1. Augmentin ES  for acute otitis media Mamodikoe Makhene, M.D. Prepared for Anti-infectives Advisory Committee meeting January 30, 2001

2. 2 Overview Formulations and Indications Pivotal Studies –Bacteriologic/clinical study Safety Summary of issues from review Questions for the Committee

3. 3 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

4. 4 Augmentin Approved Indications “For the treatment of acute otitis media caused by beta-lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis”

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

6. 6 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.”

7. 7 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.”

8. 8 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)

9. 9 Augmentin ES  Studies Pivotal studies submitted –Bacteriologic study of Augmentin 14:1 –clinical study of Augmentin 14:1 vs. Augmentin 7:1 –PK information

10. 10 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

11. 11 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)

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

13. 13 Clinical Study Demographics

14. 14 Clinical Study Clinical response at TOC FDA PP population

15. 15 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)

16. 16 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

17. 17 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)

18. 18 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

19. 19 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)

20. 20 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

21. 21 Bacteriologic Study Assessment of Primary Clinical Outcome SB: end of therapy visit (d12-15) FDA: test of cure visit (d 25-28)

22. 22 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)

23. 23 Bacteriologic Study Demographics

24. 24 Bacteriologic Study Demographics

25. 25 Bacteriologic Study Baseline Presentation

26. 26 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

27. 27 Bacteriologic Study Overall Clinical Response at TOC-PRSP

28. 28 Bacteriologic Study Overall Clinical Response at TOC-PRSP (SB results)

29. 29 Bacteriologic Study Clinical Response at TOC, by MIC-PRSP

30. 30 Bacteriologic Study Clinical responses in PRSP ITT population, by risk subgroup

31. 31 Bacteriologic Study Bacteriologic Response-PRSP On Therapy

32. 32 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

33. 33 Bacteriologic Study Presumed PRSP Response- TOC

34. 34 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%

35. 35 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%

36. 36 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

37. 37 Bacteriologic Study Safety AEs leading to withdrawal

38. 38 Bacteriologic Study Safety

39. 39 Bacteriologic study Summary of Safety No deaths Few patients with SAEs Diarrhea most common reason for withdrawal PDD in 13.4%

40. 40 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

41. 41 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