bacteremic patients

**Not prespecified**
**Covariates included:**
**Risk of mortality at baseline**
**Age**
**Sex**
**Adjusted and unadjusted results consistent**

## History: Studies 54A & 54

**Study 54 originally planned for 500 patients**
**In 6/99, blinded decision to submit patients already enrolled as Study 54A (145 patients) **
**Submitted as stand-alone study**
**“****all alpha spent” on this trial**
**Study 54 continued as “supportive trial”**
**Data on 82 patients submitted to FDA in 12/99**
**Bolstering NS results of 54A with these results could correspond to multiple looks without appropriate (prespecified) statistical adjustment**

## Study 54 (VRE)Efficacy results

***Missing outcomes scored as failures**

**       ****N =        28            35               ****	****  30           41**

## Safety analysis

**Clinical adverse events **
**Laboratory adverse events**
**Potential drug-drug interactions**

## Adverse events

## Adverse events

## Drug-related adverse events

## Discontinuations due to AEs

## Discontinuations due to drug-related AEs

## Discontinuations by adverse event

**Percentages are relative to number of patients who discontinued for any adverse event**

## Discontinuations by drug-related AE

**Percentages are relative to number of patients who discontinued for any drug-related adverse event**

## Laboratory findings

## Comparator-controlled studies: Development of thrombocytopenia*

***Percentages are relative to number of patients with normal platelet counts at baseline**

## Comparator-controlled studies: Grade III thrombocytopenia*

***Percentages are relative to number of patients with platelet count >50K at baseline**

## Effect of linezolid dose ondevelopment of thrombocytopenia*

***Percentages are relative to number of patients with normal platelet counts at baseline**

## Resolution of thrombocytopenia in comparator-controlled phase III studies

**50**

**100**

**Platelet count x 10E-3**

**100**

**200**

**Patient count**

**0**

**50**

**100**

**Platelet count x 10E-3**

**0**

**100**

**200**

**Patient count**

**Resolution of thrombocytopenia in comparator-controlled phase III studies**

**Linezolid**

**Comparator**

**M12600031**

**Sorting is by delta amount**

**  ****(smallest sort value at bottom)**

**Direction:**

**Increase**

**No change**

**Decrease**

**Start**

**End**

## Summary:  thrombocytopenia in linezolid-treated patients

**Incidence was 1 - 13% (grade III: 0-2.5%), depending on patient population**
**Higher doses associated with ******** incidence**
**Thrombocytopenia appeared to resolve in patients with laboratory follow-up**
**No related adverse events identified**
**No apparent effect on other cell lines **

## Drug-drug interactions

## MAO inhibition

## Linezolid-sympathomimetic amine interactions

## Selected concomitant medications

## Potential drug-drug interaction events

**Database examined for potential MAOI-associated drug-drug interaction events**
**Only small numbers of events found**
**No clear association between adverse events examined and use of concomitant medications**
**Classic MAOI-associated events not seen**
**No hypertensive crises **
**No cases of serotonin syndrome **

## Linezolid resistance

## Linezolid resistance

**Has been induced in laboratory **
**Mechanism - G ******** U on 23S rRNA**
**Frequency < 1 in 10****9**
**May result in cross-resistance to lincosamides and chloramphenicol **

## Linezolid resistancein clinical trials

**Only seen with *****Enterococcus***** spp.**
**Fifteen cases in NDA database as of 12/31/99**
**9/15 in compassionate use study (Study 25)**
**6/15 in dose-comparison studies (Studies 54A/54)**
**Mean duration of therapy was 32 ± 9.9 d**
**14/15 cases were *****E. faecium*****; 1/15 was *****E. faecalis***
**Increase in MIC to:**
**8 μg/mL (6 isolates)**
**16 μg/mL (8 isolates)**
**32 μg/mL (1 isolate - *****E. faecalis*****)**

## Linezolid resistance in compassionate use trial (Study 25)

**9/15 occurred during compassionate use**
**8/9 *****E. faecium*****, 1/ 9 *****E. faecalis***
**6/9 patients considered failures**
**3/9 patients considered cured**

## Linezolid resistancein dose-comparison trials

**6/15 occurred in studies 54A/54 (all***** E*****. *****faecium*****)**
**4 in low-dose group; 3/4 considered failures **
**2 in high-dose group; 1/2 considered failures**

## Linezolid Review Team

**Biopharmaceutics**
**Jenny Zheng, Ph.D.**
**Frank Pelsor, Ph.D.  (TL)**
**Chemistry**
**Jim Timper, M.S.**
**David Katague, Ph.D. (TL)**
**Clinical**
**John Alexander, M.D.**
**David Ross, M.D., Ph.D.**
**Janice Soreth, M.D. (TL)**
**Microbiology**
**Fred Marsik, Ph.D.**
**Albert Sheldon, Ph.D. (TL)**

**Pharm/Tox**
**Ken Seethaler, Ph.D.**
**Robert Osterberg, Ph.D., R.Ph. (TL)**
**Project Management**
**Beth Duvall-Miller, B.S.**
**Statistics**
**Erica Brittain, Ph.D.**
**Joel Jiang, Ph.D.**
**Daphne Lin, Ph.D. (TL)**
**Supervisory Review**
**Gary Chikami, M.D. (DAIDP)**
**Sandra Kweder, M.D. (ODE IV)**
**Dianne Murphy, M.D. (ODE IV)**