ATC Class:A03FA02

VA Class:GA900

AHFS Class:

• Prokinetic Agents 56:32

Generic Name(s):

• Cisapride

Chemical Name:

• cis -4-Amino-5-chloro- N -[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxy benzamide

Molecular Formula:

• C₂₃H₂₉ClFN₃O₄

Cisapride is a stimulant of GI motility (prokinetic agent).1,2,3,7,8,9,10,15,21

Gastroesophageal Reflux

Cisapride is used for the symptomatic (e.g., nocturnal heartburn) relief of gastroesophageal reflux.1,2,3,6,7,8,13,14,15,16,17,18,19,20,21 Drug therapy (e.g., antacids, alginic acid, prokinetic agents, histamine H₂-receptor antagonists, proton-pump inhibitors) for gastroesophageal reflux is used in adults who are unresponsive to conventional nondrug therapy alone, including changes in lifestyle, habits, and/or diet that may be contributing factors, and weight reduction in obese patients.1,2,4 Suppression of gastric acid secretion is considered by the American College of Gastroenterology (ACG) to be the mainstay of treatment for gastroesophageal reflux disease (GERD), and a proton-pump inhibitor or histamine H₂-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease.78

Because of the risk of serious, sometimes fatal ventricular arrhythmias, therapy with cisapride generally has been reserved for patients who do not respond adequately to lifestyle modifications, antacids, and gastric acid reducing agents.1 (See Cautions.)

Contributing factors for the development of increased reflux of gastric contents into the esophagus and GERD include increased gastric volume aggravated by delayed gastric emptying, decreased resting lower esophageal sphincter pressure relative to intragastric pressure, and decreased esophageal clearance.2,3,5,15 Patients with gastroesophageal reflux may experience reflux episodes throughout the day and night, and heartburn, the principal symptom of reflux, is more severe in the supine position.2 In addition, because peristalsis, swallowing, fluid intake, and saliva production are reduced or absent during sleep, the magnitude of reflux and period of exposure of the esophagus to gastric acid and enzymes may be most pronounced at this time (resulting in nocturnal heartburn and regurgitation).2 By increasing lower esophageal sphincter pressure, improving esophageal peristalsis, and accelerating gastric emptying, cisapride can reduce reflux and the period of esophageal exposure to low pH and other irritants and thus relieve associated symptoms (e.g., heartburn, regurgitation) in patients with gastroesophageal reflux.2,3,4,7,8,13,14,15,16,17,18,19,20,21

In clinical studies in patients with gastroesophageal reflux and in healthy individuals, cisapride increased lower esophageal sphincter pressure, esophageal motility, and acid clearance and also promoted gastric emptying;1,2,3,8,11,12,13,14,15,16,17,18,19,21 the effects of cisapride were superior to those of placebo and at least comparable to those of metoclopramide.3,8,11,12,13,14,15,16,17,18,19,20,21 However, in several placebo-controlled clinical trials in patients with symptomatic gastroesophageal reflux in which most patients had normal pretreatment and posttreatment lower esophageal pressures, oral cisapride dosages of 10 or 20 mg 4 times daily reduced nocturnal heartburn but produced no appreciable effect on lower esophageal sphincter pressure nor any consistent effect on daytime heartburn, regurgitation, or esophageal histopathology.1,38 In addition, oral administration of cisapride may increase lower esophageal sphincter pressure less consistently than IV administration of the drug.8 In patients with symptomatic gastroesophageal reflux and in healthy individuals, lower esophageal sphincter pressure was increased after administration of single, IV cisapride doses of 4-10 mg1,3,8 or after multiple oral doses of 10 mg 3 times daily;1,3 lower esophageal sphincter pressure also was increased in healthy individuals after a single oral 20-mg dose,1,3 but lower single oral doses were not effective.1,3 In addition to symptomatic relief, short-term endoscopic evidence of healing has been reported in about 55-90% of patients with reflux esophagitis receiving cisapride dosages of 10 mg 4 times daily for 6-16 weeks;3,14,15,16,20,21,28,31 antacid requirements also have decreased during cisapride therapy.3,14,15,16,18,20,21 While the drug has been more effective than placebo in promoting healing in several studies,3,14,15,16,20,21 there is some evidence that relatively high dosages (e.g., 20 mg 4 times daily) may be needed for substantial improvement in healing rates with cisapride relative to placebo.13,14,15

Cisapride appears to be comparably effective to H₂-receptor antagonists (e.g., cimetidine, ranitidine),15,16,21,28,29,30,31,78,80 and combined therapy with the drugs appears to be more effective in providing symptomatic relief and promoting healing than H₂-antagonists alone.15,21,32,78 However, proton-pump inhibitors are more effective than cisapride in controlling gastric acid reflux and relieving GERD symptoms without the risk of severe adverse cardiac effects associated with cisapride.78 In a controlled study comparing 5 different maintenance therapies for GERD, remission of GERD symptoms was maintained after 12 months of therapy in 80% of patients receiving omeprazole alone versus 54% of those receiving cisapride alone and 66% in those receiving cisapride in combination with ranitidine.78,79

For further information on the treatment of GERD, see Uses: Gastroesophageal Reflux, in Omeprazole 56:40.

Administration

Cisapride is administered orally.1 Cisapride should be administered orally on an empty stomach at least 15 minutes before meals in order to maintain relatively consistent GI absorption.1,8,15,21

Concomitant oral administration of cisapride and grapefruit juice should be avoided because grapefruit juice may increase the risk of QT interval prolongation.1,44,64,65 (See Cautions: Precautions and Contraindications.)

A 12-lead ECG should be performed prior to initiation of cisapride therapy, and the drug should not be administered to patients who have QT_c intervals exceeding 450 milliseconds.1 Determination of serum electrolytes (potassium, calcium, and magnesium) and serum creatinine also should be performed prior to initiation of cisapride therapy and whenever conditions develop that may affect electrolyte balance or renal function.1

Dosage

Dosage of cisapride monohydrate is expressed in terms of anhydrous cisapride1 and should be individualized according to patient response and tolerance.1,3,8,15 The recommended dosage of cisapride should not be exceeded.1

For the management of gastroesophageal reflux in adults, cisapride therapy is initiated with an oral dosage of 10 mg 4 times daily, at least 15 minutes before meals and at bedtime; the bedtime dose can reduce the potential for reflux during sleep and associated symptoms (e.g., nocturnal heartburn.1,3,8,15,16,17,18,20,21,29,31 Occasionally, it may be necessary to increase the dosage to 20 mg 4 times daily to achieve a satisfactory response.1,3,8,15,20,21 Cisapride therapy should be discontinued if relief of nocturnal heartburn does not occur.1 The minimum effective dosage of the drug should be used; the recommended dosage of cisapride should not be exceeded.1

While a prolongation in the elimination half-life of cisapride resulting in increased steady-state plasma concentrations has been observed in geriatric patients,1,3,8,15,21 the manufacturer1 states that therapeutic dosages for geriatric patients are similar to those used in younger adults.1

The manufacturer states that safety and efficacy of cisapride in children younger than 16 years of age have not been established.1

Dosage in Renal and Hepatic Impairment

The manufacturer and some clinicians state that the degree of accumulation of cisapride and/or its metabolites may be somewhat higher in patients with hepatic and/or renal impairment when compared with healthy adults,1,2,3,8,15,21 although the manufacturer states that such differences in accumulation are not consistent.1 However, the manufacturer and some clinicians recommend that patients with hepatic insufficiency be treated initially with half the usual dosage of cisapride.1,3,8,15,21 Since some evidence suggests that the risk of QT prolongation and associated serious cardiac arrhythmias, including torsades de pointes, is increased in patients with conditions that affect the metabolism and result in increased serum concentrations of cisapride, some clinicians state that the drug should be used with caution in patients with renal insufficiency;50 the manufacturer states that the drug is contraindicated in patients with renal failure.1 (See Cautions: Precautions and Contraindications.)

Numerous cases of serious cardiac arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes, QT-interval prolongation) have been reported in patients taking cisapride; fatalities have been reported.1,45,50,51,52 Many of these patients were receiving drugs expected to increase serum cisapride concentrations by inhibiting the cytochrome P-450 enzymes that metabolize cisapride (CYP3A4) or had other predisposing factors to arrhythmia development (e.g., history of QT prolongation or ventricular arrhythmias, concomitant drug therapy associated with QT-interval prolongation).1 (See Cautions: Cardiovascular Effects and see Cautions: Precautions and Contraindications.) QT prolongation,1,52 transient ventricular tachycardia (e.g., torsades de pointes),1,52 syncope,1,52 cardiac arrest,1 and/or sudden death1 also have been reported with high-dose cisapride therapy (i.e., 40 mg every 6 hours)52 and infrequently in patients without identifiable risk factors.1 Because of the risk of serious, sometimes fatal ventricular arrhythmias, therapy with cisapride generally should be reserved for patients who do not respond adequately to lifestyle modifications, antacids, and gastric acid reducing agents.1 The recommended dosage of cisapride (10-20 mg 4 times daily) should not be exceeded.1

Adverse effects on the GI tract and nervous system are the most frequently reported adverse effects of cisapride1,3,7,8,13,14,15,18,20 and those most frequently requiring discontinuance of the drug (usually because of intolerable diarrhea and/or abdominal pain).1,3,8,21 The most common adverse GI effects (e.g., diarrhea) are extensions of the drug's pharmacologic activity.3,8,15,19,21 Because of differences in the pharmacologic profiles of the drugs, adverse nervous system effects are less common with cisapride than with metoclopramide whereas diarrhea is more common with cisapride.3,8,15,19,21

In adults receiving cisapride for motility disorders in US placebo-controlled clinical trials, including those with gastroesophageal reflux disease, the most frequent adverse effects of cisapride were headache, diarrhea, abdominal pain, nausea, constipation, and rhinitis.1 The frequency of diarrhea, abdominal pain, constipation, flatulence, and rhinitis appears to be dose dependent, occurring more frequently in patients receiving oral cisapride 20 mg 4 times daily than in those receiving 10 mg 4 times daily.1 Many adverse effects reported with cisapride occurred at a frequency similar to that associated with placebo, and a causal relationship to the drug often could not be established.1,3,7,8,13,14,20,21

Cardiovascular Effects

Numerous cases of serious cardiac arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes, QT-interval prolongation) have been reported in patients taking cisapride; fatalities have been reported.1,45,50,51,52 Many of the patients experiencing these arrhythmias were receiving concomitant therapy with drugs expected to increase plasma cisapride concentrations through inhibition of the cytochrome P-450 (CYP) 3A4 isoenzyme that metabolizes cisapride,1,45,48,49,50,53,56,57 including (but not limited to) certain macrolide antibiotics (clarithromycin, erythromycin, troleandomycin), certain antifungal agents (fluconazole, itraconazole, ketoconazole), certain protease inhibitors (indinavir, ritonavir), and certain antidepressants (nefazodone).1 Other such patients had disorders predisposing them to arrhythmias with cisapride therapy, including preexisting heart disease and/or a history of arrhythmia, renal failure, or electrolyte imbalance, or were receiving concomitant therapy with other drugs associated with arrhythmia or QT prolongation.1,45,50 (See Cautions: Precautions and Contraindications.)

Current data suggest that concomitant administration of cisapride and certain azole-derivative antifungal agents (e.g., fluconazole, itraconazole, ketoconazole) can result in prolongation of the QT interval.1,45,49,50 Cisapride is metabolized by the CYP3A4 isoenzyme.1,45,48,49,50,53,56,57,58 Pharmacokinetics studies in humans demonstrate that oral ketoconazole markedly inhibits the metabolism of cisapride, resulting in an average eightfold increase in AUC of cisapride.1,45,49 A study in healthy men and women suggests that concomitant administration of cisapride and ketoconazole can produce prolongation of the QT interval.1 In vitro data suggest that itraconazole, miconazole (systemic form no longer commercially available in the US), nefazodone, indinavir, ritonavir, clarithromycin, erythromycin, and troleandomycin also markedly inhibit the biotransformation system mainly responsible for the metabolism of cisapride.1,45,48,50 In addition, several studies indicate that concomitant administration of grapefruit juice and cisapride increases the mean bioavailability of the drug by 50%.1,44,65 (See Cautions: Precautions and Contraindications.) Therefore, the manufacturer of cisapride states that concomitant administration of cisapride and oral ketoconazole, itraconazole, oral or IV fluconazole, nefazodone,1,53 oral or IV erythromycin, clarithromycin, troleandomycin, indinavir, ritonavir, or grapefruit juice is contraindicated.1,45,49 The possibility that other inhibitors of the CYP3A4 isoenzyme also may interact with cisapride should be considered, and the manufacturers of nelfinavir61 and saquinavir63 state that these drugs should not be used concomitantly with cisapride.61,63

Because cisapride is a type 4 serotonin (5-HT₄) receptor agonist, exhibiting partial agonist activity at these receptors in cardiac tissue,21,35,36,37 the drug may exhibit positive chronotropic activity.6,21,35 However, palpitation,1,33,34 which may be accompanied by chest and arm pain,33 occurred in 1% or less of patients receiving cisapride in controlled clinical trials.1

Tachycardia1,33,34,35 and extrasystoles33,34 have been reported in patients receiving cisapride in US and foreign trials and in foreign marketing experience.1 Rare occurrences of sinus tachycardia, with relapse of such tachycardia after drug rechallenge in some cases also have been reported.1

Hypertension also has been reported with cisapride therapy.33

Nervous System Effects

Headache1,3,8,13,14,20,21 was the most frequent adverse nervous system effect of cisapride in placebo-controlled clinical trials,1 occurring in about 19% of patients1 (17% of those receiving placebo) and causing discontinuance of the drug in about 1%.1 Pain1,18,33 occurred in about 3% of patients receiving cisapride (2% of those receiving placebo).1 Insomnia occurred in about 2%,1 anxiety1,18 in 1.4%,1 and nervousness in 1.4% of patients receiving cisapride (0.7-1.3% of those receiving placebo),1 and discontinuance of the drug was required in 0.3, 0.1, and 0.2% of patients, respectively.1 Dizziness,1,8,21 myalgia,1 fatigue,1,3,21 and depression1 were reported in more than 1% of patients in controlled clinical trials.1 Somnolence,1,3,21 migraine,1 and tremor1,33 occurred in 1% or less of patients receiving cisapride in controlled clinical trials.1 Seizures,1,3 extrapyramidal effects,1,3 and paresthesias33 rarely have been reported in patients receiving cisapride in US and foreign trials and in foreign marketing experience.1 However, the antidopaminergic activity of cisapride in animals is less than that of metoclopramide, and therefore the risk of extrapyramidal effects is thought to be low.1,2,3,18,15,21 Psychiatric events, including confusion, depression, suicide attempt, and hallucinations, have been reported with cisapride therapy during postmarketing surveillance.1

GI Effects

GI effects1,3,7,8,13,14,15,20,21 were among the most frequent adverse effects of cisapride reported in patients with gastroesophageal reflux or other GI motility disorders in controlled clinical trials and were those most commonly resulting in discontinuance of the drug.1

Diarrhea (usually increased stool frequency) occurred in about 14% of patients receiving cisapride for gastroesophageal reflux or other GI motility disorders (10% of those receiving placebo);1,3,7,8,13,15,18,20,21,33 occasionally, cisapride-induced diarrhea may be intolerable,1,3 and has required discontinuance of the drug in 0.7% of patients in clinical trials.1 Abdominal pain or cramping1,3,8,15,18,21 was reported in about 10% of patients receiving cisapride (8% of those receiving placebo)1 . Although abdominal pain may subside within several days despite continued therapy with the drug,15 it was severe enough to require discontinuance of cisapride1,3,8,21 in 1.2% of patients in clinical trials.1 Abdominal distension and heaviness18 and borborygmus21 also have been reported. Nausea occurred in about 8% of patients receiving cisapride or placebo and required discontinuance in 1%,1 and constipation1,18 occurred in about 7% of patients (3% of those receiving placebo) and required discontinuance of the drug in 0.1%.1 Flatulence occurred in 3.5% and dyspepsia in 2.7% of patients receiving cisapride (3 and 1%, respectively, of those receiving placebo) and required discontinuance of the drug in 0.4 and 0.1%, respectively.1 Vomiting1,13 was reported in more than 1% of patients receiving cisapride in controlled clinical trials,1 and dry mouth was reported in 1% or less of patients.1

Respiratory Effects

Respiratory effects were among the most frequent adverse effects of cisapride reported in patients with gastroesophageal reflux or other GI motility disorders in controlled clinical trials.1 Adverse respiratory effects resulted in discontinuance of the drug in 0.3% of patients.1

Rhinitis1,13 was the most frequent adverse respiratory effect of cisapride, occurring in 7.3% of patients (5.7% of those receiving placebo) and requiring discontinuance in 0.1%.1 Sinusitis occurred in about 4% of patients,1 and upper respiratory tract infection occurred in about 3% of patients receiving cisapride or placebo, and may be related to underlying gastroesophageal reflux rather than the drug in some patients.1 Cough was reported in 1.5% of patients receiving the drug in controlled clinical trials, requiring discontinuance in 0.2% of patients,1 and pharyngitis was reported in more than 1% of patients.1 Precipitation of bronchospasm and/or deterioration in asthma control, reportedly confirmed in some cases by rechallenge and dechallenge with the drug, also has been reported in several patients with asthma receiving cisapride therapy (e.g., during postmarketing surveillance).1,46,47

Genitourinary Effects

Urinary tract infection was reported in about 2% 1 and vaginitis in about 1% of patients receiving cisapride or placebo in controlled clinical trials.1 Urinary frequency was reported in about 1% and required discontinuance in 0.1% of patients receiving the drug.1 Urinary incontinence has been reported with cisapride therapy during postmarketing surveillance.1

Dermatologic and Sensitivity Reactions

Rash was reported in 1.6% and pruritus in 1.2% of patients receiving cisapride and at similar incidences in those receiving placebo in controlled clinical trials; pruritus required discontinuance of cisapride in 0.1% of patients.1 Edema was reported in 1% or less of patients.1 Allergic reactions, including bronchospasm, urticaria, and angioedema, have been reported with cisapride therapy during postmarketing surveillance.1

Musculoskeletal Effects

Arthralgia occurred in 1.4% of patients receiving cisapride (1.2% of those receiving placebo) in controlled clinical trials and required discontinuance of the drug in 0.1%.1 Chest pain1,33 and back pain1,18 were reported in more than 1% of patients.1

Ocular Effects

Abnormal vision occurred in 1.4% of patients receiving cisapride (0.3% of those receiving placebo) in controlled clinical trials and required discontinuance of the drug in 0.2% of patients.1

Hepatic Effects

Although no evidence of liver function abnormalities during cisapride therapy was observed in at least one large series of patients,3,8,15,21 elevated serum liver enzyme concentrations and hepatitis have been reported rarely in patients receiving the drug in US and foreign trials and in foreign marketing experience.1

Hematologic Effects

Thrombocytopenia, leukopenia, aplastic anemia, pancytopenia, and granulocytopenia have been reported rarely in patients receiving cisapride in US and foreign trials and in foreign marketing experience.1

Electrolyte and Metabolic Effects

Dehydration was reported in more than 1% of patients receiving cisapride in controlled clinical trials.1 Limited evidence indicates that cisapride does not adversely affect glycemic control in insulin-dependent (type I) diabetic patients with delayed gastric emptying.3,8,15,21,38,39

Other Adverse Effects

Viral infection occurred in about 4% of patients receiving cisapride in controlled clinical trials and required discontinuance of the drug in 0.2% of patients.1 Fever was reported in about 2% of patients receiving cisapride in controlled clinical trials and required discontinuance in 0.1%.1

The antidopaminergic activity of cisapride in animals is less than that of metoclopramide, suggesting that cisapride may be less likely to produce hyperprolactinemic effects (e.g., galactorrhea, gynecomastia, menstrual irregularities).1,2,3,7,8,15,21 However, hyperprolactinemia, galactorrhea, gynecomastia, and enlargement of the female breast have been reported with cisapride therapy during postmarketing surveillance.1

Precautions and Contraindications

Because of its pharmacologic effects on transit time in the stomach and small intestine, cisapride may alter the absorption of certain drugs.1,2,3,8,13,15,21,40 The extent of absorption of drugs that disintegrate, dissolve, and/or are absorbed mainly in the stomach (e.g., digoxin) may be diminished by cisapride.1,2,3,8,13,15,21,40 However, some evidence suggests that the magnitude of reductions in peak plasma digoxin concentrations and area under the plasma digoxin concentration-time curve (AUC) observed during concomitant cisapride administration are less pronounced than those observed with metoclopramide and may not be clinically important.3,8,40 The rate and extent of absorption of drugs that are mainly absorbed in the small intestine (e.g., acetaminophen, aspirin, diazepam, ethanol, levodopa, lithium, tetracycline) may be enhanced when administered concomitantly with cisapride.1,3,8,9,10,21,29 Patients receiving cisapride concomitantly with orally administered drugs that have narrow therapeutic ratios or drugs that require careful titration should be monitored closely.1,15,21 In addition, if plasma concentrations of orally administered concomitant drugs are being monitored, they should be reassessed when cisapride therapy is initiated and discontinued.1 Although cisapride does not directly affect psychomotor function or induce sedation or drowsiness when used alone, the absorption rate of benzodiazepines and alcohol may be increased by cisapride, enhancing their sedative effects.1,3,8,21,41 The manufacturer also cautions that coagulation time of patients receiving certain oral anticoagulants (e.g., warfarin) may increase with concomitant administration of cisapride;1,3,15,21 therefore, coagulation times should be monitored during the first few days after initiation or discontinuance of cisapride therapy in patients receiving oral anticoagulants, and appropriate adjustment in the anticoagulant dosage made if necessary.1,8,15,21 The possibility that oral bioavailability of cisapride (probably secondary to inhibited metabolism) could be increased during concomitant administration of cimetidine should be considered;1,3,8,21,42,43 ranitidine does not appear to interact with cisapride similarly.1,43 In addition, the possibility that cisapride may accelerate the GI absorption and decrease the oral bioavailability of cimetidine or ranitidine should be considered.1,15,21,43

Because anticholinergic drugs (e.g., belladonna alkaloids, dicyclomine) may decrease GI motility, concomitant administration of these drugs may compromise the beneficial therapeutic effects of cisapride.1,21

Some clinicians suggest that cisapride should be used with caution in patients who have a history of asthma, since bronchospasm and/or deterioration in asthma control has been reported rarely in such patients.46,47 (See Cautions: Respiratory Effects.)

Patients should be advised that lifestyle changes, including avoidance of alcohol, cessation or reduction of cigarette smoking, elevation of the head of the bed, avoidance of large meals just before bedtime, weight loss, and avoidance of fatty foods, chocolate, caffeine, and citrus, generally should be tried before using any drug, including cisapride, for nighttime heartburn.1 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.1 Patients should be questioned about their use of other medications and should be advised to inform their clinician when new medications are added to their regimen.1

Potential benefits should be weighed against risks prior to administration of cisapride to patients who have conditions, such as multiple organ failure, chronic obstructive pulmonary disease (COPD), apnea, and advanced cancer, that could predispose them to the development of serious arrhythmias.1

A 12-lead ECG should be obtained prior to initiation of cisapride therapy, and the drug should not be administered if the QT_c interval exceeds 450 milliseconds.1 Serum electrolytes (potassium, calcium, and magnesium) and serum creatinine also should be assessed prior to administration of cisapride and whenever conditions develop that may affect electrolyte balance or renal function.1 Patients should be instructed to immediately stop taking cisapride and contact a physician if they experience syncope or rapid or irregular heartbeat.1

Cisapride is contraindicated in patients with conditions predisposing them to arrhythmias, including a history of prolonged QT intervals on ECG or known family history of congenital long QT syndrome; a history of ventricular arrhythmias (e.g., torsades de pointes), ischemic or valvular heart disease; other structural heart defects; cardiomyopathy; congestive heart failure; clinically important bradycardia; sinus node dysfunction; second- or third-degree atrioventricular (AV) block; respiratory failure; or conditions that result in electrolyte disorders, such as severe dehydration, vomiting, malnutrition, eating disorders, renal failure, or during administration of potassium-wasting diuretics or insulin in acute settings.1

Cisapride is contraindicated in patients receiving concomitant therapy with drugs known to prolong the QT interval and increase the risk of arrhythmias, including (but not limited to) antiarrhythmics of class 1A (e.g., quinidine, procainamide) and class III (e.g., sotalol), tricyclic antidepressants (e.g., amitriptyline, protriptyline), certain tetracyclic or other antidepressants (e.g., maprotiline, nefazodone), certain antipsychotic agents (e.g., sertindole [not currently commercially available in the US]), certain phenothiazines (e.g., prochlorperazine, promethazine), astemizole (no longer commercially available in the US), bepridil, sparfloxacin, and terodiline (not currently commercially available in the US).1,68 Cisapride also is contraindicated in patients receiving concomitant therapy with drugs expected to increase plasma cisapride concentrations through inhibition of the cytochrome P-450 (CYP) 3A4 isoenzyme that metabolizes cisapride,1,45,48,49,50,53 including (but not limited to) clarithromycin,1,57,59 erythromycin,1 troleandomycin,1 nefazodone,1,53 fluconazole,1 itraconazole,1,55 ketoconazole,1,54 indinavir,1,60 ritonavir1,62 and aprepitant or fosaprepitant.81,82 (See Cautions: Cardiovascular Effects.)

Concomitant oral administration of grapefruit juice has been reported to increase the bioavailability and blood levels of cisapride.1,44,64 This interaction appears to result from inhibition of the intestinal cytochrome P-450 enzyme system.65 Clinicians should advise patients to refrain from ingesting grapefruit juice during cispride therapy due to the potential for prolongation of the QT interval.1,44,64,65,66,67

Cisapride is contraindicated in patients in whom an increase in GI motility could be harmful (e.g., patients with GI perforation, hemorrhage, or mechanical obstruction).1 Cisapride also is contraindicated in patients with known sensitivity or intolerance to the drug.1

Pediatric Precautions

Safety and efficacy of cisapride in children younger than 16 years of age have not been established for any indication. However, limited data in children 2 months of age and older who have received the drug (e.g., for gastroesophageal reflux),3,8,15,21 suggest that the adverse effect profile is similar to that in adults.21 Although a causal relationship to cisapride has not been established, serious adverse events, including death, have been reported in infants and children treated with cisapride.1 Several deaths in pediatric patients were related to cardiovascular events (third-degree heart block and ventricular tachycardia).1 Pediatric deaths also have been associated with seizures, and at least one case of sudden unexplained death has been reported in a 3-month-old infant.1 Other adverse effects reported specifically in pediatric patients include positive antinuclear antibody (ANA) test results, 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.1

Geriatric Precautions

Cisapride generally is well tolerated in geriatric patients; the frequency and severity of adverse effects reported in patients older than 65 years of age are similar to those in younger adults.1 However, caution in the use of cisapride must be exercised in geriatric patients since a substantial proportion of such patients have conditions or use concomitant drugs that contraindicate therapy with cisapride.1 (See Cautions: Precautions and Contraindications.) A 12-lead ECG and serum electrolyte determinations should be performed prior to initiation of cisapride in geriatric patients.1 Steady-state plasma concentrations of cisapride generally may be higher in geriatric patients than in younger adults secondary to a moderate prolongation of half-life;1,2,3,8,15,21 however, the manufacturer states that therapeutic dosages for geriatric patients are similar to those for younger adults.1

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was demonstrated by cisapride in the in vitro Ames test, the human lymphocyte chromosomal aberration test, the rat hepatocyte UDS test, the in vivo rat micronucleus test, the mouse lymphoma cell forward mutation test, the dominant lethal mutation test in male and female mice, or the sex-linked recessive lethal test in Drosophila melanogaster .1

Studies to determine the carcinogenic potential of cisapride were performed in mice and rats; cisapride was not tumorigenic in these studies.1 Mice received cisapride orally in dosages of up to 80 mg/kg daily for 76 weeks, while rats received this dosage for 100 weeks.1 The maximum dosages used in mice and rats were equal to or less than 4 and 7 times the maximum recommended human dosage on a body surface area basis, respectively, and were equal to or less than 50 times the maximum recommended human dosage on a mg/kg basis.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits receiving cisapride dosages of up to 100 and 24 times, respectively, the human daily dosage of the drug on a mg/kg basis, did not reveal evidence of teratogenicity; however, cisapride has been shown to be embryotoxic and fetotoxic in rats and rabbits when given at dosages equal to or more than 100 and 12 times, respectively, the maximum recommended dosage in humans on a mg/kg basis.1 Cisapride given to female rats at daily dosages 25 and 100 times the maximum recommended dosage in humans has been shown to decrease birth weights and adversely affect the survival rate of rat pups.1 Although there are no adequate and controlled studies to date in humans, cisapride should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

Fertility

Reproduction studies in male rats receiving cisapride doses of up to 100 times the human daily dose of the drug on a mg/kg basis did not reveal any evidence of an effect on fertility or reproductive performance; however, cisapride has been shown to prolong the breeding interval required for impregnation in female rats and in the offspring of female rats given daily dosages equal to or more than 25 and 6.25 times, respectively, the maximum recommended dosage in humans on a mg/kg basis.1 Cisapride also has been shown to exert contragestational or pregnancy-disrupting effects in female rats when given at dosages equal to 100 times the human daily dose of the drug on a mg/kg basis.

Lactation

Cisapride is distributed into human milk at concentrations about 5% of those found in plasma.1 Since the potential effect on nursing infants is not known, cisapride should be used with caution in nursing women.1

Description

Cisapride, a synthetic substituted piperidinyl benzamide, is a stimulant of GI motility (prokinetic agent).1,2,3,7,8,9,10,15,21 Cisapride is commercially available as the monohydrate;1 potency is expressed in terms of anhydrous drug.1

Cisapride is structurally related to metoclopramide.7,8,15 Like metoclopramide, the drug is a substituted benzamide derivative of p -aminobenzoic acid and is structurally related to procainamide,7 but lacks local anesthetic and antiarrhythmic properties.7 Cisapride differs structurally from metoclopramide by replacement of the 2-diethylaminoethyl substituent at the p -aminobenzamide nitrogen with a substituted piperidinyl substituent.7,8 While both drugs stimulate gastric and small intestinal motility, the pharmacologic profile of metoclopramide is more complex than that of cisapride.3,7,8,15 Cisapride appears to stimulate GI motility principally via enhancement of cholinergic excitatory processes at the postganglionic neuromuscular junction (i.e., stimulating acetylcholine release from postganglionic neurons of the myenteric [Auerbach's] plexus); 1,2,3,7,8,9,10,13,15,21 this effect appears to be indirect, and it has been suggested that serotonergic (e.g., type 4 [5-HT₄]) receptor agonist activity may be involved in the release of the neurotransmitter.1,2,3,7,9,13,15,21 While metoclopramide also exhibits such activity at postganglionic neurons, cisapride, unlike metoclopramide, does not exhibit potent dopamine-receptor antagonist activity1,2,3,7,8,15,21 nor does it appear to possess direct antiemetic or CNS depressant (e.g., sedative) activity.1,2,3,8,15 The antidopaminergic activity of cisapride has been shown to be less than that of metoclopramide in animals, and the likelihood of producing extrapyramidal or hyperprolactinemic effects (e.g., galactorrhea, gynecomastia, menstrual irregularities) with cisapride generally appears to be low.1,2,3,7,8,15,21

Like metoclopramide, cisapride increases (generally by about 20-50%) lower esophageal sphincter pressure and esophageal motility in patients with gastroesophageal reflux disease and in healthy individuals.1,3,7,8,11,18,21 Also like metoclopramide, cisapride accelerates gastric emptying and intestinal transit from the duodenum to the ileocecal valve,1,3,7,8,10,21 and the drug's stimulatory effects on GI smooth muscle coordinate gastric, pyloric, and duodenal (i.e., antroduodenal) motor activity.3,7,8,21,27 However, unlike metoclopramide, cisapride also increases colonic motility and enhances cecal and ascending colonic emptying and can increase stool frequency in both healthy and constipated individuals;3,8,15,21,22,23,24 in part, enhanced defecation may result from decreased anal sphincter tone induced by the drug.21,24,25,26

Electrophysiologic studies in anesthetized guinea pig and rabbit models and in isolated rabbit Purkinje fibers, ventricular papillary muscle, and ventricular myocytes1 have shown that cisapride prolongs cardiac repolarization without slowing conduction by selectively blocking the rapid component of the delayed rectifying potassium current (I_kr), which leads to a lengthening of the action potential (QT syndrome).1,56,58 (See Cautions.)

Additional Information

SumMon^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity.

1. Janssen Pharmaceutica. Propulsid^® (cisapride monohydrate) tablets and suspension prescribing information. Titusville, NJ; 2000 Jan. [Web]

2. Anon. Cisapride. Phase III Prof . 1992; 2:10-17.

3. McCallum RW. Cisapride: a new class of prokinetic agent. The American College of Gastroenterology Committee on FDA-Related Matters. Am J Gastroenterol . 1991; 86:135-49. [PubMed 1992624]

4. Garnett WR. Efficacy, safety, and cost issues in managing patients with gastroesophageal reflux disease. Am J Hosp Pharm . 1993; 50(Suppl 1): S11-18. [PubMed 8097363]

5. Bozymski EM. Pathophysiology and diagnosis of gastroesophageal reflux disease. Am J Hosp Pharm . 1993; 50(Suppl 1): S4-6. [PubMed 8475926]

6. Anon. Janssen's Propulsid approved July 29 for nocturnal heartburn. Trade and Govt. Memos, FDC Reports 1993(Aug 2): T&G 1-2.

7. Reynolds JC, Putnam PE. Prokinetic agents. Gastroenterol Clin North Am . 1992; 21:567-98. [PubMed 1516959]

8. McCallum RW, Prakash C, Campoli-Richards DM et al. Cisapride. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use as a prokinetic agent in gastrointestinal motility disorders. Drugs . 1988; 36:652-81. [PubMed 3065057]

9. Holtmann G, Talley NJ. Functional dyspepsia: current treatment recommendations. Drugs . 1993; 45:918-30. [PubMed 7691499]

10. Tonini M, Galligan JJ, North RA. Effects of cisapride on cholinergic neurotransmission and propulsive motility in the guinea pig ileum. Gastroenterology . 1989; 96:1257-64. [PubMed 2539305]

11. Weiser H, Holscher A, Zimmerman T. Effects of cisapride and metoclopramide on the lower esophageal motility: a pressure and pH-metric study. Digestion . 1986; 34:142.

12. Weinbeck M, Cuder-Wiesinger E, Berges W. Comparative study of cisapride's versus metoclopramide's effect on esophageal motility. Digestion . 1986; 34:141.

13. Anon. Cisapride for nocturnal heartburn. Med Lett Drugs Ther . 1994; 36:11-3. [PubMed 8283956]

14. Faruqui S, Sigmund C, Smith R et al. Cisapride in the treatment of GERD: a double-blind, placebo-controlled multicenter dose-response trial. Gastroenterology . 1992; 102(4 Part 2):A66. [PubMed 1568602]

15. Barone JA, Jessen LM, Colaizzi JL et al. Cisapride: a gastrointestinal prokinetic drug. Ann Pharmacother . 1994; 28:488-500. [PubMed 8038476]

16. Lepoutre L, Van Der Spek P, Vanderlinden I et al. Healing of grade-II and III oesophagitis through motility stimulation with cisapride. Digestion . 1990; 45:109-14. [PubMed 2190850]

17. Baldi F, Ferrarini F, Longanesi A et al. Effect of short-term cisapride treatment on gastro-oesophageal reflux disease. Progr Med . 1987; 43(Suppl 1):29-34.

18. Baldi F, Bianchi Porro G, Dobrilla G et al. Cisapride versus placebo in reflux esophagitis: a multicenter double-blind trial. J Clin Gastroenterol . 1988; 10:614-8. [PubMed 3068300]

19. Manousos ON, Mandidis A, Michailidis D. Treatment of reflux symptoms in esophagitis patients: comparative trial of cisapride and metoclopramide. Curr Ther Res . 1987; 42:1-7.

20. DeMicco M, Berenson M, Wu W et al. Cisapride in the treatment of GERD: a double-blind, placebo-controlled multicenter dose-response trial. Gastroenterology . 1992; 102(4 Part 2):A59.

21. Wiseman LR, Faulds D. Cisapride: an updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders. Drugs . 1994; 47:116-52. [PubMed 7510617]

22. Krevsky B, Maurer AH, Malmud LS et al. Cisapride accelerates colonic transit in constipated patients with colonic inertia. Am J Gastroenterol . 1989; 84:882-7. [PubMed 2667336]

23. Tolleson PO, Cassuto J, Rimback G et al. Treatment of postoperative paralytic ileus with cisapride. Scand J Gastroenterol . 1991; 26:477-82. [PubMed 1871540]

24. Wienbeck M, Reitz B, Barnert J et al. Intrarectal application of cisapride: does it alter anorectal function in constipation and incontinence? Gastroenterology . 1992; 102(4 Part 2):A46. Abstract.

25. Enck P, Arping HG, Engel S et al. Effects of cisapride on ano-rectal sphincter function. Aliment Pharmacol Ther . 1989; 3:539-45. [PubMed 2518867]

26. Berger V, Armbrecht U, Heusinger A et al. The effect of cisapride on defaecation in normal human subjects—lack of effect on faecal excretion of water, fat, and bile acids. Aliment Pharmacol Ther . 1989; 3:547-52. [PubMed 2518868]

27. Johnson AG. The effects of cisapride on antroduodenal co-ordination and gastric emptying. Scand J Gastroenterol . 1989; 24(Suppl 165):36-43.

28. Janisch HD, Hüttemann W, Bouzo MH. Cisapride versus ranitidine in the treatment of reflux esophagitis. Hepato-gastroenterology . 1988; 35:125-7. [PubMed 3042576]

29. Geldof H, Hazelhoff B, Otten MH. Two different dose regimens of cisapride in the treatment of reflux esophagitis: a double-blind comparison with ranitidine. Aliment Pharmacol Ther . 1993; 7:409-15. [PubMed 8218755]

30. Maleev A, Mendizova A, Popov P et al. Cisapride and cimetidine in the treatment of erosive esophagitis. Hepato-gastroenterology . 1990; 37:403-7. [PubMed 2210608]

31. Galmiche JP, Fraitag B, Filoche B et al. Double-blind comparison of cisapride and cimetidine in treatment of reflux esophagitis. Dig Dis Sci . 1990; 35:649-55. [PubMed 2331957]

32. Galmiche JP, Brandstatter G, Evreux M et al. Combined therapy with cisapride and cimetidine in severe reflux oesophagitis: a double-blind controlled trial. Gut . 1988; 29:675-81. [PubMedCentral][PubMed 3294124]

33. Olsson S, Edwards IR. Tachycardia during cisapride treatment. BMJ . 1992; 305:748-9. [PubMedCentral][PubMed 1384896]

34. Inman W, Kubota K. Tachycardia during cisapride treatment. BMJ . 1992; 305:1019. [PubMedCentral][PubMed 1458129]

35. Humphrey PPA, Bunce KT. Tachycardia during cisapride treatment. BMJ . 1992; 305:1019-20. [PubMedCentral][PubMed 1458130]

36. Medhurst AD, Kaumann AJ. Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium. Br J Pharmacol . 1993; 110:1023-30. [PubMedCentral][PubMed 8298790]

37. Kaumann AJ, Sanders L,Brown AM et al. A 5-HT4-like receptor in human right atrium. Naunyn Schmiedebergs Arch Pharmacol . 1991; 344:150-9. [PubMed 1658664]

38. Horowitz M, Maddox A, Harding PE et al. Effect of cisapride on gastric and esophageal emptying in insulin-dependent diabetes mellitus. Gastroenterolgy . 1987; 92:1899-1907.

39. Horowitz M, Roberts AP. Long-term efficacy of cisapride in diabetic gastroparesis. Am J Med . 1990; 88:195-6. [PubMed 2301447]

40. Kirch W, Janisch HD, Santos SR et al. Effect of cisapride and metoclopramide on digoxin bioavailability. Eur J Drug Metab Pharmacokinet . 1986; 11:249-50. [PubMed 3582418]

41. Roine R, Heikkonen E, Salaspuro M et al. Cisapride enhances alcohol absorption and leads to high blood alcohol levels. Gastroenterology . 1992; 102(4Part 2):A507.

42. H2-Receptor antagonist drug interactions: cisapride. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:541.

43. Cisapride/histamine H2 antagonists. In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1994(Apr):192.

44. Janssen Pharmaceutica, Titusville, NJ: Personal communication.

45. Klausner MA. Dear Doctor letter. Titusville, NJ: Janssen Pharmaceutica; 1995.

46. Pillans P. Bronchospasm associated with cisapride. BMJ . 1995; 311:1472. [PubMedCentral][PubMed 8520336]

47. Nolan P, Philips M, Williamson B. Cisapride and brittle asthma. Lancet . 1990; 336:1443. [PubMed 1978892]

48. Sekkarie MA. Torsades de pointes in two chronic renal failure patients treated with cisapride and clarithromycin. Am J Kidney Dis . 1997; 30:437-9. [PubMed 9292575]

49. Chan-Tompkins NH, Babinchak TJ. Cardiac arrhythmias associated with coadministration of azole compounds and cisapride. Clin Infect Dis . 1997; 24:1285. [PubMed 9195113]

50. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med . 1996; 335:290-1. [PubMed 8657260]

51. Lewin MB, Bryant RM, Fenrich AL et al. Cisapride-induced long QT interval. J Pediatr . 1996; 128:279-81. [PubMed 8636830]

52. Bran S, Murray WA, Hirsch IB et al. Long QT syndrome during high-dose cisapride. Arch Intern Med . 1995; 155:765-8. [PubMed 7695465]

53. Bristol-Myers Squibb. Serzone^® (nefazodone hydrochloride) tablets prescribing information. Princeton, NJ; 1995 Oct. [Web]

54. Janssen Pharmaceutica. Nizoral^® (ketoconazole) tablets prescribing information. Titusville, NJ; 1995 Nov. [Web]

55. Janssen Pharmaceutica. Sporanox^® (itraconazole) capsules prescribing information. Titusville, NJ; 1992 Oct. [Web]

56. Thomas AR, Chan LN, Bauman JL et al. Prolongation of the QT interval related to cisapride-diltiazem interaction. Pharmacotherapy . 1998; 18:381-5. [PubMed 9545159]

57. Gray VS. Syncopal episodes associated with cisapride and concurrent drugs. Ann Pharmacother . 1998; 32:648-51. [PubMed 9640482]

58. Hill SL, Evangelista JK, Pizzi AM et al. Proarrhythmia associated with cisapride in children. Pediatrics . 1998; 101:1053-6. [PubMed 9606235]

59. Abbott Laboratories. Biaxin^® (clarithromycin) Filmtab tablets and granules for oral suspension prescribing information. Abbott Park, IL; 1997 Oct. [Web]

60. Merck & Company Inc. Crixivan^® (indinavir sulfate) capsules prescribing information. West Point, PA; 1997 Nov. [Web]

61. Agouron Pharmaceuticals. Viracept^® (nelfinavir mesylate) tablets and oral powder prescribing information. La Jolla, CA; 1997 Jul 2. [Web]

62. Abbott Laboratories. Norvir^® (ritonavir) capsules and oral solution prescribing information. North Chicago, IL; 1997 Mar. [Web]

63. Roche Pharmaceuticals. Fortovase^® (saquinavir) soft gelatin capsules prescribing information. Nutley, NJ; 1997 Nov. [Web]

64. Klausner MA. Dear doctor regarding Propulsid^® (cisapride) labeling changes. Titusville, NJ: Janssen Pharmaceutica; 1999 Jun.

65. Gross AS, Goh YD, Addison RS et al. Influence of grapefruit juice on cisapride pharmacokinetics. Clin Pharmacol Ther . 1999; 65(4):395-401. [PubMed 10223776]

66. Bailey DG, Malcolm J, Arnold O et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol . 1998; 46(2): 101-10. [PubMedCentral][PubMed 9723817]

67. Michalets EL. Update: Clinically significant cytochrome P-450 drug interactions. Pharmacotherapy . 1998; 18(1): 84-112. [PubMed 9469685]

68. Davis AS. The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods. Hum Exp Toxicol . 1998; 17:677-80. [PubMed 9988372]

69. Anon. Janssen Pharmaceutica stops marketing cisapride in the US. FDA Talk Paper . Rockville, MD: Food and Drug Administration; 2000 Mar 23.

70. Reuters Medical News. Janssen to pull cisapride from US market: 2000 Mar 24 from Reuters web site. [Web]

71. Anon. Information regarding withdrawal of Propulsid (cisapride) by Janssen Pharmaceutica. From FDA website. [Web]

72. Medications News Release. FDA strengthens warning label for Propulsid. From Medications website. [Web]

73. Gheuens J. Dear health-care professional letter regarding labeling changes of Propulsid^® (cisapride). Titusville, NJ: Janssen Pharmaceutica; 2000 Jan.

74. Anon. FDA updates warnings for cisapride. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2000 Jan 24. regarding important safety and efficacy information on Propulsid^® (cisapride).

75. Klausner MA. Dear doctor letter Titusville, NJ: Janssen Pharmaceutica; 1998 Jun 26.

76. Janssen Pharmaceutica. Propulsid^® (cisapride) tablets prescribing information. In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996(Suppl A):A110-1. [Web]

78. DeVault KR, Castell DO, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol . 1999; 94:1434-42. [PubMed 10364004]

79. Vigneri S, Termini R, Leandro G et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med . 1995; 333:1106-10. [PubMed 7565948]

80. Richter JE, Long JF. Cisapride for gastroesophageal reflux disease: A placebo-controlled, double-blind study. Am J Gastroenterol . 1995; 90:423-30. [PubMed 7872282]

81. Merck. Emend^® (aprepitant) capsules prescribing information. Whitehouse Station, NJ; 2008 Feb. [Web]

82. Merck. Emend^® (fosaprepitant dimeglumine) for injection prescribing information. Whitehouse Station, NJ; 2008 Feb. [Web]