# Presentation: 681950

## 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 (ECG)**

**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

## 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

## 
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.

- 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

## 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

## Supplemental Slides

## AERS Reports:  Quality and Causation*

- Variable			Macrolides
- 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

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

- Drug		*Reports*1	*Utilization*2  **Ratio**
- 			(N)		(Millions)	   (Reports/1 million Rx)
- Clarithromycin	31		90		  **0.34**
- Erythromycin	17		151		  **0.11**
- Azithromycin	10		124		  **0.08**
- Cefuroxime	1		42		  **0.02**

- 1.  Spontaneous reports,  2.  IMSTM HEALTH NPA Data

- *  Ratio based upon domestic, oral-formulation reports and 1993-2000 utilization

## Cardiac Disease

- Variable*					Frequency [%]
- Cardiomyopathy/			23%
- 	   Congestive Heart Failure
- Coronary Artery				17%
-        Disease
- Valve Disease				10%
- Atrial Fibrillation			9%
- Pacemaker/Defibrillator		6%

- *  Frequency of concomitant risks based upon occurrence in AERS reports

- macrolides

## “Surrogate” Cardiac Events Reported*

- Variable					Frequency [%]
- QT Prolongation				40%
- Ventricular Tachycardia		36%
- Syncope					28%
- Cardiopulmonary Arrest/		18%
-    Sudden Death
- Ventricular Fibrillation		15%
- Bradycardia				3%
- Tachycardia				1%

- * not exclusive,
-    macrolides only

- macrolides

## <footer>

- <date/time>

## Data through 8/00

- Ketoconazole -
- Terfenadine DI:
- JAMA

- Terfenadine
- Withdrawal

- Astemizole
- Withdrawal

- Cisapride
- Withdrawal

- TdP
- Coding

## Macrolide & Quinolone TdP Reports

**TdP Reports**
- Macrolide = 156
- Quinolone =  46
- Total            202

## AERS Reports:  Quality and Causation*

- Variable			Macrolides		Quinolones
- 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

## Quinolone Antibiotics and TdP

- Quinolone		    		Reports*, N  [%]
- Levofloxacin				12   [26.1]
- Ciprofloxacin				10   [21.7]
- Gatifloxacin				6     [13.0]
- Norfloxacin, Sparfloxacin **		5     [10.9]
- Ofloxacin				3     [6.5]
- Grepafloxacin		 		2     [4.3]
- Lomefloxacin, Moxifloxacin,		1     [2.2]
- 	and Trovafloxacin **
- 						**47**

- *  10 (22%)  IV: Levofloxacin = 5, Ciprofloxacin = 3, Gatifloxacin = 2                         ** each

## Demographic/Anthropometric Data

- Variable*			Macrolides	Quinolones
- 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 [%]

## TdP Event* Characteristics

- Variable			Macrolide		Quinolone
- 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%]**

## 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

## Concomitant Drugs

- Variable			Macrolides	Quinolones
- Number of Drugs	4 (3), range: 0-15	4 (3), range: 0-10
- Drug Interaction1 	  31%
- QT Prolonging2,3	  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

## Moxifloxacin = 844,000 and

- Gatifloxacin = 1,797,000 in 2000

- * IMS HEALTHTM NPA Data

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