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

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

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.

Telithromycin and Macrolides - Properties Relevant to Postmarketing Analyses Cytochrome P-450 3A4 metabolism1 Concentration related lengthening of the QTc interval2 FDA Background Package - Ketek™ Advisory Committee 1. Pre-clinical/Phase 1 - Summary of Selected Microbiologic Information 2. Appendices - FDA Cardio-Renal Consult

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

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

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

1. FDA AERS Analysis

Methods Search Criteria (1968-2000) Data Search Results 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

Macrolide Antibiotics and TdP Macrolide Reports*, N [%] Erythromycin 82 [53%] Clarithromycin 56 [36%] Azithromycin 18 [11%] Dirithromycin 0 156 * 44 (28 %) IV: Azithromycin = 4, Erythromycin = 40

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%

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) Fatalities = 14 events/156 reports [9%] * N (%) reported: Baseline = 25%, Event = 36%, QT change = 24%, Days = 64% § 59% of cases reported QTc ** 3 outliers (> 120 days) excluded

Comorbid Risks Variable* Frequency [%] Cardiac Disease 42% Renal Disease 11% Hepatic Disease 6% Hypokalemia/ 17% Hypomagnesemia * Frequency of concomitant risks based upon occurrence in AERS reports

Concomitant Drugs Variable Mean (SD) or Frequency [%] Number of Drugs 4 (3), range: 0-15 Drug Interaction1 31% QT Prolonging2,3 22% mutually exclusive 1. Physician’s Desk Reference (2000) 2. European Heart Journal 2000;21:1216-1231 3. Eur J Clin Pharmacol 2000;56:10-18

Concomitant Drugs

Clarithromycin and Erythromycin TdP Reports - Contraindicated Drugs

2. IMS HEALTH

Methods Data Source (1993-2000) Data Application 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

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

Macrolides and TdP - Adjusted Report-Utilization Ratio* Drug Reports1 Utilization2 Ratio (N) (Millions) (Reports/1 million Rx) Clarithromycin 16 90 0.18 Erythromycin 11 151 0.07 Azithromycin 7 124 0.06 Cefuroxime 1 42 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

Summary and Conclusions

Postmarketing Summary Demographics of macrolide-associated TdP reflect those described: older, female population. 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 7 and 3.5 times that of cefuroxime, respectively.

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

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

Conclusions 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. Monitoring of postmarketing data and development of risk management strategies would be critical if the drug was marketed in the US.

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