1. Macrolide Antibiotics and Torsade de Pointes Postmarketing Analysis Telithromycin (Ketek™) Advisory Committee April 26, 2001 Douglas N. Shaffer, MD, MHS Sarah J. Singer, RPh Office of Postmarketing Drug Risk Assessment

2. Outline Goal and Rationale Postmarketing Analysis –Adverse Event Reporting System (AERS) –IMS HEALTH –Reporting Rate Comparisons Summary and Conclusions

3. The goal of this analysis is to systematically evaluate postmarketing data in attempt to provide the Advisory Committee with a descriptive overview of Torsade de Pointes in association with macrolide antibiotics.

4. Telithromycin and Macrolides - Properties Relevant to Postmarketing Analyses Cytochrome P-450 3A4 metabolism 1 Concentration related lengthening of the QTc interval 2 FDA Background Package - Ketek™ Advisory Committee 1. Pre-clinical/Phase 1 - Summary of Selected Microbiologic Information 2. Appendices - FDA Cardio-Renal Consult

5. Torsade de Pointes Analysis - Rationale & Public Health Significance “Of concern is the interval, usually measured in years, from the marketing of these drugs to initial recognition of their association with QT interval prolongation and/or TdP.” Report on a Policy Conference of the European Society of Cardiology; European Heart Journal (2000) 21:1216-1231

6. Rx Confounding Variables: 1. Concomitant Drugs 2. Disease States 3. Electrolyte Abnormalities QT Prolongation Pro-arrhythmic milieu No Pathophysiological Event Cardiac Sudden Death Non-sustained Arrhythmia Iatrogenic QT Prolongation and Torsade de Pointes Adverse Events in the Postmarketing Setting

7. Iatrogenic QT Prolongation and Torsade de Pointes Representative AERS Report: Non-sustained Arrhythmia (e.g. TdP) Syncope Emergency Room (ECG) QT Prolongation (TdP) Drug discontinuation and resolution Rapid deterioration and treatment Rarely death

8. 1. FDA AERS Analysis

9. Methods Search Criteria (1968-2000) –Exposure - Individual macrolide drug –Outcome - TdP (Ventricular Tachycardia < 1995) Data –Inclusions - All reports (regardless of nationality or administration) –Exclusions - Duplicate reports/Reports < 1995 w/o TdP text –Systematic pharmacoepidemiological data extraction –PC SAS v6.12 (The SAS Institute™, Cary, NC) Search Results –268 reports reviewed (- 112 exclusions) –156 analyzed

10. Macrolide Antibiotics and TdP Macrolide Reports*, N [%] Erythromycin82 [53%] Clarithromycin56 [36%] Azithromycin 18 [11%] Dirithromycin0 156 * 44 (28 %) IV: Azithromycin = 4, Erythromycin = 40

11. Demographic/Anthropometric Data Variable* Mean (SD) or Frequency [%] Age (years) 61 (22) Female 70% Caucasian 60% Weight (lbs.) 152 (32) * Based upon N (%) of 156 reported: age = 93%, gender = 94%, race = 16%, weight = 26%

12. TdP Event Characteristics Variable*Mean ( SD) Baseline QT (msec) § 432 (50) Event QT (msec) § 594 (80) QT Change (msec) 172 (67) Days to Event ** 4 (3) * N (%) reported: Baseline = 25%, Event = 36%, QT change = 24%, Days = 64% § 59% of cases reported QTc ** 3 outliers (> 120 days) excluded Fatalities = 14 events/156 reports [9%]

13. Comorbid Risks Variable*Frequency [%] Cardiac Disease42% Renal Disease11% Hepatic Disease 6% Hypokalemia/17% Hypomagnesemia * Frequency of concomitant risks based upon occurrence in AERS reports

14. Concomitant Drugs VariableMean (SD) or Frequency [%] Number of Drugs4 (3), range: 0-15 Drug Interaction 1 31% QT Prolonging 2,3 22% 1. Physician’s Desk Reference (2000) 2. European Heart Journal 2000;21:1216-1231 3. Eur J Clin Pharmacol 2000;56:10-18 mutually exclusive

15. Concomitant Drugs

17. Clarithromycin and Erythromycin TdP Reports - Contraindicated Drugs N = 49: Clarithromycin = 21 Erythromycin = 28

18. 2. IMS HEALTH

19. Methods Data Source (1993-2000) –IMS Health’s National Prescription Audit Plus –Retail, out patient prescriptions –Oral formulations only Data Application –Descriptive representation (annual drug use) –Comparison of relative estimated reporting rate ratios reports (“numerator”) - domestic, oral-formulation, out-patient utilization (surrogate analytical population, “denominator”) cefuroxime used as control

20. Dirithromycin utilization on average < 500,000/year * IMS HEALTH’s National Prescription Audit Plus

21. Macrolides and TdP - Adjusted Report-Utilization Ratio* Ratio DrugReports 1 Utilization 2 Ratio (N)(Millions) (Reports/1 million Rx) Clarithromycin 1690 0.18 Erythromycin 11151 0.07 0.06 Azithromycin 7124 0.06 0.02 Cefuroxime 142 0.02 * Ratio based upon domestic, oral-formulation, out-patient reports and 1993-2000 utilization 1. Spontaneous reports, 2. IMS HEALTH’s National Prescription Audit Plus

22. Summary and Conclusions

23. Macrolide-associated TdP reports are from primarily older, female patients. Concomitant diseases/drugs are prevalent and potentially modifiable risks. Erythromycin overall accounts for most reports. Clarithromycin has the greatest reporting rate when considering domestic, out patient, oral cases & accounting for drug utilization. Clarithromycin and erythromycin TdP reporting rates are 9 and 3.5 times that of cefuroxime, respectively. Postmarketing Summary

24. Limitations Germane to spontaneous reporting systems Influence of biases Specificity of AERS data Inability to establish causation Reporting Rate Estimates are not synonymous with Incidence Rates

25. Advantages Systematic pharmacoepidemiological data extraction and evaluation Cost-efficient “Best Available Evidence” Detailed analysis of individual drugs

26. Conclusions Telithromycin, the first of a new class of antimicrobials related to macrolides, interacts with cytochrome P450 metabolism and prolongs the QT interval.Telithromycin, the first of a new class of antimicrobials related to macrolides, interacts with cytochrome P450 metabolism and prolongs the QT interval. Recognition of the potential for Torsade de Pointes should clearly be acknowledged.Recognition of the potential for Torsade de Pointes should clearly be acknowledged. Monitoring of postmarketing data and development of risk management strategies would be critical if the drug was marketed in the US.Monitoring of postmarketing data and development of risk management strategies would be critical if the drug was marketed in the US.

27. http://www.fda.gov/medwatch/ 1-800-FDA-1088

28. Supplemental Slides

29. AERS Reports: Quality and Causation* VariableMacrolides Quality Mean 3.2 (1.1) Proportion “Average” 53% or greater Causality Mean 2.8 (1.0) Proportion “Likely” or 44% “Strongly Suspect” * See Data Definitions macrolides

30. Macrolides and TdP: Adjusted Report-Utilization Ratio* Ratio DrugReports 1 Utilization 2 Ratio (N)(Millions) (Reports/1 million Rx) Clarithromycin 3190 0.34 Erythromycin 17151 0.11 0.08 Azithromycin 10124 0.08 0.02 Cefuroxime 142 0.02 1. Spontaneous reports, 2. IMS™ HEALTH NPA Data * Ratio based upon domestic, oral-formulation reports and 1993-2000 utilization

31. Cardiac Disease Variable*Frequency [%] Cardiomyopathy/23% Congestive Heart Failure Coronary Artery17% Disease Valve Disease10% Atrial Fibrillation9% Pacemaker/Defibrillator6% * Frequency of concomitant risks based upon occurrence in AERS reports macrolides

32. “Surrogate” Cardiac Events Reported* VariableFrequency [%] QT Prolongation40% Ventricular Tachycardia36% Syncope28% Cardiopulmonary Arrest/18% Sudden Death Ventricular Fibrillation15% Bradycardia3% Tachycardia1% * not exclusive, macrolides only macrolides

34. Ketoconazole - Terfenadine DI: JAMA Terfenadine Withdrawal Astemizole Withdrawal Cisapride Withdrawal TdP Coding Data through 8/00

35. Macrolide & Quinolone TdP Reports TdP Reports Macrolide = 156 Quinolone = 46 Total 202

36. AERS Reports: Quality and Causation* VariableMacrolidesQuinolones Quality Mean 3.2 (1.1) 3.3 (1.0) Proportion “Average” 53% 54% or greater Causality Mean 2.8 (1.0) 2.8 (1.2) Proportion “Likely” or 44% 39% “Strongly Suspect” * See Data Definitions

37. Quinolone Antibiotics and TdP Quinolone Reports*, N [%] Levofloxacin12 [26.1] Ciprofloxacin10 [21.7] Gatifloxacin6 [13.0] Norfloxacin, Sparfloxacin ** 5 [10.9] Ofloxacin3 [6.5] Grepafloxacin 2 [4.3] Lomefloxacin, Moxifloxacin,1 [2.2] and Trovafloxacin ** 47 * 10 (22%) IV: Levofloxacin = 5, Ciprofloxacin = 3, Gatifloxacin = 2 ** each

38. Demographic/Anthropometric Data Variable*MacrolidesQuinolones Age (years) 61 (22) 72 (15) Female 70% 67% Caucasian 60% 67% Weight (lbs.) 152 (32) 154 (27) * N (%) reported:age = 93%, gender = 94%, race = 16%, weight = 26% age = 89%, gender = 93%, race = 7%, weight = 20% Mean (SD) or Frequency [%]

39. TdP Event* Characteristics VariableMacrolideQuinolone Baseline QT (msec) § 432 (50) 434 (44) Event QT (msec) § 594 (80) 530 (151) QT Change (msec) 172 (67) 112 (70) Days to Event ** 4 (3) 5 (8) * N reported: Baseline = 25%, Event = 36%, QT change = 24%, Days = 64% Baseline = 24%, Event = 33%, QT change = 20%, Days = 72% § 59% & 67% of cases reported QTc ** 3 outliers excluded (> 120 days) Fatalities [14/156 = 9%][6/46= 13%]

40. Comorbid Risks Variable Macrolides Quinolones Cardiac Disease 42%63% Renal Disease 11%7% Hepatic Disease 6% 0 Hypokalemia/ 17%15% Hypomagnesemia * Frequency [%] of concomitant risks based upon occurrence in AERS reports

41. Concomitant Drugs VariableMacrolidesQuinolones Number of Drugs4 (3), range: 0-15 4 (3), range: 0-10 Drug Interaction 1 31% QT Prolonging 2,3 22% 24% 1. Physician’s Desk Reference (2000) 2. European Heart Journal 2000;21:1216-1231 3. Eur J Clin Pharmacol 2000;56:10-18

42. Moxifloxacin = 844,000 and Gatifloxacin = 1,797,000 in 2000 * IMS HEALTH™ NPA Data