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.
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 (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, PRECAUTIONS, and 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.