Prescription Drugs

CLINICAL PHARMACOLOGY Pharmacokinetics Cisapride is metabolized mainly via the cytochrome P450 3A4 enzyme. Cisapride is extensively metabolized; unchanged drug accounts for less than 10% of urinary and fecal recovery following oral administration. Norcisapride, formed by N-dealkylation, is the principal metabolite in plasma, feces, and urine. Cisapride is rapidly absorbed after oral administration; peak plasma concentrations are reached 1 to 1.5 hours after dosing. The absolute bioavailability of cisapride is 35-40%. When gastric acidity was reduced by high dose histamine H2 receptor blocker and sodium bicarbonate in fasting subjects, there was a decrease in the rate, and to a lesser degree the extent, of cisapride tablet absorption. (This has not been established for the suspension.) Cisapride binds to an extent of 97.5-98% to plasma proteins, mainly to albumin. The volume of distribution of cisapride is about 180 L, indicating extensive tissue distribution. The plasma clearance of cisapride is about 100 ml/min. The mean terminal half-life reported for cisapride ranges from 6 to 12 hours; longer half-lives, up to 20 hours, have been reported following intravenous (IV) administration. There was no unusual drug accumulation due to time-dependent or non-linear changes in pharmacokinetics. After cessation of the repeated dosing, the elimination half-lives (8 to 10 hr) were in the same order as after single dosing. The degree of accumulation of cisapride and/or its metabolites may be somewhat higher in patients with hepatic or renal impairment and in elderly patients compared to young healthy volunteers, but the differences are not consistent. Dose adjustments are recommended in patients with hepatic impairment. (See DOSAGE AND ADMINISTRATION.) The pharmacokinetics of cisapride in pediatric patients are not well characterized. Therefore, it is unknown if the dose-response relationship in the adult population can be extrapolated to the pediatric population. (See PRECAUTIONS, Pediatric Use.) Pharmacodynamics The onset of pharmacological action of cisapride is approximately 30 to 60 minutes after oral administration. Cisapride promotes gastric motility. The mechanism of action of cisapride is thought to be primarily enhancement of release of acetylcholine at the myenteric plexus. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. It is less potent than metoclopramide in dopamine receptor-blocking effects in rats. It does not increase or decrease basal or pentagastrin-induced gastric acid secretion. In vitro studies have shown that cisapride is a serotonin-4 (5-HT4) receptor agonist. Electrophysiological studies in in vivo anesthetized guinea pig and rabbit models and in vitro isolated rabbit Purkinje fibers and ventricular papillary muscle and isolated rabbit ventricular myocyte models, have shown that cisapride prolonged cardiac repolarization without slowing conduction by selectively blocking the rapid component of the delayed rectifying K+ current (lkr) which leads to a lengthening of the action potential (QT Syndrome). Esophagus: Twenty milligrams oral cisapride given once to healthy volunteers increased LESP, starting 45 minutes after dosing, with a peak response at 75 minutes. The full duration of the effect was not monitored, and doses smaller than 20 mg were ineffective. Ten milligrams oral cisapride, administered 3 times daily for several days to patients with GERD, resulted in a significant increase in LESP, and an increased esophageal acid clearance. Stomach: Cisapride (single 10 mg doses or 10 mg given orally 3 times daily up to 6 weeks) significantly accelerated gastric emptying of both liquids and solids. Acceleration of gastric emptying, measured over a 4 hour period following a radio-labeled test meal given at lunch time, was greatest when 10 mg cisapride was given both in the morning and again before the test meal, intermediate when 20 mg was given as a single administration in the morning and least when only 10 mg was given on the morning of the test meal. The increases in gastric emptying were proportional to the plasma levels of cisapride measured in these subjects over the same 4 hours that the gastric emptying test was conducted. CLINICAL STUDIES Clinical trials have shown that cisapride can reduce the severity of symptoms of nocturnal heartburn associated with gastroesophageal reflux disease. Two placebo-controlled studies, one using a dose of 10 mg qid, the other both 10 and 20 mg qid, showed effects on nighttime heartburn, although the 10 mg dose in the second study was only marginally effective. There were no consistent effects on daytime heartburn, symptoms of regurgitation, or histopathology of the esophagus. Use of antacids was only infrequently affected and slightly decreased. In a third controlled trial of similar design to the others, neither 10 mg nor 20 mg taken 4 times daily was superior to placebo. In these clinical trials cisapride did not wshow a significant effect on LESP. In a clinical trial comparing 10 mg cisapride to placebo, pH probe evaluation, in a relatively small number of patients, did not reveal a significant difference in pH.

WARNING Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking cisapride. 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. Cisapride is contraindicated in patients taking any of these drugs. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DRUG INTERACTIONS.) QT prolongation, torsades de pointes (cisapride removed from us market) (sometimes with syncope), cardiac arrest, and sudden death have been reported in patients taking cisapride without the above-mentioned contraindicated drugs. Most patients had disorders that may have predisposed them to arrhythmias with cisapride. Cisapride is contraindicated for those patients with: history of prolonged electrocardiographic QT intervals or known family history of congenital long QT syndrome; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; clinically significant bradycardia; 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 cisapride should not be exceeded. DESCRIPTION Propulsid (cisapride removed from us market) tablets and suspension contain cisapride as the monohydrate, which is an oral gastrointestinal agent chemically designated as (±)-cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy) propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate. Its empirical formula is C23H29ClFN3O4·H2O. The molecular weight is 483.97. Cisapride as the monohydrate is a white to slightly beige odorless powder. It is practically insoluble in water, sparingly soluble in methanol, and soluble in acetone. Each 1.04 mg of cisapride as the monohydrate is equivalent to one mg of cisapride. Propulsid (cisapride removed from us market) is available for oral use in tablets containing cisapride as the monohydrate equivalent to 10 mg or 20 mg of cisapride and as a suspension containing the equivalent of 1 mg/ml of cisapride. The inactive ingredients in the tablets are colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, povidone, and starch (corn). The 20 mg tablets also contain FD&C blue no. 2 aluminum lake. The inactive ingredients in the suspension are hydroxypropyl methylcellulose, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 20, propylparaben, sodium chloride, sorbitol, and water. The 1 mg/ml suspension also contains artificial cherry cream flavor and FD&C red no. 40.

INDICATIONS 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), cisapride should generally be reserved for patients who do not respond adequately to lifestyle modifications (see PRECAUTIONS, Information for the Patient and PATIENT PACKAGE INSERT), antacids and gastric acid reducing agents. DOSAGE AND ADMINISTRATION 5 ml (1 teaspoon) suspension = 5 mg. Adults Initiate therapy with one 10 mg tablet of cisapride or 10 ml of the suspension 4 times daily at least 15 minutes before meals and at bedtime. In some patients the dosage will need to be increased to 20 mg, given as above, to obtain a satisfactory result. Cisapride should be discontinued if relief of nocturnal heartburn does not occur. The minimum effective dose should be used. Recommended doses of cisapride should not be exceeded. It is recommended that the daily dose be halved in patients with hepatic insufficiency. In elderly patients, steady-state plasma levels are generally higher due to a moderate prolongation of the elimination half-life. Therapeutic doses, however, are similar to those used in younger adults. HOW SUPPLIED Propulsid (cisapride (removed from us market)) tablets are provided as scored white tablets debossed "Janssen" and "P/10" containing the equivalent of 10 mg of cisapride. Propulsid (cisapride (removed from us market)) is also provided as blue tablets, debossed "Janssen" and "P/20", containing the equivalent of 20 mg cisapride. Propulsid (cisapride (removed from us market)) suspension is provided as a bright pink homogeneous suspension containing the equivalent of 1 mg/ml of cisapride. Unit of use bottles should be dispensed as an intact unit. The PATIENT PACKAGE INSERT should be dispensed with the product. Storage: Store at 15-25°C (59-77°F). Protect the tablets from moisture. The 20 mg tablets should also be protected from light.

PATIENT INFORMATIONPATIENT PACKAGE INSERT READ COMPLETELY BEFORE USE. If you have a medical condition or take a drug listed here, including erythromycin (such as E.E.S., E-Mycin, Ilotycin, Pediazole), clarithromycin (Biaxin) or fluconazole (Diflucan), Do Not Take Cisapride. Brand Name: PROPULSID (cisapride (removed from us market)) (pro-pul-sid) Generic Name: Cisapride Available As: 10 mg & 20 mg tablets (P/10, P/20) 1 mg/ml suspension (liquid form). What is the Most Important Information I Should Know About Cisapride? Cisapride may cause serious irregular heartbeats that may be fatal. Taking cisapride together with certain other medicines increases the likelihood that you will have irregular heartbeats. Cisapride should never be taken with these other medicines. A list of these medicines is supplied below (see Who Should Not Take Cisapride?). If you faint or feel faint, become dizzy or have irregular heartbeats while using cisapride, stop taking your medication and seek medical attention immediately. What is Cisapride? Cisapride is a medication intended only to treat the symptoms of nighttime heartburn in adults. Nocturnal, or nighttime, heartburn is a common symptom of a medical condition called gastroesophageal reflux disease (GERD). It occurs when stomach contents wash back, or "reflux," into the esophagus (a muscular tube that carries food from the mouth to the stomach). Reflux is very common at nighttime because stomach contents can easily wash backwards when you are lying down. Usually, physicians recommend that patients with nighttime heartburn make simple lifestyle changes and use antacids or acid-reducing agents to relieve their symptoms. (See What Else Can I do for Nighttime Heartburn? for more details.) These other medications should be tried first because of the risk of serious, and sometimes fatal, irregular heartbeats associated with the use of cisapride. Who Should Not Take Cisapride? Some patients who have taken certain medications together with cisapride have experienced serious problems such as fainting, dizziness, and irregular heartbeats. These interactions can be fatal. Medications that should not be taken with cisapride include: Antibiotics: Erythromycin (such as E.E.S., E-Mycin, Ilotycin, Pediazole), clarithromycin (Biaxin), troleandomycin (TAO). Antidepressants: Nefazodone (Serzone). Antifungals: Fluconazole (Diflucan), itraconazole (Sporanox), oral ketoconazole (Nizoral). Protease Inhibitors: Indinavir (Crixivan), ritonavir (Norvir). Also, you should not take cisapride with certain heart medications and certain allergy medications. There are also other medications that are handled by your body in the same way as the drugs listed above and may cause the same serious problems (fainting, dizziness, and possibly fatal irregular heartbeats) when taken with cisapride. Tell your doctor about all other drugs you are taking, especially diuretics ("water pills") and heart medications. While taking cisapride, do not start a new medicine without first consulting your doctor or pharmacist. Cisapride should not be used in patients with certain medical conditions. In particular, tell your doctor if you have any type of heart condition or kidney or lung disease before taking cisapride. Be sure your doctor knows about your personal and family medical history. If you have not tried other medications to relieve your nighttime heartburn, tell your doctor before using cisapride. The safety and effectiveness of cisapride in children younger than 16 years have not been demonstrated for any use. Serious adverse events, including death, have been reported in infants and children while being treated with cisapride, although there is no conclusive evidence that cisapride caused them. How Should I Take Cisapride? Take cisapride exactly as your doctor prescribes it. Cisapride does not work for everyone. If you do not get relief of your nighttime heartburn, talk to your doctor about whether to stop using cisapride. Never take more than the recommended dose of cisapride. Always take your medication for as long as the doctor has prescribed it, even if you are beginning to feel better right away. If you forget to take a dose, do not take the missed dose. Take the next dose at the regularly scheduled time. Never take more than your normal dose at any one time to make up for the missed dose. What Should I Avoid While Taking Cisapride? Never take cisapride with the medications listed in Who Should Not Take Cisapride? Do not take cisapride with grapefruit juice. Tell your doctor if you are pregnant or nursing. Your doctor will recommend whether you should take cisapride while pregnant or nursing, based on the benefits and risks. What are the Possible Side Effects of Cisapride? If you faint or feel faint, become dizzy or have irregular heartbeats while using cisapride, stop taking it and contact your doctor immediately. Call your doctor if you experience any unusual symptoms after or while taking cisapride. All prescription medications have some potential side effects for some users. The most common side effects associated with cisapride are headache, diarrhea, stomach pain, nausea, constipation, and a runny nose. Other side effects have been reported less frequently. Be sure to ask your doctor or pharmacist about the side effects of any medication you are taking, including cisapride. What Else Can I do for Nighttime Heartburn? Stop smoking or reduce the number of cigarettes you smoke Elevate the head of your bed when you sleep Avoid eating large meals or eating just before bedtime Do not lie down right after eating If you are overweight or your doctor recommends it, try to lose weight Avoid fatty foods and foods containing chocolate, caffeine or citrus Avoid alcoholic beverages All of these lifestyle changes will help to restore your body to a more normal way of functioning. General Information This information provides a summary about cisapride. Medicines are sometimes prescribed for purposes other than those listed in the PATIENT PACKAGE INSERT. If you have additional questions or concerns, need to report problems associated with the use of cisapride, or want more information about cisapride, contact your doctor or pharmacist. You can also call the Janssen One-to-One Customer Action Center toll-free at 1-800-526-7736 for more information. This medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.

OVERDOSE With overdose, rare cases of QT prolongation and ventricular arrhythmia have been reported. A one-month-old male infant received 2 mg/kg of cisapride 4 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. In instances of overdose, patients should be evaluated for possible QT prolongation and ventricular arrhythmias, including torsades de pointes. Treatment should include gastric lavage and/or activated charcoal, close observation and general supportive measures. Reports of overdosage with cisapride also include an adult who took 540 mg and for 2 hours experienced retching, borborygmi, flatulence, stool frequency, and urinary frequency. Single oral doses of cisapride at 4000 mg/kg, 160 mg/kg, 1280 mg/kg, and 640 mg/kg were lethal in adult rats, neonatal rats, mice, and dogs, respectively. Symptoms of acute toxicity were ptosis, tremors, convulsions, dyspnea, loss of righting reflex, catalepsy, catatonia, hypotonia, and diarrhea. CONTRAINDICATIONS Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking 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 IV erythromycin, clarithromycin (Biaxin), troleandomycin (TAO). Antidepressants: Nefazodone (Serzone). Antifungals: Oral or IV fluconazole (Diflucan), itraconazole (Sporanox), oral ketoconazole (Nizoral). Protease Inhibitors: Indinavir (Crixivan), ritonavir (Norvir). Cisapride is Also Contraindicated for Patients With: History of prolonged electrocardiographic QT intervals or known family history of congenital long QT syndrome; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; clinically significant bradycardia; 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. Cisapride should not be used in patients with uncorrected hypokalemia or hypomagnesemia or who might experience rapid reduction of plasma potassium such as those administered potassium-wasting diuretics and/or insulin in acute settings. Cisapride should not be used in patients in whom an increase in gastrointestinal motility could be harmful, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation. Cisapride is contraindicated in patients with known sensitivity or intolerance to the drug.

SIDE EFFECTS In the U.S. clinical trial population of 1728 patients (comprising 506 with gastroesophageal reflux disorders, and the remainder with other disorders) the following adverse experiences were reported in more than 1% of patients treated with cisapride and at least as often on cisapride as on placebo. (See TABLE 1.) TABLE 1 System/Adverse Events Cisapride N=1042 Placebo N=686 Central & Peripheral Nervous Systems Headache 19.3% 17.1% Gastrointestinal Diarrhea 14.2 10.3 Abdominal pain 10.2 7.7 Nausea 7.6 7.6 Constipation 6.7 3.4 Flatulence 3.5 3.1 Dyspepsia 2.7 1.0 Respiratory System Rhinitis 7.3 5.7 Sinusitis 3.6 3.5 Coughing 1.5 1.2 Resistance Mechanism Viral infection 3.6 3.2 Upper respiratory tract infection 3.1 2.8 Body as a Whole Pain 3.4 2.3 Fever 2.2 1.5 Urinary System Urinary tract infection 2.4 1.9 Micturition frequency 1.2 0.6 Psychiatric Insomnia 1.9 1.3 Anxiety 1.4 1.0 Nervousness 1.4 0.7 Skin & Appendages Rash 1.6 1.6 Pruritus 1.2 1.0 Musculoskeletal System Arthralgia 1.4 1.2 Vision Abnormal vision 1.4 0.3 Reproductive, Female Vaginitis 1.2 0.9 The following adverse events also reported in more than 1% of cisapride patients were more frequently reported on placebo: dizziness, vomiting, pharyngitis, chest pain, fatigue, back pain, depression, dehydration, and myalgia. Diarrhea, abdominal pain, constipation, flatulence, and rhinitis all occurred more frequently in patients using 20 mg of cisapride than in patients using 10 mg. Additional adverse experiences reported to occur in 1% or less of patients in the U.S. clinical studies are: dry mouth, somnolence, palpitation, migraine, tremor, and edema. In other U.S. and international trials and in postmarketing experience, there have been rare reports of seizures and extrapyramidal effects. Also reported have been tachycardia, elevated liver enzymes, hepatitis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia, and granulocytopenia. The relationship of cisapride to the event was not clear in these cases. Cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation, in some cases resulting in death, have been reported. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DRUG INTERACTIONS.) 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 product information 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; extrapyramidal effects including akathisia, Parkinson-like symptoms, dyskinetic and dystonic reactions; 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 reaction. There have been rare cases of sinus tachycardia reported. Rechallenge precipitated the tachycardia again in some of those patients. DRUG INTERACTIONS Cisapride is metabolized mainly via the cytochrome P450 3A4 enzyme. In some cases where serious ventricular arrhythmias, QT prolongation, and torsades de pointes have occurred when cisapride was taken in conjunction with one of the cytochrome P450 3A4 inhibitors, elevated blood cisapride levels were noted at the time of the QT prolongation. Antibiotics: In vitro and/or in vivo data show that clarithromycin, erythromycin, and troleandomycin markedly inhibit the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG. Anticholinergics: Concurrent administration of certain anticholinergic compounds, such as belladonna alkaloids and dicyclomine, would be expected to compromise the beneficial effects of cisapride. Anticoagulants (Oral): In patients receiving oral anticoagulants, the coagulation times were increased in some cases. It is advisable to check coagulation time within the first few days after the start and discontinuation of cisapride therapy, with an appropriate adjustment of the anticoagulant dose, if necessary. Antidepressants: In vitro data indicate that nefazodone inhibits the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG. Antifungals: In vitro and/or in vivo data indicate that fluconazole, itraconazole, and oral ketoconazole markedly inhibit the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG. Human pharmacokinetic data indicate that oral ketoconazole markedly inhibits the metabolism of cisapride, resulting in a mean eight-fold increase in AUC of cisapride. A study in 14 normal male and female volunteers suggests that coadministration of cisapride and ketoconazole can result in prolongation of the QT interval on the ECG. H2 Receptor Antagonists: Cimetidine coadministration leads to an increased peak plasma concentration and AUC of cisapride, there is no effect on cisapride absorption when it is coadministered with ranitidine. The gastrointestinal absorption of cimetidine and ranitidine is accelerated when they are coadministered with cisapride. Protease Inhibitors: In vitro data indicate that indinavir and ritonavir markedly inhibit the metabolism of cisapride which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG. Other: Coadministration of grapefruit juice with cisapride increases the bioavailability of cisapride and concomitant use should be avoided. Cisapride should not be used concomitantly with other drugs known to prolong the QT interval: certain antiarrhythmics, including those of Class IA (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 sertindole); astemizole, bepridil, sparfloxacin, and terodiline. The preceding lists of drugs are not comprehensive. The acceleration of gastric emptying by cisapride could affect the rate of absorption of other drugs. Patients receiving narrow therapeutic ratio drugs or other drugs that require careful titration should be followed closely; if plasma levels are being monitored, they should be reassessed.

WARNINGS Cisapride undergoes metabolism mainly by the hepatic cytochrome P450 3A4 isoenzyme. Drugs which inhibit this enzyme can lead to elevated cisapride blood levels. (See PRECAUTIONS and DRUG INTERACTIONS.) Numerous cases of serious cardiac arrhythmias, including ventricular arrhythmias and torsades de pointes associated with QT prolongation, have been reported in patients taking cisapride with clarithromycin (Biaxin), erythromycin, troleandomycin (TAQ), nefazodone (Serzone), fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), indinavir (Crixivan) or ritonavir (Norvir). Some of these patients did not have cardiac disease; however, most had been receiving multiple other medications and had pre-existing cardiac disease or risk factors for arrhythmias. Some of these cases have been fatal. QT prolongation, torsades de pointes (cisapride (removed from us market)) (sometimes with syncope), cardiac arrest and sudden death have been reported in patients taking cisapride without the above-mentioned contraindicated drugs. Most patients had disorders that may have predisposed them to arrhythmias with cisapride. 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 IA (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 to administration of cisapride to patients who have conditions that could predispose them to the development of serious arrhythmias, such as multiple organ failure, COPD, apnea, and advanced cancer. (See CONTRAINDICATIONS.) Information for the Patient Patients should be warned against concomitant use of clarithromycin (Biaxin), erythromycin, troleandomycin (TAO), nefazodone (Serzone), fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), indinavir (Crixivan) or ritonavir (Norvir). Recommended doses should not be exceeded. Patients should be advised to seek medical attention if they faint or become faint, dizzy, experience an irregular heartbeat or pulse, or any other unusual symptoms while using cisapride. (See PATIENT PACKAGE INSERT.) Patients should be questioned about concomitant medication use. Patients taking cisapride should also be advised to inform their physician when new medications are prescribed. Patients should be advised not to take cisapride with grapefruit juice. Although cisapride does not affect psychomotor function nor does it induce sedation or drowsiness when used alone, patients should be advised that the sedative effects of benzodiazepines and of alcohol may be enhanced by cisapride. Patients should be advised that generally the following lifestyle changes should be tried before using any drug for nighttime heartburn, including cisapride, avoiding alcohol, quitting/decreasing cigarette smoking, elevating the head of the bed, avoiding large meals/meals just before bedtime, losing weight, avoiding fatty foods, chocolate, caffeine, or citrus. Carcinogenesis, Mutagenesis, and Impairment of Fertility In a 25 month oral carcinogenicity study in rats, cisapride at daily doses up to 80 mg/kg was not tumorigenic. For a 50 kg person of average height (1.46 m2 body surface area), this dose represents 50 times the maximum recommended human dose (1.6 mg/kg/day) on a mg/kg basis and 7 times the maximum recommended human dose (54.4 mg/m2) on a body surface area basis. In a 19 month oral carcinogenicity study in mice, cisapride at daily doses up to 80 mg/kg was not tumorigenic. This dose represents 50 times the maximum recommended human dose on a mg/kg basis and about 4 times the maximum recommended human dose on a body surface area basis. Cisapride was not mutagenic in the in vitro Ames test, human lymphocyte chromosomal aberration test, mouse lymphoma cell forward mutation test, and rat hepatocyte UDS test and in vivo rat micronucleus test, male and female mouse dominant lethal mutations tests, and sex linked recessive lethal test in male Drosophila melanogaster. Fertility and reproductive performance studies were conducted in male and female rats. Cisapride was found to have no effect on fertility and reproductive performance of male rats at oral doses up to 160 mg/kg/day (100 times the maximum recommended human dose on a mg/kg basis and 14 times the maximum recommended human dose on a mg/m2 basis). In the female rats, cisapride at oral doses of 40 mg/kg/day and higher prolonged the breeding interval required for impregnation. Similar effects were also observed at maturity in the female offspring (F1) of the female rats (F0) treated with oral doses of cisapride at 10 mg/kg/day or higher. Cisapride at an oral dose of 160 mg/kg/day also exerted contragestational/pregnancy disrupting effects in female rats (F0). Pregnancy, Teratogenic Effects, Pregnancy Category C Oral teratology studies have been conducted in rats (doses up to 160 mg/kg/day) and rabbits (doses up to 40 mg/kg/day). There was no evidence of a teratogenic potential of cisapride in rats or rabbits. Cisapride was embryotoxic and fetotoxic in rats at a dose of 160 mg/kg/day (100 times the maximum recommended human dose on a mg/kg basis and 14 times the maximum recommended human dose on a mg/m2 basis) and in rabbits at a dose of 20 mg/kg/day (approximately 12 times the maximum recommended human dose on a mg/kg basis) or higher. It also produced reduced birth weights of pups in rats at 40 and 160 mg/kg/day and adversely affected the pup survival. There are no adequate and well-controlled studies in pregnant women. Cisapride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the mother and the fetus. Nursing Mothers Cisapride is excreted in human milk at concentrations approximately 1/20 of those observed in plasma. Caution should be exercised when cisapride is administered to a nursing woman, and particular care must be taken if the nursing infant or the mother is taking a drug that might alter cisapride's metabolism in the infant. (See CONTRAINDICATIONS, WARNINGS , DRUG INTERACTIONS.) Pediatric Use Safety and effectiveness in pediatric patients under the age of 16 years have not been established for any indication. 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. (See OVERDOSAGE.) Geriatric Use Steady-state plasma levels are generally higher in older than in younger patients, due to a moderate prolongation of the elimination half-life. Therapeutic doses, however, are similar to those used in younger adults. The rate of common adverse experiences in patients greater than 65 years of age in clinical trials was similar to that in younger adults.