International Drug Information Notes
Larry D. Sasich* and Sana R. Sukkari
"1"
CISAPRIDE (PREPULSID)
In a recently published meta-analysis in the Journal of the American Medical Association, Lazarou et al. estimated that in 1994, in the U.S., 2,216,000 hospitalized patients had serious adverse drug reactions (ADR's) and 106,000 patients suffered fatal events. This estimation includes patients who were admitted to the hospital because of ADR's and those experiencing ADR's while in the hospital. Undoubtedly, many of these adverse events are preventable and one way of preventing them is to withdraw the marketing applications for drugs with known serious safety problems when acceptable safer alternatives are available.
Cisapride (Prepulsid, Propulsid) is a drug with known serious safety problems that have resulted in deaths and safer alternatives are available. New warnings were added to the labeling for cisapride in June 1998 that suggest that the risks from this drug outweigh its benefits. Between September 1993 when cisapride was first cleared for marketing and April 1996 the Food and Drug Administration's (FDA) MedWatch adverse reaction reporting program received 38 reports of deaths occurring in the U.S there have been 57 reports in which torsades de pointes and prolonged QT intervals observed in patients on cisapride also taking drugs that inhibit the cytochrome P450 (CYP) 3A4 enzyme system or had other risk factors for cardiac arrhythmia's. Four of these patients died and 16 were resuscitated after cardiopulmonary arrest. Although cisapride is not approved for use in children, deaths have been reported in infants and children treated with cisapride. Pediatric deaths have been associated with seizures and cardiovascular events (third degree heard block and ventricular tachycardia). Following more death reports (total of 38 reports of deaths from 1993 to 1998), Janssen Pharmaceutica, the cisapride (Propulsid(r)) pharmaceutical company, circulated on June 26, 1998 "Dear Doctor" letters to the U.S physicians informing them of labeling changes concerning new contraindications, warnings, precautions, adverse reactions, drug interactions, and pediatric use.
Cisapride is indicated in Canada and the United States for the symptomatic management and the prophylaxis of the gastroesophegeal reflux disease and nocturnal heartburn. This drug is classified as a gastrointestinal prokinetic agent and is widely used in hospital settings. Despite cisapride's unexplained extensive consumption, physicians should bear in mind that the risks of this drug now appear to outweigh any documented benefit of the drug. Alternatives to cisapride that are not associated with serious cardiac adverse effects and a large number of potentially life-threatening drug interactions are the non-pharmacological management of heartburn, histamine-2 blockers, and proton pump inhibitors.
Below is a summary of risk factors and drug interactions that may increase cisapride's serious cardiovascular adverse effects. Patients who fit into one of the following clinical conditions should not receive cisapride.
History of coronary artery disease or arrhythmia, hepatic or renal insufficiency, or chronic obstructive pulmonary disease.
Patients with hypokalemia, hypomagnesemia, or electrolyte imbalance; these include patients with severe dehydration, vomiting, diarrhea, or malnutrition, or those taking potassium-wasting diuretics and/or insulin in acute settings.
Concomitant administration of imidazoles, triazoles, macrolides, or protease inhibitors. These include ketoconazole (Nizoral), fluconazole (Diflucan), itraconazole (Sporanox), metronidazole, erythromycin, clarithromycin (Biaxin), azithromycin (Zithromax), spiramycin (Rovamycin), indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase).
Cisapride use with medications associated with arrhythmia or prolonged QT Interval (e.g. Amiodarone, quinidine, procainamide, sotalol, bepridil (Bepadin), Vascor, tricyclic/tetracyclic antidepressants phenothiazines, nefazodone (Serzone), astemizole (Hismanal), and terfenadine (Seldane).
In addition to the cardiovascular adverse events, the following events have been identified during post-approval use of cisapride in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion in the labeling due to a combination of their seriousness, frequency of reporting, or potential causal connection to cisapride: allergic reactions, including bronchospasm, urticaria, and angioedema; possible exacerbation of asthma; psychiatric events, including confusion, depression, suicide attempt, and hallucinations; gynecomastia, female breast enlargement, urinary incontinence, hyperprolactinemia and galactorrhea.
The new U.S labeling for cisapride recommends an EKG before the initiation of treatment with cisapride and that the drug should be discontinued if relief of nocturnal heartburn does nor occur.
In order to protect patients from needless harm, the Saudi Ministry of Health should take immediate steps to withdraw the marketing approval for cisapride and hospital pharmacy departments in Saudi Arabia are advised to discontinue cisapride from their formularies.
Update: Cisapride was withdrawn recently (year 2000).
References:
1. Lazarou J, Pomeranz B. Corey P. Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies JAMA 1998;279(15):1200-05.
2. Anonymous. Cisapride drug interactions can be fatal. Drugs 1997:9(7):11-13.
3. Dear Doctor Letter. Important Safety and Efficacy Information. Market A. Klausner, M.D., Vice President, Medical Affairs, Janssen Pharmaceutica, June 26,1998.
From Saudi Pharmaceutical Journal, Vol. 6, No. 3-4, July-October 1998