# Presentation: 067615

## Augmentin ES for acute otitis media

- Mamodikoe Makhene, M.D.
- Prepared for Anti-infectives  Advisory Committee meeting
- January 30, 2001

## Overview

- Formulations and Indications
- Pivotal Studies
- Bacteriologic/clinical study
- Safety
- Summary of issues from review
- Questions for the Committee

## Augmentin Approved formulations

- Augmentin (4:1)
- 		40/10 mg/kg/day q8 hours
- 		250mg Amox/62.5 mg Clav/5mL;
- Augmentin (7:1)
- 		45/6.4mg/kg/day q12 hours
- 		400mg Amox/57 mg Clav/5mL

## Augmentin Approved Indications

- “For the treatment of acute otitis media caused by beta-lactamase-producing strains of *Haemophilus influenzae* *and Moraxella (Branhamella) catarrhalis”*

## Augmentin New Formulation

- Augmentin ES****
- 600mg Amox/42.9mg Clav/5mL 90/6.4mg/kg/day (14:1 ratio)

## Augmentin ES Proposed Labeling

***Proposed Indication (by the sponsor)***
- “Acute Otitis media--caused by -lactamase-producing strains of *H. influenzae or M. catarrhalis, *and* S. pneumoniae* (including penicillin-resistant strains, MIC value for penicillin 2 μg/mL) when suspected.”

## Augmentin ES Proposed Labeling

***Proposed Dosage and Administration***** **
- Pediatric patients aged 12 weeks (3 months) and older
- “The recommended dose of *Augmentin ES* is 90 mg/kg/day divided q12h, based on the amoxicillin component.”

## Products currently approved for PRSP

- No anti-infective agent approved to treat AOM due to penicillin resistant *S. pneumoniae *
- Levofloxacin
- Community-acquired pneumonia:
*   **Streptococcus pneumoniae* (including penicillin resistant strains with penicillin MIC 2 g/mL)

## Augmentin ES Studies 

-  Pivotal studies submitted
- Bacteriologic study of Augmentin 14:1
- clinical study of Augmentin 14:1 vs. Augmentin 7:1
- PK information

## Clinical study

- Augmentin 14:1 vs. Augmentin 7:1 for 10 days
- 11 December 1996-27 February 1997
- 3 months to 12 years; n=453
- “All comers” trial not enriched for patients with penicillin resistant *S. pneumoniae*
- No tympanocenteses performed

## Clinical study 

**Study Visits**
- Baseline
- On-therapy telephone contact days 3-5
- End of Therapy (EOT) days 12-14
- Test of Cure (TOC) days 22-28
- Interim visit (condition worsened/ not improved)

## Clinical Study

**Primary Efficacy Endpoint**
- SB: clinical response at EOT days 12-14
- FDA: clinical response at TOC days 22-28

## Clinical Study Demographics

##  Clinical Study Clinical response at TOC FDA PP population 

## Bacteriologic study 

- Open label, non-comparative, multi-center study
- 24 February-5 November, 1999
*Augmentin* 14:1 q12 hours for 10 days
- 3 to 48 months of age; n=521
- Tympanocentesis (baseline and  on therapy or at time of failure)

## Bacteriologic Study

**Population**
- Strategies for enrichment for penicillin resistant *S. pneumoniae *(PRSP)
- young age
- failure of previous therapy  for AOM
- prophylaxis for recurrent OM
- day care attendees

## Bacteriologic studyStudy Visits

-    Visit 1	    Visit 2	     Visit 3	         Visit 4
-    Prelim	       On	     End of            Test of
- 			    therapy        therapy	           cure
- 	(d1)              (d4-6)	     (d12-15)       (d25-28)
- 			       Interim (optional)

## Bacteriologic Study Procedures

- Tympanocentesis at baseline
- Repeat tympanocentesis:
- patients with *S. pneumoniae* at baseline retapped at on-therapy visit (d4-6)
- all remaining patients retapped at on-therapy visit (d4-6), or at the time declared clinical failure

## Bacteriologic study 

**Primary Efficacy Endpoint**
- SB: Bacteriologic response in patients with *S. pneumoniae *with penicillin MICs _>_2g/mL at on therapy visit (day 4-6 )
- FDA: Bacteriologic response presumed from clinical response at TOC (d25-28)

## Bacteriologic Study 

**Secondary endpoints**
- Clinical response at the EOT and TOC visits
- Bacteriologic response of other pathogens (on therapy and at EOT)
- Adverse experiences (AEs), especially diarrhea

## Bacteriologic Study

**Assessment of Primary Clinical Outcome**
- SB: end of therapy visit (d12-15)
- FDA: test of cure visit (d 25-28)

## Bacteriologic Study 

**Patient Enrollment and Disposition **
- 521 patients received** ******1 dose of study therapy
- 359 had baseline pathogen (ITT)
- 157 with *S. pneumoniae*
- 41 with penicillin resistant strains of *S. pneumoniae*  (PRSP ITT)

## Bacteriologic Study Demographics 

## Bacteriologic Study Demographics

## Bacteriologic Study Baseline Presentation

## Bacteriologic Study

**FDA Assessment **
- 4 additional clinical failures in the FDA analysis were considered successes in the sponsor’s analysis
- clinical presentation consistent with AOM at either on therapy visit (n=2) or at TOC visit (n=2)
- no additional anti-infective agents  given

## Bacteriologic StudyOverall Clinical Response at TOC-PRSP

## Bacteriologic StudyOverall Clinical Response at TOC-PRSP (SB results)

## Bacteriologic Study Clinical Response at TOC, by MIC-PRSP

## Bacteriologic StudyClinical responses in PRSP ITT population, by risk subgroup

## Bacteriologic StudyBacteriologic Response-PRSPOn Therapy

## Bacteriologic Study Bacteriologic Eradication-TOC

- Bacteriologic response presumed from clinical response at TOC (d25-28)
- Some patients had taps at the time of failure
- 2 patients with *H. influenzae* and PRSP (pen MIC=2g/mL) at baseline
- no growth of PRSP, *H. influenzae* persisted

## Bacteriologic Study Presumed PRSP Response-TOC

## Bacteriologic Study Summary of Response Rates-PRSP 

-  Clinical response in PRSP at TOC : 					41.2%                 			     (95% CI: 25- 59)
- Bacteriologic response for PRSP at on-therapy visit: 93.9%
- Presumed bacteriologic response at TOC: 52.9%

## Bacteriologic study Summary of Response Rates-PRSP

**Clinical response  rates, by MIC:**
- Pen MIC=4g/mL:  35.7%
- Pen MIC =2g/mL: 45.0%

## Bacteriologic StudySafety

**Deaths and Serious Adverse Events**
- no deaths (n=521)
- _>_1 SAE (n=7)
- Diarrhea in 2/521 (0.04%)
- Other SAEs: vomiting, asthma, pneumonia, dehydration, overdose, injury

##  Bacteriologic  Study Safety AEs leading to withdrawal 	

## Bacteriologic StudySafety

## Bacteriologic study Summary of Safety

- No deaths
- Few patients with SAEs
- Diarrhea most common reason for withdrawal
- PDD in 13.4%

## Issues from review 

- a) Inconsistency between on-therapy bacteriologic responses and clinical outcomes at TOC
- b) Clinical response results at TOC are   difficult to interpret without:
- natural history of AOM due to PRSP
- approved comparator

## Other Issues from review 

- c) The proposed empiric treatment     when AOM due to PRSP is suspected
- d) Augmentin 7:1* *adequately treats AOM due to* H. influenzae* and *M. catarrhalis*
- e) Selection of timing of assessment of       bacteriologic and clinical outcomes