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 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

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:

6. 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

7. 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

8. 1. FDA AERS Analysis

9. 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

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

11. Demographic/Anthropometric Data
Variable* Mean (SD) or Frequency [%]
Age (years) (22)
Female %
Caucasian %
Weight (lbs.) (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) § (80)
QT Change (msec) (67)
Days to Event** (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

13. 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

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

15. Concomitant Drugs

16. Clarithromycin and Erythromycin TdP Reports - Contraindicated Drugs

17. 2. IMS HEALTH

18. 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

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

20. Macrolides and TdP - Adjusted Report-Utilization Ratio*
Drug Reports1 Utilization2 Ratio
(N) (Millions) (Reports/1 million Rx)
Clarithromycin
Erythromycin
Azithromycin
Cefuroxime
* Ratio based upon domestic, oral-formulation, out-patient reports and utilization
1. Spontaneous reports, 2. IMS HEALTH’s National Prescription Audit Plus

21. Summary and Conclusions

22. 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.

23. 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

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

25. 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.

26.
1-800-FDA-1088