The Dangers of Cisapride Drug Interactions

Updated April 12, 2000

Since 1995 several labeling changes for cisapride (Propulsid, Janssen Pharmaceutica) have been required by the Food and Drug Administration (FDA) following serious adverse effects that were reported through the MedWatch reporting program.56 This system is in place to ensure that new safety information is rapidly communicated to the health care field in order to improve patient care. During post-marketing surveillance, cisapride has been associated with prolongation of the QT interval on the electrocardiogram (ECG).4,7,16,56Subsequently, cisapride was associated with the potentially fatal arrhythmia torsades de pointes when taken with certain medications or in patients who have certain underlying conditions predisposing them to arrhythmias.7,14,34,50,55,56

A recent FDA analysis of 270 adverse event reports (including 70 fatalities) revealed that approximately 85% of these cases occurred in patients with identifiable risks such as drug-QTDrug interactions and underlying heart conditions. 13,14 Most recent reports include 80 reports of death associated with cisapride-induced arrhythmia.67 This has occurred despite repeated warnings, resulting in the manufacturer's decision to stop marketing cisapride in the United States as of July 14, 2000.67 However, cisapride will still be available for specific patients, requiring health care providers and patients receiving cisapride to be familiar with the recommendations for reducing risk.

The QT interval reflects the duration of cardiac repolarization.55 It is determined by measuring the interval from the beginning of the Q to the end of the T wave, the position where the tangent to the down-sloping portion of the T wave crosses the isoelectric line.55 The QTc is the QT interval corrected for differences in heart rate. Normal QTc intervals are < 420 milliseconds in men and 440 milliseconds in women.55The risk of arrhythmia increases significantly when the QTc interval is > 450 milliseconds.15,56

Cisapride is metabolized primarily by the cytochrome P450 3A4 enzyme.7,56Medications that inhibit cytochrome P450 3A4, (Table I), can lead to increased plasma cisapride concentrations in patients.7,40 This increase in serum concentration has lead to serious cardiac complications including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation.7,34,40,50,56 Some of these interactions have lead to fatal outcomes.56

Risk Factors:

Recent recommendations by Janssen Pharmaceutica and the FDA have identified patients who may be at risk for this complication associated with cisapride.13 They are patients who:14,15

  • Take medications that inhibit cytochrome P450 3A4 (Table I and http://www.Drug-Interactions.com )
  • Take medications that cause QT prolongation such as quinidine, sotalol, disopyramide, procainamide, and amitriptyline (See Table II and our drug lists)
  • Have underlying disorders that may predispose patients to arrhythmias
  • Take medications such as diuretics that deplete serum electrolytes
  • Patients that are hypokalemic, hypocalcemic or hypomagnesemic
  • Patients with eating disorders such as bulimia or anorexia
  • Patients with underlying kidney or lung disease

New Warnings:

In light of new publicized warnings as of January 24, 2000 the manufacturer recommends the following:15

  • All patients should have a 12-lead ECG obtained before initiating cisapride therapy.
  • Cisapride should not be given if the QTc is > 450 milliseconds.
  • Cisapride is contraindicated in patients with electrolyte imbalances (hypokalemia, hypocalcemia and hypomagnesmia).
  • Serum electrolytes should be evaluated in patients treated with diuretics prior to initiating cisapride and periodically thereafter during treatment with cisapride.

Table I:
Cytochrome P450 3A4 inhibitors
(For a complete list please see www.Drug-Interactions.com)

 

amiodarone

antifungals - 
fluconazole, itraconazole, ketoconazole

cimetidine

delavirdine

fluvoxamine

grapefruit juice

HIV protease inhibitors - 
indinavir, nelfinavir, ritonavir, saquinavir

macrolide antibiotics (EXCEPT azithromycin)


Table II:
Compilation of contraindicated medications that have been obtained from in vitro studies, clinical trials and case reports

 

Medication Class

Documented Medication

Inhibits CYP450 3A4

Prolongs QT Interval

References

Macrolide antibiotics

clarithromycin

X

 

16,34,43,44,47,50,56

 

erythromycin

X

 

4,43,47,56

 

troleandomycin

X

 

33

Antifungals

fluconazole

X

 

12,26,56

 

itraconazole

X

 

26,56

 

ketoconazole

X

 

12,26,56

H2-receptor antagonists

cimetidine

X

 

21,28,31

Non-nucleoside, reverse transcriptase inhibitors

delavirdine

X

 

2,36

Protease inhibitors

amprenavir

X

 

2,35

 

indinivir

X

 

2,6,10,22,53

 

nelfinavir

X

 

2,24

 

ritonavir

X

 

2,10,22,53

 

saquinavir

X

 

2,10,51

Phenothiazines

prochlorperazine

 

 

40

 

promethazine

 

 

40

Class 1A antiarrhythmics

quinidine

 

X

3,41,42

 

procainamide

 

X

32,41

Class III antiarrhythmics

amiodarone

X

X

1,9,17,29,48,49

 

sotalol

 

X

11,25,54

Tricyclic antidepressants

amitriptyline

 

X

46

 

imipramine

 

X

46

Tetracyclic antidepressant

maprotiline

 

X

18

Selective seratonin re-uptake inhibitors

fluvoxamine

X

 

5,8,30

 

norfluoxetine

X

 

5,8,30

5-HT2 receptor antagonist

nefazodone

X

 

5,8,30,52

Antipsychotics

sertindole

 

X

40

Fluroquinolones

gatifloxacin

 

X

37

 

moxifloxicin

 

X

38

 

sparfloxacin

 

X

57

Calcium channel antagonists

bepridil

 

X

23,27,45

Others

grapefruit juice

X

 

19,20

 

quinupristin-dalfopristin

X

 

39


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