1 Zithromax  (Azithromycin) Oral Suspension Single-Dose & 3-day Treatment of Acute Otitis Media Anti-Infective Drugs Advisory Committee November 7, 2001 Nasim Moledina, M.D.

2 Background Zithromax  (Azithromycin) has been approved in the United States with a 5-day dosing regimen. –Adults: Acute exacerbation of chronic bronchitis (AECB), Pharyngitis/Tonsillitis, Community-Acquired Pneumonia (CAP), and Uncomplicated Skin and Skin Structure (SSSI) Infections

3 Background (cont) Children: Acute Otitis Media (AOM), Pharyngitis/Tonsillitis, and CAP Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. Dosing Regimen For AOM: 30 mg/kg (10 mg/kg on day one and 5 mg/kg on days 2-5)

4 Results of 5-day Studies Study Clinical only study (553 pts) Success Rate on Day 11 –Azi % - 88% –Comparator - 88% Success Rate on Day 30 –Azi % - 73% –Comparator - 71%

5 Results of 5-day Studies (cont) Study Non-comparative clinical and bacteriologic study (131 pts) Success Rate on Day 11 –Azi - 84% Success Rate on Day 30 –Azi % - 70%

6 Results of 5-day Studies (cont) Bacteriologic -Study 176

7 Results of 5-day Studies (cont) Study Comparative clinical and bacteriologic study (91 pts) Success Rate on Day 11 –Azi - 88% –Comparator - 100% Success Rate on Day 30 – Azi % - 82% – Comparator - 80%

8 Results of 5-day Studies (cont) Bacteriologic -Study 128

9 Comparison of Exposure Among Azithromycin Regimens 5-Day vs. 3-Day regimens in adults –The overall exposure associated with a 3-day regimen is similar to a 5-day regimen 3-Day vs. 1-Day regimens in adults –The overall exposure associated with a 3-day regimen may be similar to a 1-day regimen

10 Comparison of Exposure Among Azithromycin Regimens (cont) 5-Day vs. 3-Day regimens in pediatrics –The overall exposure associated with a 3-day regimen may be similar to a 5-day regimen 3-Day vs. 1-Day regimens in pediatrics –Not evaluated

11 Pivotal Studies

12 Study 1014 Clinical-only study of Azi three-day treatment vs. Amox/clav for AOM

13 Description A double-blind, multicenter, randomized trial comparing 10 mg/kg daily dose of azithromycin for 3 days with a ten-day course of amox/clav (45 mg/kg/day given BID) 373 patients from 28 U. S. Study sites Age - 6 months to 12 years Mean age: 3.5 yrs

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17 Study R-0581 Clinical-only study of Azi one-day treatment vs. Amox/clav for AOM

18 Description A double-blind, double-dummy, multicenter, randomized trial comparing a single 30 mg/kg dose of Azi with a ten day course of Amox/Clav (45 mg/kg/day given BID) 350 patients (175 Azi,175 Amox/Clav) from nine U.S. Study sites Age - 6 months to 12 years Mean age: 2.7 yrs

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21 Study R-0581: Clinical Outcome by Age at TOC (MITT Population)

22 Study 1015 Single-tap study of Azi one-day treatment for AOM

23 Description An open-label, non-comparative, multi-center trial of AOM using a single 30 mg/kg dose of Azi Tympanocentesis performed at baseline 248 patients from 22 U. S. and Latin American study sites Age - 6 months to 12 years Mean age: 3.4 yrs

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26 Study 1015: Clinical Outcomes by Age at TOC (MITT Population)

27 Study 1015: Clinical Outcome By Baseline Pathogen at EOT

28 Study 1015: Clinical Outcome By Baseline Pathogen at TOC

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30 Study Supportive single-tap study of one-day Azi vs. three-day Azi vs. IM Ceftriaxone

31 Description A single center (Costa Rica) trial of AOM comparing a single 30 mg/kg dose of Azi, 10 mg/kg daily of Azi for 3 days, and 50 mg/kg of I.M. CFTX. Outcome assessments at EOT (days 9 to 19) and follow-up (days 26 to 44). Mean age: 2.5 yrs (Range yrs)

32 Study : Clinical Outcome by Baseline Pathogen at EOT (MITT Population)

33 Summary of Clinical Outcome TOC Study Number Cure Rate (%)

34 Summary of Bacteriological Outcome (Study1015) Organism Outcome (%)

35 Published Studies Reviewer identified AOM studies with tympanocentesis from the literature Two double-tap studies by Dagan et al. Low bacteriologic eradication rates for H. influenzae on therapy Limitations of evidence from publications

36 Published Studies Doern et al. - AAC 2001 Clinical isolates of S. pneumoniae obtained from (N=1531) 25.7% Resistant to Azithromycin (all) 77.2% Resistant to Azithromycin (Pen-R; N=329)

37 Safety As of the June 30, 2000 cutoff date, 2590 subjects received Azithromycin in the phase 2-4 pooled studies. A total of 1897 subjects received other antibiotics in the comparative trials.

38 All Adverse Events for AOM Studies Only

39 % (n/N) of Subjects Reporting Vomiting by Day and Treatment Group for AOM Studies Only

40 Acknowledgments Dr. John Alexander Dr. Thomas Smith Dr. Mamodikoe Makhene Dr. Janice Soreth Dr. Mark Goldberger Dr. Lillian Gavrilovich Dr. David Ross Mr. Jose Cintron Ms. Frances LeSane Dr. George Rochester Dr. Daphne Lin Mr. Harold Silver Dr. Albert Sheldon Dr. Charles Bonapace Dr. Frank Pelsor Dr. Andrew Yu Dr. David Katague