1. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 1 Telithromycin-Associated Hepatotoxicity Allen Brinker, MD, MS Epidemiology Team Leader Division of Drug Risk Evaluation (DDRE) Office of Surveillance and Epidemiology (OSE) Allen Brinker, MD, MS Epidemiology Team Leader Division of Drug Risk Evaluation (DDRE) Office of Surveillance and Epidemiology (OSE)

2. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 2 Telithromycin-Associated Acute Liver Failure (ALF) and Clinically Significant Liver Injury Outline of Speakers –Allen Brinker, MD (FDA) Case material / DDRE signal assessment –Leonard Seeff, MD Expert Consultant for FDA Principles of ALF causality assessment –William Lee, MD Expert Consultant for FDA Telithromycin ALF causality assessment Outline of Speakers –Allen Brinker, MD (FDA) Case material / DDRE signal assessment –Leonard Seeff, MD Expert Consultant for FDA Principles of ALF causality assessment –William Lee, MD Expert Consultant for FDA Telithromycin ALF causality assessment

3. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 3 Telithromycin-Associated ALF Overview Summarize DDRE review Methods –spontaneous adverse event (MedWatch) reports Analysis of cases Pharmacoepidemiology Reporting rates Two supporting ALF reporting rate analyses Telithromycin ALF reporting rate analysis Conclusions and status as of September 2006 Summarize DDRE review Methods –spontaneous adverse event (MedWatch) reports Analysis of cases Pharmacoepidemiology Reporting rates Two supporting ALF reporting rate analyses Telithromycin ALF reporting rate analysis Conclusions and status as of September 2006

4. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 4 Summary of DDRE Analysis Telithromycin-Associated ALF Spectrum of injury Per FDA review, 12 cases of telithromycin- associated ALF “clinically remarkable” –Short time-to-onset (median 4 days) One case following first dose –Profound hepatic injury –4 deaths 1 transplant –Patients appeared healthy and with few confounding factors Spectrum of injury Per FDA review, 12 cases of telithromycin- associated ALF “clinically remarkable” –Short time-to-onset (median 4 days) One case following first dose –Profound hepatic injury –4 deaths 1 transplant –Patients appeared healthy and with few confounding factors

5. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 5 Summary of DDRE Analysis Telithromycin-Associated ALF Reporting rate for telithromycin- associated ALF similar ALF reporting rates for selected comparators (moxi-, gatifloxacin) given variation inherent in spontaneous adverse event reporting

6. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 6 Summary of DDRE Analysis Telithromycin-Associated ALF Recommended regulatory actions consistent with actions advanced for the fluoroquinolones Review of this analysis included DDRE recommendations realized with addition of WARNING for ALF within approved labeling for telithromycin - June 2006 Recommended regulatory actions consistent with actions advanced for the fluoroquinolones Review of this analysis included DDRE recommendations realized with addition of WARNING for ALF within approved labeling for telithromycin - June 2006

7. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 7 Summary of DDRE Analysis Telithromycin-Associated ALF Set a reporting rate level (bar) for further regulatory action for telithromycin –based on experience with trovafloxacin- associated ALF Review of this analysis included Set a reporting rate level (bar) for further regulatory action for telithromycin –based on experience with trovafloxacin- associated ALF Review of this analysis included

8. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 8 Methods Spontaneous Adverse Event Reports

9. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 9 Spontaneous Adverse Event Reports Spontaneous Adverse Event Reports “MedWatch reports” Designed to detect –Rare –Serious –Unexpected Substantial variation in quality and information report to report

10. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 10 Spontaneous Adverse Event Reports Fraction of incident adverse events attributable to a selected drug AND reported is unknown Estimates of 1% to 10% commonly cited –These are likely to be overestimates –Assume variation between products Fraction of incident adverse events attributable to a selected drug AND reported is unknown Estimates of 1% to 10% commonly cited –These are likely to be overestimates –Assume variation between products

11. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 11 Spontaneous Adverse Event Reports Three DDRE reviews of antibiotic- associated ALF –Separated in time and by authors Utilized generally similar case definitions –Totality of information could not exclude telithromycin as a factor in liver injury Typical for FDA case series –Inclusion “case” criteria –Exclusion “confounding” criteria Three DDRE reviews of antibiotic- associated ALF –Separated in time and by authors Utilized generally similar case definitions –Totality of information could not exclude telithromycin as a factor in liver injury Typical for FDA case series –Inclusion “case” criteria –Exclusion “confounding” criteria

12. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 12 DDRE review of telithromycin-Associated ALF Conducted January - May 2006 –Ron Wassel and Allen Brinker –Telithromycin market appearance - July 2004 Conducted January - May 2006 –Ron Wassel and Allen Brinker –Telithromycin market appearance - July 2004

13. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 13 DDRE Review of Telithromycin- Associated ALF Ongoing review –Initial review (June 2005) Continued monitoring –Annals of Internal Medicine January 2006 Three patients who experienced serious liver toxicity following administration of telithromycin –Concern for hepatotoxicity observed in controlled clinical trials Ongoing review –Initial review (June 2005) Continued monitoring –Annals of Internal Medicine January 2006 Three patients who experienced serious liver toxicity following administration of telithromycin –Concern for hepatotoxicity observed in controlled clinical trials

14. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 14 DDRE Review of Telithromycin- Associated ALF Identified cases of: –Acute Liver Failure (ALF) –Acute Serious Liver Injury (ASLI) Identified cases of: –Acute Liver Failure (ALF) –Acute Serious Liver Injury (ASLI)

15. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 15 DDRE review of telithromycin- associated ALF Acute Liver Failure (ALF) defined as a report describing: –diagnosis of acute “liver failure,” or –acute and severe liver injury with encephalopathy, or –liver transplant following acute illness, or –death in the setting of acute severe liver injury Acute Liver Failure (ALF) defined as a report describing: –diagnosis of acute “liver failure,” or –acute and severe liver injury with encephalopathy, or –liver transplant following acute illness, or –death in the setting of acute severe liver injury

16. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 16 DDRE Review of Telithromycin- Associated ALF Acute Serious Liver Injury (ASLI) defined as a report of: –hepatic transaminase elevations, or –hyperbilirubinemia, or –clinical jaundice leading to hospitalization Acute Serious Liver Injury (ASLI) defined as a report of: –hepatic transaminase elevations, or –hyperbilirubinemia, or –clinical jaundice leading to hospitalization

17. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 17 DDRE Review of Telithromycin- Associated ALF Exclusion criteria included: –“Hearsay” reports –Infectious hepatitis –Sepsis –Pancreatitis –Rhabdomyolysis –Cancer –Selected concomitant therapies Exclusion criteria included: –“Hearsay” reports –Infectious hepatitis –Sepsis –Pancreatitis –Rhabdomyolysis –Cancer –Selected concomitant therapies

18. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 18 DDRE Review of Telithromycin- Associated ALF 110 unduplicated, domestic reports of liver injury in association with telithromycin Excluded 31 as confounded or hearsay reports Excluded 44 as minor liver injury 23 cases of Acute Serious Liver Injury 12 cases of Acute Liver Failure 110 unduplicated, domestic reports of liver injury in association with telithromycin Excluded 31 as confounded or hearsay reports Excluded 44 as minor liver injury 23 cases of Acute Serious Liver Injury 12 cases of Acute Liver Failure

19. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 19 DDRE Review of Telithromycin- Associated ALF Causality assessment project –2 FDA + 3 expert consultants –Review of 109 unduplicated, domestic reports of liver injury with telithromycin by Seeff 38 cases as very likely, possible or probable 12 cases “ALF” or “ASLI” per DDRE review 3 cases from DILIN network –Reviewed 53 cases in total Causality assessment project –2 FDA + 3 expert consultants –Review of 109 unduplicated, domestic reports of liver injury with telithromycin by Seeff 38 cases as very likely, possible or probable 12 cases “ALF” or “ASLI” per DDRE review 3 cases from DILIN network –Reviewed 53 cases in total

20. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 20 Clinical characteristics of domestic (US) ALF cases (n=12) reported in association with telithromycin (through April 2006) Age Median—52 years Range—26 to 85 years Gender Female (9), Male (3) Indication for use (verbatim from report) Sinusitis—5 Pneumonia—2 URI—2 Bronchitis/pneumonia—1 Bronchitis—1 RTI—1

21. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 21 Clinical characteristics of domestic (US) ALF cases (n=12) reported in association with telithromycin through April 2006. continued Latency (time to onset of symptoms from initiation of treatment) Median—4 days Range—1 to 20 days Jaundice reported at Dx8 Highest reported bilirubin (mg/dL)Median—18.3 Range—1.7 to 24.3 Highest reported AST (IU/L)Median—3638 Range—812 to 34,423 Highest reported ALT (IU/L)Median—2489 Range—833 to 19,888 Death / transplant4 / 1

22. DDRE Review of Telithromycin- Associated ALF AERS # 4892304-351 year old female (North Carolina) PMHx-Non significant; Current meds-ASA, MVit, Vit E no prior hx of liver disease social drinker (up to 2-3 glasses wine/day) Received telithromycin after presentation to her PCP with 2 wk h/o symptoms c/w URI. Developed icterus and elevated liver enzymes, bilirubin, and PT 7 days after initiation of therapy with telithromycin; alk phos only mildly elevated. Negative for hepatitis A, B, and C. Abdominal US that showed a small, echogenic liver with ascites. One month later bili increased; listed for liver transplant. Subsequently pt readmitted with systemic symptoms and underwent liver transplant. Explanted liver was small and remarkable for massive necrosis on histologic examination. **As published within: Clay KD, Hanson JS, Pope SD, et al. Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med 2006;144(6):415-20. AERS # 4892304-351 year old female (North Carolina) PMHx-Non significant; Current meds-ASA, MVit, Vit E no prior hx of liver disease social drinker (up to 2-3 glasses wine/day) Received telithromycin after presentation to her PCP with 2 wk h/o symptoms c/w URI. Developed icterus and elevated liver enzymes, bilirubin, and PT 7 days after initiation of therapy with telithromycin; alk phos only mildly elevated. Negative for hepatitis A, B, and C. Abdominal US that showed a small, echogenic liver with ascites. One month later bili increased; listed for liver transplant. Subsequently pt readmitted with systemic symptoms and underwent liver transplant. Explanted liver was small and remarkable for massive necrosis on histologic examination. **As published within: Clay KD, Hanson JS, Pope SD, et al. Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med 2006;144(6):415-20.

23. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 23 DDRE Review of Telithromycin- Associated ALF

24. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 24 DDRE Review of Telithromycin- Associated ALF Case material sufficient for addition of serious liver injury including ALF to telithromycin label What is risk compared to similar agents? –Reporting rates Two supporting analyses Case material sufficient for addition of serious liver injury including ALF to telithromycin label What is risk compared to similar agents? –Reporting rates Two supporting analyses

25. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 25 PharmacoepidemiologyPharmacoepidemiology Reporting rates –Drug-against-drug comparisons –Observed versus expected comparisons Reporting rates –Drug-against-drug comparisons –Observed versus expected comparisons

26. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 26 PharmacoepidemiologyPharmacoepidemiology Reporting rates calculated as: Spontaneous cases of selected event ----------------------------------------------------------- exposure or utilization –Expressed as: Cases per million Rx, per 10 million Rx Incidence density (cases per unit person- time) –Typically restricted to cases that arise during oral (ambulatory) therapy. Reporting rates calculated as: Spontaneous cases of selected event ----------------------------------------------------------- exposure or utilization –Expressed as: Cases per million Rx, per 10 million Rx Incidence density (cases per unit person- time) –Typically restricted to cases that arise during oral (ambulatory) therapy.

27. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 27 PharmacoepidemiologyPharmacoepidemiology Spontaneous reports data offer limited insight into population risk Reporting rates are not incidence rates Have been used in addition to other data to support previous regulatory actions by the agency Large differences in reporting rate ratios may support differential in risk Spontaneous reports data offer limited insight into population risk Reporting rates are not incidence rates Have been used in addition to other data to support previous regulatory actions by the agency Large differences in reporting rate ratios may support differential in risk

28. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 28 PharmacoepidemiologyPharmacoepidemiology Drug-against-drug reporting rate comparisons require very similar drug products –time on market Assumption that reporting practices are similar for similar drug products over the observed reporting period. Drug-against-drug reporting rate comparisons require very similar drug products –time on market Assumption that reporting practices are similar for similar drug products over the observed reporting period.

29. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 29 Relevant Case Studies Including Reporting Rate Comparisons and Regulatory Recommendations ALF in association with trovafloxacin ALF in association with moxifloxacin, gatifloxacin, and levofloxacin ALF in association with trovafloxacin ALF in association with moxifloxacin, gatifloxacin, and levofloxacin

30. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 30 Acute Liver Failure in Association with Trovafloxacin July 1999 –David Graham and Sarah Singer Analysis included drug-against-drug reporting rate comparisons –trovafloxacin –levofloxacin July 1999 –David Graham and Sarah Singer Analysis included drug-against-drug reporting rate comparisons –trovafloxacin –levofloxacin

31. ALF in Association with Trovafloxacin: Reporting Rate Analysis Drug US market appear- ance US cases Onset median (days) Rxs* ( in millions ) Reporting rate (per 10 million Rx) Levo Jan 19971---6.8681.5 Trova Jan 199812252.07358 *IMS Health, National Prescription Audit Plus™, Years 1997 and 1998, Hardcopy book.

32. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 32 Acute Liver Failure in Association with Trovafloxacin Absolute ratio in case counts –12:1 Adjusted ratio in case counts (reporting rate ratio) –39:1 Absolute ratio in case counts –12:1 Adjusted ratio in case counts (reporting rate ratio) –39:1

33. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 33 Acute Liver Failure in Association with Trovafloxacin Regulatory action: June 1999 Trovafloxacin restricted to initial therapy for in-hospital use for treatment of life and limb-threatening infections Regulatory action: June 1999 Trovafloxacin restricted to initial therapy for in-hospital use for treatment of life and limb-threatening infections

34. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 34 Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin August 2004 –Sarah Singer and Allen Brinker Analysis included drug-against-drug reporting rate comparisons –levofloxacin –moxifloxacin –gatifloxacin August 2004 –Sarah Singer and Allen Brinker Analysis included drug-against-drug reporting rate comparisons –levofloxacin –moxifloxacin –gatifloxacin

35. ALF with Moxi-, Gati-, and Levofloxacin: Reporting Rate Comparison Drug US market appear- ance US Cases Onset median (days) Rxs* ( millions ) Reporting rate (cases per 10 mil Rx) LevoJan 1997 127.057.4362.1 GatiDec 199964.010.0686.0 MoxiDec 199952.57.5636.6 IMS Health, National Prescription Audit Plus™, Years 1997 through September 2003, extracted July 2004.

36. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 36 Acute Liver Failure in Association with Moxifloxacin,, and Levofloxacin Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin Absolute ratio in case counts About 2:1 Adjusted ratio in case counts (reporting rate ratio) About 3:1 Absolute ratio in case counts About 2:1 Adjusted ratio in case counts (reporting rate ratio) About 3:1

37. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 37 Acute Liver in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin Acute Liver Failure in Association with Moxifloxacin, Gatifloxacin, and Levofloxacin Observed ALF reporting rates for these three agents appeared similar DDRE recommended addition of ALF as a WARNING within product labeling for all fluoroquinolones Observed ALF reporting rates for these three agents appeared similar DDRE recommended addition of ALF as a WARNING within product labeling for all fluoroquinolones

38. Telithromycin-Associated ALF: Reporting Rate Comparison Drug US market appear- ance US Cases Onset Median (days) Rxs (in millions) Reporting rate (Per 10 million Rx) GatiDec 9964.010.068*6.0 MoxiDec 9952.57.563*6.6 TeliJuly 0412 (Apr 06) 4.05.198**23 *IMS Health, National Prescription Audit Plus™, Years 1997 through September 2003, extracted July 2004. **Verispan Vector One®:National, months May 2004-April 2006, extracted May 2006.

39. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 39 DDRE Review of Telithromycin- Associated ALF Absolute ratio in case counts About 2:1 Adjusted ratio in case counts (reporting rate ratio) About 4:1 (April 2006) Absolute ratio in case counts About 2:1 Adjusted ratio in case counts (reporting rate ratio) About 4:1 (April 2006)

40. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 40 DDRE Review of Telithromycin- Associated ALF Observed reporting rates generally similar Not consistent with trovafloxacin analysis –Absolute ratio of case count not ~12:1 –Adjusted ratio of case count not ~39:1 Recommended regulatory actions similar to that advanced for the recent ALF-FQ review Observed reporting rates generally similar Not consistent with trovafloxacin analysis –Absolute ratio of case count not ~12:1 –Adjusted ratio of case count not ~39:1 Recommended regulatory actions similar to that advanced for the recent ALF-FQ review

41. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 41 DDRE Review of Telithromycin- Associated ALF Also noted rising trend in the cumulative telithromycin-ALF reporting rate –12 per 10 million Rx through Dec 2005 –17 per 10 million Rx through February 2006 –23 per 10 million Rx through April 2006 Liver injury was a concern pre-approval –to be addressed within Study 3014 Also noted rising trend in the cumulative telithromycin-ALF reporting rate –12 per 10 million Rx through Dec 2005 –17 per 10 million Rx through February 2006 –23 per 10 million Rx through April 2006 Liver injury was a concern pre-approval –to be addressed within Study 3014

42. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 42 DDRE Review of Telithromycin- Associated ALF DDRE recommended a “bar” for further regulatory actions based on ALF-reporting rate for trovafloxacin (58 per 10 million Rx) –Would not wait until: Absolute ratio of case counts ~12:1, or Adjusted ratio of case counts ~39:1 –As seen with ALF with trovafloxacin DDRE recommended a “bar” for further regulatory actions based on ALF-reporting rate for trovafloxacin (58 per 10 million Rx) –Would not wait until: Absolute ratio of case counts ~12:1, or Adjusted ratio of case counts ~39:1 –As seen with ALF with trovafloxacin

43. DDRE Review of Telithromycin- Associated ALF - Update 13 th case added in 2 QTR 06 Reporting rate for telithromycin- associated ALF through September 2006 with: –13 cases / 5,650,000 Rx* –23 per 10 million Rx Unchanged from RR observed in April 2006 13 th case added in 2 QTR 06 Reporting rate for telithromycin- associated ALF through September 2006 with: –13 cases / 5,650,000 Rx* –23 per 10 million Rx Unchanged from RR observed in April 2006 *Verispan Vector One®:National, months May 2004-September 2006, extracted Nov 2006.

44. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 44 Sanofi-Aventis Population-Based Epidemiology Studies Received completed studies last week (early December 2006) –Pharmetrics –i3 drug safety Review ongoing –Comments at this time preliminary Received completed studies last week (early December 2006) –Pharmetrics –i3 drug safety Review ongoing –Comments at this time preliminary

45. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 45 Sanofi-Aventis Population-Based Epidemiology Studies Comments (preliminary) –Both studies appear underpowered for both drug-associated ALF and serious liver injury –Medical record validation required Done in i3 study; not done in Pharmetrics study Comments (preliminary) –Both studies appear underpowered for both drug-associated ALF and serious liver injury –Medical record validation required Done in i3 study; not done in Pharmetrics study

46. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 46 Sanofi-Aventis Population-Based Epidemiology Studies Comments (preliminary) –The point estimate for severe liver injury observed in the i3 study is consistent with an elevated risk for serious liver injury with telithromycin in comparison to clarithromycin. –The finding in the i3 study of an elevated risk of serious liver injury with sequential use of telithromycin and clarithromycin deserves attention (further study) but based on 3 cases. Comments (preliminary) –The point estimate for severe liver injury observed in the i3 study is consistent with an elevated risk for serious liver injury with telithromycin in comparison to clarithromycin. –The finding in the i3 study of an elevated risk of serious liver injury with sequential use of telithromycin and clarithromycin deserves attention (further study) but based on 3 cases.

47. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 47 DDRE Review of Telithromycin- Associated ALF End of Presentation Acknowledgements Jenna Lyndly, RN Ron Wassel, PharmD Melissa Truffa, PharmD Mark Avigan, MD, CM End of Presentation Acknowledgements Jenna Lyndly, RN Ron Wassel, PharmD Melissa Truffa, PharmD Mark Avigan, MD, CM

48. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 48 Back-up Slides Return to agenda

49. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 49 Crude Assessment of Agreement on ALF “Case” Status between 3 Disparate DDRE Reviews of Antibiotic-Associated ALF DrugCrude count (“serious”) “Cases” after review Percent Trova1151412 Levo1071918 Gati55916 Moxi49612 Teli661218

50. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 50 Rx Versus Person-Time Reporting Rate Comparison Rx-based comparisons preferred by this reviewer as: –1 Rx = 1 Pt (in most cases) –Time to onset falls within typical treatment course for most cases Rx-based reporting rates –Absolute difference in case counts About 2:1 –Adjusted difference (reporting rate ratio) About 4:1 Rx-based comparisons preferred by this reviewer as: –1 Rx = 1 Pt (in most cases) –Time to onset falls within typical treatment course for most cases Rx-based reporting rates –Absolute difference in case counts About 2:1 –Adjusted difference (reporting rate ratio) About 4:1

51. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 51 Rx Versus Person-Time Reporting Rate Comparison Person-time reporting rates –Transformation based on typical treatment courses of: 10 days for moxifloxacin and gatifloxacin 5 days for telithromycin –Results in incidence density for moxi- or gati associated ALF of ~22 per million person years –Results in incidence density for telithromycin- associated ALF of 168 per million person-years Background (expected) rate of idiosyncratic ALF in the general population ~1 per million person-years. Person-time reporting rates –Transformation based on typical treatment courses of: 10 days for moxifloxacin and gatifloxacin 5 days for telithromycin –Results in incidence density for moxi- or gati associated ALF of ~22 per million person years –Results in incidence density for telithromycin- associated ALF of 168 per million person-years Background (expected) rate of idiosyncratic ALF in the general population ~1 per million person-years.

52. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 52 Rx Versus Person-Time Reporting Rate Comparison Person-time reporting rates –Absolute difference in case counts About 2:1 (unchanged) –Adjusted difference (incidence ratio) About 8:1 fold (increased from 4:1) Trovafloxacin –Absolute difference in case counts: 12:1 –Adjusted difference (reporting rate ratio): 39:1 Person-time reporting rates –Absolute difference in case counts About 2:1 (unchanged) –Adjusted difference (incidence ratio) About 8:1 fold (increased from 4:1) Trovafloxacin –Absolute difference in case counts: 12:1 –Adjusted difference (reporting rate ratio): 39:1

53. Joint Meeting of the Anti-Infective Drugs Advisory Committee and the Drug Safety and Risk Management Committee Meeting December 14 & 15, 2006 53 ReturnReturn Return to agenda