Macrolide Antibiotics and Macrolide Antibiotics and Torsade de PointesTorsade de Pointes

Postmarketing AnalysisPostmarketing Analysis

Telithromycin (Ketek™) Advisory CommitteeTelithromycin (Ketek™) Advisory CommitteeApril 26, 2001April 26, 2001

Douglas N. Shaffer, MD, MHS

Sarah J. Singer, RPh

Office of Postmarketing Drug Risk Assessment

OutlineOutline

• 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 The goal of this analysis is to

systematically evaluate postmarketing data systematically evaluate postmarketing data

in attempt to provide the in attempt to provide the

Advisory Committee with a descriptive Advisory Committee with a descriptive

overview of Torsade de Pointes in overview of Torsade de Pointes in

association with macrolide antibiotics.association with macrolide antibiotics.

Telithromycin and Macrolides - Telithromycin and Macrolides - Properties Relevant toProperties Relevant to

Postmarketing Analyses Postmarketing Analyses

• Cytochrome P-450 3A4 metabolism1

• Concentration related lengthening of the QTc interval2

FDA Background Package - Ketek™ Advisory Committee1. Pre-clinical/Phase 1 - Summary of Selected Microbiologic Information2. Appendices - FDA Cardio-Renal Consult

Torsade de Pointes Analysis -Torsade de Pointes Analysis -

Rationale & Public Health SignificanceRationale & 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 ofthe European Society of Cardiology;European Heart Journal (2000) 21:1216-1231

Rx

ConfoundingVariables:1. Concomitant Drugs2. Disease States3. Electrolyte Abnormalities

QT Prolongation

Pro-arrhythmicmilieu

No PathophysiologicalEvent

Cardiac Sudden Death

Non-sustainedArrhythmia

Iatrogenic QT Prolongation and Torsade de PointesIatrogenic QT Prolongation and Torsade de Pointes

Adverse Events in the Postmarketing Setting Adverse Events in the Postmarketing Setting

Iatrogenic QT Prolongation and Torsade de PointesIatrogenic QT Prolongation and Torsade de Pointes

Representative AERS Report: Non-sustained Arrhythmia (e.g. TdP)Representative AERS Report: Non-sustained Arrhythmia (e.g. TdP)

Syncope

EmergencyRoom (ECG)

QT Prolongation(TdP)

Drug discontinuation and resolution

Rapid deterioration and treatment

Rarely death

1. FDA AERS Analysis1. FDA AERS Analysis

MethodsMethods

• 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

Macrolide Antibiotics and TdPMacrolide 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 DataDemographic/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 CharacteristicsTdP 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%]Fatalities = 14 events/156 reports [9%]

Comorbid RisksComorbid 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 DrugsConcomitant 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;21:1216-12313. Eur J Clin Pharmacol 2000;56:10-18

mutuallyexclusive

47%

31%

22%

Sole Suspect Drug

Contraindicated Drug Interaction

QT Prolonging Drug Co-Administration

Concomitant DrugsConcomitant Drugs

47%

31%

22%

Sole Suspect Drug

Contraindicated Drug Interaction

QT Prolonging Drug Co-Administration

Concomitant DrugsConcomitant Drugs

Cisapride78%

Terfenadine14%

Astemizole8%

Clarithromycin and Erythromycin TdP Reports -Clarithromycin and Erythromycin TdP Reports - Contraindicated DrugsContraindicated Drugs

N = 49:Clarithromycin = 21Erythromycin = 28

2. IMS HEALTH2. IMS HEALTH

MethodsMethods

• 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

Annual Macrolide Antibiotic Utilization

0

5,000,000

10,000,000

15,000,000

20,000,000

25,000,000

30,000,000

35,000,000

1993 1994 1995 1996 1997 1998 1999 2000

To

tal P

res

cri

pti

on

s *

Azithromycin Clarithromycin Erythromycin

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

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

Drug Reports1 Utilization2 RatioRatio(N) (Millions) (Reports/1 million Rx)

Clarithromycin 16 90 0.18

Erythromycin 11 151 0.07

Azithromycin 7 124 0.060.06

Cefuroxime 1 42 0.020.02

* 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 ConclusionsSummary 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.

Postmarketing SummaryPostmarketing Summary

LimitationsLimitations

• 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

AdvantagesAdvantages

• Systematic pharmacoepidemiological data extraction and evaluation

• Cost-efficient

• “Best Available Evidence”

• Detailed analysis of individual drugs

ConclusionsConclusions

• Telithromycin, the first of a new class of antimicrobials Telithromycin, the first of a new class of antimicrobials related to macrolides, interacts with cytochrome related to macrolides, interacts with cytochrome P450 metabolism and prolongs the QT interval.P450 metabolism and prolongs the QT interval.

• Recognition of the potential for Torsade de Pointes Recognition of the potential for Torsade de Pointes should clearly be acknowledged.should clearly be acknowledged.

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

http://www.fda.gov/medwatch/

1-800-FDA-1088

Supplemental Slides

AERS Reports: Quality and Causation*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:Macrolides and TdP:Adjusted Report-Utilization Ratio*Adjusted Report-Utilization Ratio*

Drug Reports1 Utilization2 RatioRatio(N) (Millions) (Reports/1 million Rx)

Clarithromycin 31 90 0.34

Erythromycin 17 151 0.11

Azithromycin 10 124 0.080.08

Cefuroxime 1 42 0.020.02

1. Spontaneous reports, 2. IMS™ HEALTH NPA Data

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

Cardiac DiseaseCardiac DiseaseVariable* 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

Macrolide Antibiotics – Fatal Outcomes Reported (N=14)

Obs Sex Age Drug Route Base/EventQT

DI CardiacAbnormality

Hypo-K

1 F 40 Clarith Oral Cisapride2 F 89 Clarith Oral Y3 M 42 Clarith Oral4 F Eryth Y5 F 18 Eryth Oral Cisapride Y6 F 65 Eryth Oral Cisapride7 F 79 Eryth Oral8 F 78 Eryth IV Y9 F 90 Eryth Oral Cisapride Y

10 F 61 Eryth Oral/IV /380 Y11 F 83 Eryth Y12 Azith Oral13 F 70 Clarith Oral Y14 M 77 Clarith Oral 320/600 Y

Macrolides and TdP Reports (N)

0

5

10

15

20

25

30

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

Year

N

Ketoconazole -Terfenadine DI:JAMA

TerfenadineWithdrawal

Astemizole Withdrawal

CisaprideWithdrawal

TdPCodingData through 8/00

Macrolide & Quinolone Macrolide & Quinolone TdP ReportsTdP Reports

Macrolides77%

Quinolones23%

TdP ReportsTdP Reports

Macrolide = 156Quinolone = 46

Total 202

AERS Reports: Quality and Causation*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 TdPQuinolone 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 DataDemographic/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 [%]

TdP Event* CharacteristicsTdP 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 Fatalities [14/156 = 9%] [14/156 = 9%] [6/46= 13%][6/46= 13%]

Comorbid RisksComorbid 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 DrugsConcomitant 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;21:1216-12313. Eur J Clin Pharmacol 2000;56:10-18

Annual Quinolone Antibiotic Utilization

0

2,000,000

4,000,000

6,000,000

8,000,000

10,000,000

12,000,000

14,000,000

16,000,000

1993 1994 1995 1996 1997 1998 1999 2000

To

tal

Pre

sc

rip

tio

ns

*

Ciprofloxacin Levofloxacin Ofloxacin Trovafloxacin

Norfloxacin Lomefloxacin Grepafloxacin

Moxifloxacin = 844,000 andGatifloxacin = 1,797,000 in 2000* IMS HEALTH™ NPA Data

QT Prolonging Drugs / Drug Classes

Class DrugAntiarrhythmic Drugs Amiodarone, Bretylium, Dofetilide, Disopyramide,

Ibutilide, Procainamide, Quinidine, SotalolPsychiatric Drugs Amitriptyline, Chlorpromazine, Desipramine, Doxepin,

Droperidol, Fluphenazine, Haloperidol, Imipramine,Lithium, Maprotaline, Nortriptyline, Pimozide,Prochlorperazine, Sertindole, Thioridazine, Trifluoperazine

Antimicrobial Drugs Amantadine, Clarithromycin, Chloroquine, Cotrimoxazole,Erythromycin, Gatifloxacin, Grepafloxacin, Halofantrine,Ketoconazole, Levofloxacin, Pentamidine, Quinine,Sparfloxacin

Antihistamines Astemizole, Diphenhydramine, Hydroxazine, TerfenadineMiscellaneous Cisapride

Contraindicated Drug Interactions

Drug Labeled Contraindication / Drug InteractionAzithromycinClarithromycin Cisapride, Pimozide, TerfenadineDirithromycin TerfenadineErythromycin Astemizole, Cisapride, Terfenadine

Appendix B: Subjective Variables

1. “Quality of Report” Criteria

Quality – subjective evaluation based upon quantity and quality of information available,based upon the contents expected of a reasonable and prudent report.

1 = excellent (all drug, dates, QT, and relevant information available and understandable)2 = above “normal”3 = normal (the expected “norm,” – perhaps QT missing, but clear documentation of event)4 = suboptimal5 = poor (gross under-representation of data, perhaps simply “torsade de pointes” stated)

2. “Degree of Causation”

Causal – subjective evaluation based upon how likely you believe there is a causalrelationship

1 = strongly suspect (high degree of certainty [temporal, QT, no strong DI])2 = likely (EKG documentation, potentially due to DI, some other confounder)3 = possible (suspect drug with multiple comorbidities/confounders)4 = questionable (questionable data, other pharmacodynamic interactions)5 = doubtful (likely due to another etiology, strongly suspect causality)