JANSSEN
PHARMACEUTICA
RESEARCH FOUNDATION

IMPORTANT SAFETY AND EFFICACY INFORMATION

June 26, 1998

Dear Doctor,

Janssen Pharmaceutica would like to inform you of labeling changes concerning new CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DRUG INTERACTIONS with PROPULSID (cisapride). In addition, revisions have been made in the PEDIATRIC USE, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION sections.

We wish to draw your attention to the following sections of the revised PROPULSID labeling which contain the essential changes.

Warning: Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking PROPULSID. Many of these patients also took drugs expected to increase cisapride blood levels by inhibiting the cytochrome P450 3A4 enzymes that metabolize cisapride. These drugs include clarithromycin, erythromycin, troleandomycin, nefazodone, fluconazole, itraconazole, ketoconazole, indinavir and ritonavir. Some of these events have been fatal. PROPULSID is contraindicated in patients taking any of these drugs. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DRUG INTERACTIONS). QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest and sudden death have been reported in patients taking PROPULSID without the above-mentioned contraindicated drugs. Most patients had disorders that may have predisposed them to arrhythmias with cisapride. PROPULSID is contraindicated for those patients with: history of prolonged electrocardiographic QT intervals; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; uncorrected electrolyte disorders (hypokalemia, hypomagnesemia); respiratory failure; and concomitant medications known to prolong the QT interval and increase the risk of arrhythmia, such as certain antiarrhythmics, including those of Class 1A (such as quinidine and procainamide) and Class III (such as sotalol); tricyclic antidepressants (such as amitriptyline); certain tetracyclic antidepressants (such as maprotiline); certain antipsychotic medications (such as certain phenothiazines and sertindole), astemizole, bepridil, sparfloxacin and terodiline. (The preceding lists of drugs are not comprehensive.) Recommended doses of PROPULSID should not be exceeded.

INDICATIONS & USAGE

PROPULSID (cisapride) is indicated for the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. Because of the risk of serious, and sometimes fatal, ventricular arrhythmias (see Boxed Warning), PROPULSID should generally be reserved for patients who do not respond adequately to lifestyle modifications (See PRECAUTIONS: Information for Patients), antacids and gastric acid reducing agents.

CONTRAINDICATIONS

Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking PROPULSID (cisapride) with other drugs that inhibit cytochrome P450 3A4. Some of these events have been fatal.

Concomitant oral or intravenous administration of the following drugs with cisapride may lead to elevated cisapride blood levels and is contraindicated (See WARNINGS, PRECAUTIONS and DRUG INTERACTIONS):

Antibiotics:	Oral or i.v. erthromycin, clarithromycin (BIAXIN), troleandomycin (TAO)
Antidepressants:	Nefazodone (SERZONE)
Antifungals:	Oral or i.v. fluconazole (DIFLUCAN), itraconazole (SPORANOX), oral ketoconazole (NIZORAL)
Protease inhibitors:	Indinavir (CRIXIVAN), ritonavir (NORVIR)

PROPULSID is also contraindicated for patients with: history of prolonged electrocardiographic QT intervals; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; uncorrected electrolyte disorders (hypokalemia, hypomagnesemia); respiratory failure; and concomitant medications known to prolong the QT interval and increase the risk of arrhythmia, such as certain antiarrhythmics, certain antipsychotics, certain antidepressants , astemizole, bepridil, sparfloxacin and terodiline. The preceding lists of drugs are not comprehensive.

WARNINGS

ECG should be considered prior to initiation of cisapride. Cisapride should not be used in patients with a prolonged QT interval at baseline, those with a history of torsades de pointes, or those with long QT syndrome. Cisapride should also be avoided in patients with sinus node dysfunction, and in those with second or third degree atrioventricular block.

Cisapride should not be used concomitantly with other drugs known to prolong the QT interval; certain antiarrhythmics, including those of Class 1A (such as quinidine and procainamide) and Class III (such as sotalol): tricyclic antidepressants (such as amitriptyline); certain tetracyclic antidepressants (such as maprotiline); certain antipsychotic medications (such as certain phenothiazines and sertindole); astemizole, bepridil, sparfloxacin and terodiline. (See CONTRAINDICATIONS, PRECAUTIONS and DRUG INTERACTIONS.) The preceding lists of drugs are not comprehensive.

PRECAUTIONS

General: Potential benefits should be weighed against risks prior administration of cisapride to patients who have or may develop prolongation of cardiac conduction intervals, particularly QT_c. These include patients with conditions that could predispose them to the development of serious arrhythmias, such as multiple organ failure, COPD, apnea and advanced cancer. (See CONTRAINDICATIONS.)

PROPULSID (cisapride) should not be used in patients with uncorrected hypokalemia or hypomagnesemia, such as those with severe dehydration, vomiting or malnutrition, or those taking potassium-wasting diuretics. PROPULSID should not be used in patients who might experience rapid reduction of plasma potassium, such as those administered potassium-wasting diuretics and/or insulin in acute settings.

Pediatric Use: Safety and effectivenesss in pediatric patients have not been established. Although causality has not been established, serious adverse events, including death, have been reported in infants and children treated with cisapride. Several pediatric deaths were due to cardiovascular events (third degree heart block and ventricular tachycardia).

Pediatric deaths have been associated with seizures and there has been at least one case of "sudden unexplained death" in a 3-month-old infant. Other unlabeled potentially serious events which have been reported in pediatric patients include: antinuclear antibody (ANA) positive, anemia, hemolytic anemia, methemoglobinemia, hyperglycemia, hypoglycemia with acidosis, unexplained apneic episodes, confusion, impaired concentration, depression, apathy, visual changes accompanied by amnesia, and severe photosensitivity reaction.

A one-month-old male infant received 2 mg/kg of cisapride four times per day for 5 days. The patient developed third degree heart block and subsequently died of right ventricular perforation caused by pacemaker wire insertion.

ADVERSE REACTIONS

Postmarketing Reports: 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 this insert 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 following events were specifically reported in the pediatric population: antinuclear antibody (ANA) positive, anemia, hemolytic anemia, methemoglobinemia, hyperglycemia, hypoglycemia with acidosis, unexplained apneic episodes, confusion, impaired concentration, depression, apathy, visual changes accompanied by amnesia, and severe photosensitivity reactions.

DOSAGE AND ADMINISTRATION

PROPULSID should be discontinued if relief of nocturnal heartburn does not occur. The minimum effective dose should be used. Recommended doses of PROPULSID should not be exceeded.

It is recommended that the daily dose be halved in patients with hepatic insufficiency.

We at Janssen want you to be aware of this important information to ensure the proper use of PROPULSID in your patients. Please refer to the enclosed revised package insert for full prescribing information. The Medical Community can further our understanding of adverse events by reporting all cases to Janssen at 1-800-Janssen (526-7736) or to the FDA MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857. For additional medical information, please call 1-800-Janssen from 8 AM to 8 PM Eastern Time, Monday through Friday.

Sincerely,

Mark A. Klausner, M.D.
Vice President, Medical Affairs

The following brand names are registered trademarks of the companies listed below.

Abbott Laboratories	BIAXINÒ (clarithromycin), NORVIRÒ (ritonavir)
Bristol-Myers Squibb	SERZONEÒ (nefazodone)
Janssen Pharmaceutica, Inc.	SPORANOXÒ (itraconazole), NIZORALÒ (ketoconazole)
Merck & Co. Inc.	CRIXIVANÒ (indinavir)
Pfizer, Inc.	DIFLUCANÒ (fluconazole), TAOÒ (troleandomycin)

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