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.
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,
, DRUG INTERACTIONS.)
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.)
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.