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Augmentin ES  for acute otitis media

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

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Augmentin ES  for acute otitis media

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

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

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

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

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

  13. Clinical Study Demographics

  14. Clinical Study Clinical response at TOCFDA PP population

  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. 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. Bacteriologic studyStudy 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. 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. Bacteriologic study Primary Efficacy Endpoint SB: Bacteriologic response in patients with S. pneumoniae with penicillin MICs >2g/mLat on therapy visit (day 4-6 ) FDA: Bacteriologic response presumed from clinical response at TOC (d25-28)

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

  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. Bacteriologic Study Demographics

  24. Bacteriologic Study Demographics

  25. Bacteriologic Study Baseline Presentation

  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. Bacteriologic StudyOverall Clinical Response at TOC-PRSP

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

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

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

  31. Bacteriologic StudyBacteriologic Response-PRSPOn Therapy

  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. Bacteriologic Study Presumed PRSP Response-TOC

  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. 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. Bacteriologic StudySafety 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. Bacteriologic Study Safety AEs leading to withdrawal

  38. Bacteriologic StudySafety

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

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

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