# Presentation: 242086

## Macrolide Antibiotics and  Torsade de PointesPostmarketing Analysis

**Telithromycin (KetekTM) 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 - KetekTM 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

## Iatrogenic QT Prolongation and Torsade de Pointes  

-     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 **

## 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)
- 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 InstituteTM, 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)

- *    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%]**

## 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%

- 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

## Concomitant Drugs

## Clarithromycin and Erythromycin TdP Reports - Contraindicated Drugs

- Clarithromycin and Erythromycin TdP Reports - Contraindicated Drugs

- N = 49:
- Clarithromycin = 21
- Erythromycin   = 28

## 2.  IMS HEALTH

## 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

## Dirithromycin utilization on average < 500,000/year

- * IMS HEALTH’s
-    National Prescription Audit Plus

## Macrolides and TdP -Adjusted Report-Utilization Ratio*

- Drug		*Reports*1	*Utilization*2     **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

## 
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.

- 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.

- Postmarketing Summary

## 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