Cisapride

Pronunciation

U.S. Brand Names

Propulsid®

Generic Available

Use

Treatment of nocturnal symptoms of gastroesophageal reflux disease (GERD); has demonstrated effectiveness for gastroparesis, refractory constipation, and nonulcer dyspepsia

Restrictions

In U.S., available via limited-access protocol only (1-800-JANSSEN).

Pregnancy Risk Factor

Lactation

Enters breast milk/use caution (AAP rates "compatible")

Contraindications

Hypersensitivity to cisapride or any component of the formulations; GI hemorrhage, mechanical obstruction, GI perforation, or other situations when GI motility stimulation is dangerous

Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsade de pointes, and QT prolongation have been reported in patients taking cisapride with other drugs that inhibit CYP3A4. 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:

Antibiotics: Oral or I.V. erythromycin, clarithromycin, troleandomycin

Antidepressants: Nefazodone

Antifungals: Oral or I.V. fluconazole, itraconazole, miconazole, oral ketoconazole

Protease inhibitors: Indinavir, ritonavir, amprenavir, atazanavir

Cisapride is also contraindicated for patients with a prolonged electrocardiographic QT intervals (QTc >450 msec), a history of QTc prolongation, or known family history of congenital long QT syndrome; clinically significant bradycardia, 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, 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.

Warnings/Precautions

Safety and effectiveness in children have not been established.

On March 24, 2000 the FDA announced that the manufacturer of cisapride would voluntarily withdraw its product from the U.S. market on July 14, 2000. This decision was based on 341 reports of heart rhythm abnormalities including 80 reports of deaths. The company will continue to make the drug available to patients who meet specific clinical eligibility criteria for a limited-access protocol (contact 1-800-JANSSEN).Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsade de pointes, and QT prolongation have been reported in patients taking this drug. 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. QT prolongation, torsade de pointes (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; renal failure; history of ventricular arrhythmias, ischemic heart disease, and CHF; 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), protease inhibitors, bepridil, sparfloxacin and terodiline. (The preceding lists of drugs are not comprehensive.) Recommended doses of cisapride should not be exceeded.

Patients should have a baseline ECG and an electrolyte panel (magnesium, calcium, potassium) prior to initiating cisapride (see Contraindications). Potential benefits should be weighed against risks prior administration of cisapride to patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc. 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. 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. Cisapride 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.

Adverse Reactions

>5%:

Central nervous system: Headache

Dermatologic: Rash

Gastrointestinal: Diarrhea, GI cramping, dyspepsia, flatulence, nausea, xerostomia

Respiratory: Rhinitis

<5%:

Cardiovascular: Tachycardia

Central nervous system: Extrapyramidal effects, somnolence, fatigue, seizure, insomnia, anxiety

Hematologic: Thrombocytopenia, increased LFTs, pancytopenia, leukopenia, granulocytopenia, aplastic anemia

Respiratory: Sinusitis, cough, upper respiratory tract infection, increased incidence of viral infection

Drug Interactions

Substrate of CYP1A2 (minor), 2A6 (minor), 2B6 (minor), 2C8/9 (minor), 2C19 (minor), 3A4 (major); Inhibits CYP2D6 (weak), 3A4 (weak)

Azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole) increase cisapride's concentration. Pre-existing cardiovascular disease or electrolyte imbalances increase the risk of malignant arrhythmias; concurrent use is contraindicated.

Bepridil increases the risk of malignant arrhythmias; concurrent use is contraindicated

Cimetidine increases the bioavailability of cisapride; use an alternative H2 antagonist

Class Ia (quinidine, procainamide) and Class III (amiodarone, sotalol) antiarrhythmics increase the risk of malignant arrhythmias; concurrent use is contraindicated

CYP3A4 inhibitors: May increase the levels/effects of cisapride. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. Concurrent use of azole antifungals, clarithromycin, erythromycin, nefazodone, and protease inhibitors is contraindicated.

Grapefruit juice may increase the bioavailability of cisapride; concomitant use should be avoided.

Macrolides (clarithromycin, erythromycin, troleandomycin) increase serum concentrations of cisapride. Risk of arrhythmias; concurrent use is contraindicated.

Nefazodone and maprotiline may increase the risk of malignant arrhythmias; concurrent use is contraindicated

Phenothiazines (prochlorperazine, promethazine) may increase the risk of malignant arrhythmias; concurrent use is contraindicated

Pimozide may prolong the QT interval; concurrent use is contraindicated.

Protease inhibitors (amprenavir, atazanavir, indinavir, nelfinavir, ritonavir) increase cisapride's concentration. Increased risk of malignant arrhythmias; concurrent use is contraindicated.

Quinolone antibiotics: Sparfloxacin, gatifloxacin, moxifloxacin increase the risk of malignant arrhythmias; concurrent use is contraindicated

Sertindole may increase the risk of malignant arrhythmias; concurrent use is contraindicated

TCAs increase the risk of malignant arrhythmias; concurrent use is contraindicated

Warfarin: Isolated cases of increased INR; monitor closely

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Coadministration of grapefruit juice with cisapride increases the bioavailability of cisapride and concomitant use should be avoided.

Herb/Nutraceutical: St John's wort may decrease cisapride levels.

Mechanism of Action

Enhances the release of acetylcholine at the myenteric plexus. In vitro studies have shown cisapride to have serotonin-4 receptor agonistic properties which may increase gastrointestinal motility and cardiac rate; increases lower esophageal sphincter pressure and lower esophageal peristalsis; accelerates gastric emptying of both liquids and solids.

Pharmacodynamics/Kinetics

Onset of action: 0.5-1 hour

Protein binding: 97.5% to 98%

Metabolism: Extensively hepatic to norcisapride

Bioavailability: 35% to 40%

Half-life elimination: 6-12 hours

Excretion: Urine and feces (<10%)

Dosage

Oral:

Children: 0.15-0.3 mg/kg/dose 3-4 times/day; maximum: 10 mg/dose

Adults: Initial: 10 mg 4 times/day at least 15 minutes before meals and at bedtime; in some patients the dosage will need to be increased to 20 mg to obtain a satisfactory result

Patient Education

It is absolutely vital that you inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take before meals. Avoid alcohol and grapefruit juice. May cause increased sedation, headache, anxiety (use caution when driving or engaging in hazardous tasks until response to drug is known). Immediately report rapid heartbeat, palpitations, chest pain, or tightness. Report severe abdominal pain, prolonged diarrhea, weight loss, extreme fatigue, or other persistent adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Anesthesia and Critical Care Concerns/Other Considerations

IMPORTANT NOTE: On March 24, 2000, the FDA announced that the manufacturer of cisapride would voluntarily withdraw its product from the U.S. market on July 14, 2000. This decision was based on 341 reports of heart rhythm abnormalities including 80 reports of deaths. The company will continue to make the drug available to patients who meet specific clinical eligibility criteria for a limited-access protocol (contact 1-800-JANSSEN).

The potential for arrhythmogenic effects may also increase secondary to significant drug interactions (see Drug Interactions).

In the absence of a known disease or drug contraindication, all patients should have a 12-lead ECG and an electrolyte panel (potassium, calcium, and magnesium) completed prior to initiating cisapride therapy. Serum electrolytes and 12-lead ECG should be again evaluated within the first 48 hours of therapy and periodically thereafter. Patients on diuretic and cisapride therapies should be monitored more closely for the development of hypokalemia, hypocalcemia, and hypomagnesemia. Cisapride therapy should be stopped and the patient monitored closely in patients who develop hypokalemia, hypocalcemia, hypomagnesemia, or QT prolongation (QTc >450 milliseconds).

Cardiovascular Considerations

Recent concerns have arisen regarding the arrhythmogenic potential of cisapride. Cisapride is associated with serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsade de pointes, and QT prolongation. For these reasons, cisapride should be avoided in patients with cardiovascular disease, particularly in those patients with a history of arrhythmias or prolonged QT interval, ischemic heart disease, heart failure, respiratory failure, renal failure, and conditions which may predispose to electrolyte imbalances (hypokalemia, hypocalcemia, hypomagnesemia). Cisapride levels and the potential for arrhythmogenic effects may also increase secondary to significant drug interactions (see Drug Interactions). Cisapride therapy is contraindicated with macrolide antibiotics (eg, clarithromycin, erythromycin, troleandomycin), antifungals (eg, fluconazole, itraconazole, ketoconazole), protease inhibitors (eg, indinavir, ritonavir), phenothiazines (eg, prochlorperazine, promethazine), antiarrhythmics (Class Ia agents: quinidine, procainamide, disopyramide and Class III agents: amiodarone, sotalol), and tricyclic antidepressants, nefazodone, maprotiline, sertindole, bepridil, and sparfloxacin.

In the absence of a known disease or drug contraindication, all patients should have a 12-lead ECG and an electrolyte panel (potassium, calcium, and magnesium) completed prior to initiating cisapride therapy. Cisapride is contraindicated in patients with hypokalemia, hypocalcemia, hypomagnesemia, and in patients with a QTc interval >450 milliseconds. Serum electrolytes and 12-lead ECG should be again evaluated within the first 48 hours of therapy and periodically thereafter. Patients on diuretic and cisapride therapies should be monitored more closely for the development of hypokalemia, hypocalcemia, and hypomagnesemia. Cisapride therapy should be stopped and the patient monitored closely in patients who develop hypokalemia, hypocalcemia, hypomagnesemia, or QT prolongation (QTc >450 milliseconds).

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause sedation, insomnia, anxiety, or extrapyramidal symptoms

Mental Health: Effects on Psychiatric Treatment

Contraindicated with nefazodone and ziprasidone; may increase cisapride levels which have been associated with QT prolongation and torsade de pointes

References

Barone JA, Huang YC, Bierman RH, et al, "Bioavailability of Three Oral Dosage Forms of Cisapride, a Gastrointestinal Stimulant Agent,"Clin Pharm, 1987, 6(8):640-5.

Bran S, Murray WA, Hirsch IB, et al, "Long QT Syndrome During High-Dose Cisapride,"Arch Intern Med, 1995, 155(7):765-8.

Bucci KK, Haverstick DE, and Abercrombie SA, "Dystonic-like Reaction Following Cisapride Therapy,"J Fam Pract, 1995, 40(1):86-8.

Cucchiara S, Staiano A, Boccieri A, et al, "Effects of Cisapride on Parameters of Oesophageal Motility and on the Prolonged Intraoesophageal pH Test in Infants With Gastro-oesophageal Reflux Disease,"Gut, 1990, 31(1):21-5.

Hill SL, Evangelista KJ, Pizzi AM, et al, "Proarrhythmia Associated With Cisapride in Children,"Pediatrics, 1998, 101(6):1053-6.

Khongphatthanayothin A, Lane J, Thomas D, et al, "Effects of Cisapride on QT Interval in Children,"J Pediatr, 1998, 133(1):51-6.

Koelz HR, "Treatment of Reflux Esophagitis With H2-Blockers, Antacids, and Prokinetic Drugs,"Scand J Gastroenterol Suppl, 1989, 156:25-36.

Lander A, "The Risks and Benefits of Cisapride in Premature Neonates, Infants and Children,"Arch Dis Child, 1998, 79:469-71.

Lewin MB, Bryant RM, Fenrich AL, et al, "Cisapride-Induced QT Interval,"J Pediatr, 1996, 128(2):279-81.

Olsson S and Edwards IR, "Tachycardia During Cisapride Treatment,"BMJ, 1992, 305(6856):748-9.

Rizwanuddin S and Wolfe SM, "Cisapride and Torsade de Pointes,"Lancet, 1995, 345:508.

Sempere AP, Duarte J, Cabezas C, et al, "Aggravation of Parkinsonian Tremor by Cisapride,"Clin Neuropharmacol, 1995, 18:76-8.

Tack J, Coremans G, and Janssens J, "A Risk-Benefit Assessment of Cisapride in the Treatment of Gastrointestinal Disorders,"Drug Saf, 1995, 12(6):384-92.

Tolia V, "Long-Term Use of Cisapride in Premature Neonates of <34 Weeks Gestational Age,"J Pediatr Gastroenterol Nutr, 1990, 11:420-2.

Van Eygen M and Van Ravensteyn H, "Effect of Cisapride on Excessive Regurgitation in Infants,"Clin Ther, 1989, 11(5):669-77.

Wax PM and Reiser JR, "Extrapyramidal Reaction Associated With Cisapride Therapy,"Clin Toxicol, 1995, 33(5):515.

Woodard-Jenkins J and Woolf A, "Spectrum of Toxicity Seen in Cisapride Poisoning,"Clin Toxicol, 1995, 33(5):490.

International Brand Names

Acpulsif® (ID); Adamin® (DO, GT, PA, SV); Alimex® (GR); Alimix® (GB); Alipride® (IN); Apulcid® (BD); Arcasin® (ES); Cinetic® (BR); Cipasid® (TH); Ciped® (BD); Cipride® (BD, TH); Cisalone® (IN); Cisap® (AR, PL, RU, YU); Cisapin® (TH); Cisaprida® (CL); Cisaprida Genfar® (EC); Cisaprida L.CH.® (CL); Cisapride Ilab® (AR); Cisarid® (BD); Cisid® (BD); Cispride® (AR, BR); Coordinax® (BG, HU, PL, RU); Cyprid® (BE, LU); Digenol® (SI); Digenormotil® (AR); Disflux® (ID); Enteropride® (BR, MX); Etacril® (AR); Ethiprid® (ID); Fabrapride® (AR); Fisiogastrol® (CR, DO, ES, GT, HN, PA, SV); Gasprid® (PL); Gastonom® (BD); Gastrokin® (CL); Gastromet® (CL); Gastronax® (PL); Gastropride® (LB, RO); Guarposid® (ID); Hebacpyl® (DO); Kelosal® (ES); Kinestase® (MX); Kinetizine® (AR); Marovil® (CL); Metison® (TH); Mopride® (BD); Ondax® (CL); Palcid® (TH); Pangest® (BR); Pepmotil® (BD); Peristil® (RU); Prepulsid 5® (ID); Prepulsid® (AR, AT, AU, BE, BR, CL, CO, CR, CY, CZ, DK, DO, EG, ES, FI, FR, GT, HK, HN, ID, IE, IL, JO, LB, LU, MT, MX, NL, NO, NZ, PA, SE, SV, TH, YU, ZA); Pri-De-Sid® (TH); Pronetic® (ID); Properistal® (CL); Pulsar® (AR); Pulsid® (BD); Pulsitil® (AT); Rapulid® (ID); Stimulit® (ID); Tono-cis® (CL); Unamol® (DO, MX, SV)