P&T News: January 1999
Kathryn A. Miller, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Joel
V. Weinstock, M.D., Director of Gastroenterology/Hepatology
Reports of serious adverse reactions, including heart rhythm disorders and deaths, are associated mostly with the use of the drug in people taking certain other medications or who have particular underlying medical conditions. The FDA reports that from 1993 to 1998 there were 38 reports of death in patients receiving cisapride in the United States, but the agency has not been able to directly link reported deaths to the drug.2
The purpose of this article is to increase health care provider awareness of new safety issues associated with the use of cisapride.
Drug-Drug Interactions
There are several mechanisms for the drug-drug interactions that have
been reported with cisapride:
Metabolism
Cisapride undergoes metabolism mainly by isoenzyme 3A4 of the hepatic
cytochrome P-450 family (CYP 3A4). The CYP 3A4 isoenzyme is
responsible for the metabolism of the largest number of drugs in
humans. Some drugs metabolized by CYP 3A4 may compete with cisapride
for metabolism. Concomitant administration of cisapride with these
drugs may result in elevated cisapride blood concentrations which
have been associated with prolongation of ventricular repolarization
(as manifested by long Q-Tc intervals) and which predispose the
patient to polymorphous ventricular tachycardia (torsades de
pointes), monomorphic ventricular tachycardia, and ventricular
fibrillation.4,5
There have been numerous case reports of antiarrhythmic drug interactions with cisapride and CYP 3A4 inhibitors.3,6 Some of these events have been fatal. However, not all of the drug contraindications listed by the manufacturer are due to actual case reports, but rather in vitro data regarding enzyme inhibition7-11 (Table 1).
Although not listed as contraindications by the manufacturer, various other drugs inhibit the metabolism of the CYP 3A4 system and have the potential for clinically significant drug interactions. These potentially significant interactions are based upon recent literature reports, significant in vitro data by the manufacturers, and similar interactions seen with comparable agents (e.g., drug-drug interactions documented with the antihistamine terfenadine) (Table 1).
| Table 1. Drug-Drug Interactions Associated with P-450 Hepatic Enzymes | |
| Manufacturer Contraindications7-11 | Use with Caution 3,12 |
|
Itraconazole (Sporonox[R]) |
Diltiazem (Cardizem[R], Dilacor[R],
Tiazac[R]) |
Although the CYP 3A4 isoenzyme accounts for the metabolism of many drugs, some drugs that go through this route of metabolism do not result in clinically significant interactions with cisapride. For example, cimetidine inhibits the CYP 3A4 isoenzyme which in turn has been shown to increase cisapride bioavailability. However, this interaction has not been proven to be of clinical significance.13,14
Concomitant Effect on QT Interval
QT prolongation, torsades de pointes (sometimes with syncope),
cardiac arrest and sudden death have all been observed with the use
of cisapride without the above mentioned contraindicated drugs. Most
of the cases reported include patients which had disorders that may
have predisposed them to arrhythmias with cisapride. In addition, QT
prolongation, syncope and nonsustained ventricular tachycardia have
also been associated with high doses of 4 cisapride. Due to the
potential additive effects, cisapride should not be used
concomitantly with other drugs known to prolong the QT interval
(Table 2).
| Table 2. QT Interval Interactions - Manufacturer Contraindications |
|
Class I A antiarrhythmics including quinidine and
procainamide |
Although not contraindicated by the manufacturer, the following drugs are known to prolong the QT interval and should be used with caution if taken concurrently:6,15,16
Absorption Interactions
The acceleration of gastric emptying by cisapride could affect the
rate of absorption of other drugs. Patients receiving narrow
therapeutic index drugs (e.g., cyclosporine, digoxin, warfarin) or
other drugs that require careful titration should be followed
closely; if plasma levels are being monitored, they should be
reassessed upon initiation or discontinuation of cisapride.17-19
| Table 3. Drugs That May Interact with Cisapride | ||
|
Antibiotics Clarithromycin(2) Antifungals Fluconazole(2) Antidepressants Amitriptyline(1) Calcium channel blockers Bepridil(1) |
Antiarrhythmics Bepridil(1) Antineoplastic agents Cyclophosphamide(1,3) |
Antipsychotic drugs Thioridazine(1) Antihistamines Astemizole(2) Hypolipidemic agents Lovastatin(3) Immunosuppressive agents Cyclosporine(3) HIV protease inhibitors Indinavir(2) Miscellaneous Quinine(2) |
|
Manufacturer- listed contraindications are in bold
italics |
||
Drug-Disease State Interactions
The new warnings also contraindicate cisapride's use in patients with
certain disorders, such as congestive heart failure, multiple organ
failure, chronic obstructive pulmonary disease characterized by
serious respiratory problems, and advanced cancer. Additionally,
cisapride should not be administered to patients with electrolyte
disorders. These include patients with severe dehydration, vomiting,
diarrhea, or malnutrition; those taking potassium-wasting diuretics
and/or insulin in acute settings; or those who might experience a
rapid reduction of plasma potassium (e.g., amphotericin B).1
Dosing
The recommended dose of cisapride is 10 mg orally four times a day up
to a maximum of 20 mg orally four times a day. The minimum effective
dose should be used, and recommended doses should not be exceeded. In
addition, the manufacturer states that an electrocardiogram should be
considered prior to initiation of treatment with cisapride. Cisapride
should be discontinued if relief of nocturnal heartburn does not
improve within four to six weeks.1
The manufacturer states that there is some evidence that the accumulation of cisapride and/or its metabolites may be somewhat higher in patients with hepatic impairment, but the differences have not been found to be consistent. According to the manufacturer's update, a recommendation is made to give one-half the dose in patients with hepatic insufficiency.1
Patient Education
The manufacturer has developed a Patient Medication Guide to
distribute to patients when cisapride is prescribed. The guide
provides an overview of adult nocturnal heartburn due to GERD and its
treatment, including:
Summary
New warnings issued in June 1998 from both the manufacturer and the
FDA are intended to educate prescribers about potential cardiac
problems associated with the use of cisapride. Mechanisms for cardiac
risks to the patient include drug-drug interactions (Table 3),
drug-disease state interactions, and doses of cisapride that exceed
the manufacturer's recommendations. Due to the risks associated with
its use and the many factors that need to be considered when properly
administering the drug, cisapride should be reserved for patients
who have not responded adequately to lifestyle modifications or other
drugs for treating nighttime heartburn due to gastroesophageal reflux
disease. In addition, cisapride should be discontinued if relief
of nocturnal heartburn does not improve within four to six weeks.
References
1. Janssen Pharmaceutica Inc. Cisapride Package Insert. Titusville,
NJ. 1998.
2. FDA Talk Paper. June 29, 1998. FDA Strengthens Warning Label For
Propulsid.
3. Pharmacother. 1998;18:84-112.
4. Arch Intern Med. 1995; 155:765-8.
5. J Pediatr. 1996;128:279-81.
6. Am Fam Physicians. 1995;52:1447-53.
7. Bristol-Myers Squibb. Nefazadone Package Insert. Princeton, NJ.
1998.
8. Merck & Co, Inc. Indinavir Package Insert. West Point, PA.
1998.
9. Pfizer Roerig. Fluconazole Package Insert. New York,NY. 1998.
10. Abbott Laboratories. Ritonavir Package Insert. North Chicago, IL
1998.
11. Abbott Laboratories. Clarithromycin Package Insert. North
Chicago, IL. 1998.
12. Pharmacother. 1998;18:381-5.
13. Ther Drug Monit. 1989; 11:411-4.
14. Drugs. 1988;36:652-81.
15. Drugs. 1993;46:219-48.
16. Adverse Drug React Toxicol. 1994; 13:77-102.
17. Drug Safety. 1996;15:167-75.
18. Eur J Clin Pharmacol. 1989;36(Suppl): PA 117.
19. Eur J Drug Metab Pharmacokinet. 1986;11:249-50.