CISAPRIDE
DESCRIPTION:
WARNING
Serious cardiac arrhythmias including
ventricular tachycardia, ventricular
fibrillation, torsades de pointes, and QT
prolongation have been reported in patients
taking PROPULSID(R) with other drugs that
inhibit cytochrome P450 3A4, such as
ketoconazole, itraconazole, miconazole,
troleandomycin, erythromycin, fluconazole,
and clarithromycin. Some of these events
have been fatal. PROPULSID(R) is
contraindicated in patients taking any of
these drugs. (See CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS, and DRUG
INTERACTIONS).
PROPULSID(R) (cisapride) Tablets and Suspension contain cisapride as the
monohydrate, which is an oral gastrointestinal prokinetic 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 onemg of
cisapride.
PROPULSID(R) 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 1mg/mL of cisapride.
ACTIONS/CLINICAL PHARMACOLOGY:
PHARMACOKINETICS
PROPULSID(R) is rapidly absorbed after oral administration+ADs- peak plasma
concentrations are reached 1 to 1.5 hours after dosing. The absolute
bioavailability of PROPULSID(R) is 35-40+ACU-. 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 PROPULSID(R) tablet absorption. (This has not been established for the
suspension.) PROPULSID(R) binds to an extent of 97.5-98+ACU- to plasma proteins,
mainly to albumin. The volume of distribution of PROPULSID(R) is about 180 L,
indicating extensive tissue distribution.
The plasma clearance of PROPULSID(R) is about 100mL/min. The mean terminal half-
life reported for PROPULSID(R) ranges from 6 to 12 hours+ADs- longer half-lives, up
to 20 hours, have been reported following intravenous (IV) administration.
Cisapride is metabolized mainly via the cytochrome P 450 3A4 enzyme.
PROPULSID(R) is extensively metabolized+ADs- unchanged drug accounts for less than
10+ACU- of urinary and fecal recovery following oral administration. Norcisapride,
formed by N-dealkylation, is the principal metabolite in plasma, feces and
urine.
There was no unusual drug accumulation due to time-dependent or non-linear
changes in PK. After cessation of the repeated dosing, the elimination half-
lives (8 to 10 hr) were in the same order as after single dosing. There is some
evidence that the degree of accumulation of PROPULSID(R) 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 and do not require dosage adjustment.
PHARMACODYNAMICS
The onset of pharmacological action of cisapride is approximately 30 to 60
minutes after oral administration.
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. This agonistic action may result in increased gastrointestinal motility
and cardiac rate.
ESOPHAGUS: Single doses of cisapride (4 to 10 mg IV) increased the lower
esophageal sphincter pressure (LESP) and lower esophageal peristalsis compared
to placebo and/or metoclopramide. In patients with gastroesophageal reflux
disease (GERD) and a LESP of +ADw-10 mm Hg, cisapride dose- dependently increased
the strength of esophageal peristalsis and more than doubled LESP, raising it to
normal values. The increase in LESP was partially reversed by atropine,
suggesting that the effect is partly, but not exclusively, cholinergically-
mediated. Twenty mg oral cisapride given once to healthy volunteers similarly
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 mg 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 IV or oral or 10 mg given orally 3 times
daily up to six weeks) significantly accelerated gastric emptying of both
liquids and solids. Acceleration of gastric emptying, measured over a four 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
Clinical trials have shown that cisapride can reduce the 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 was superior to placebo.
These clinical trials did not show a significant effect on LESP, perhaps because
the majority of these patients had normal LESP's at the beginning and end of the
study period. 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.
INDICATIONS AND USAGE:
PROPULSID(R) (cisapride) is indicated for the symptomatic treatment of patients
with nocturnal heartburn due to gastroesophageal reflux disease.
CONTRAINDICATIONS:
Concomitant administration of NIZORAL(R) (ketoconazole) tablets, SPORANOX(R)
(itraconazole) capsules, MONISTAT i.v.(TM) (miconazole), fluconazole,
erythromycin, clarithromycin, or TAO(R) (troleandomycin) capsules with
PROPULSID(R) is contraindicated (See WARNINGS and PRECAUTIONS: Drug
Interactions).
PROPULSID(R) (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.
PROPULSID(R) is contraindicated in patients with known sensitivity or
intolerance to the drug.
WARNINGS:
WARNING
Serious cardiac arrhythmias including
ventricular tachycardia, ventricular
fibrillation, torsades de pointes, and QT
prolongation have been reported in patients
taking PROPULSID(R) with other drugs that
inhibit cytochrome P450 3A4, such as
ketoconazole, itraconazole, miconazole,
troleandomycin, erythromycin, fluconazole,
and clarithromycin. Some of these events
have been fatal. PROPULSID(R) is
contraindicated in patients taking any of
these drugs. (See CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS, and DRUG
INTERACTIONS).
PROPULSID(R) undergoes metabolism mainly by the hepatic cytochrome P450 3A4
isoenzyme. Drugs which inhibit this enzyme such as ketoconazole, itraconazole,
miconazole, clarithromycin, erythromycin, fluconazole, or troleandomycin can
lead to elevated cisapride blood levels.
Rare cases of serious cardiac arrhythmias, including ventricular arrhythmias and
torsades de pointes associated with QT prolongation, have been reported in
patients taking cisapride with ketoconazole, itraconazole, miconazole,
erythromycin, clarithromycin, or fluconazole. Some of these patients did not
have known cardiac histories+ADs- 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.
PRECAUTIONS:
GENERAL
Potential benefits should be weighed against risks prior to administration of
cisapride to patients with conditions associated with QT prolongation, such as
congenital prolonged QT syndrome, uncorrected electrolyte disturbances or in
patients who are taking other medications known to prolong QT interval.
INFORMATION FOR PATIENTS
Patients should be warned against concomitant use of oral ketoconazole,
itraconazole, miconazole, erythromycin, clarithromycin, fluconazole, or
troleandomycin with PROPULSID(R).
Although PROPULSID(R) (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 accelerated
by PROPULSID(R).
DRUG INTERACTIONS
Cisapride is metabolized mainly via the cytochrome P450 3A4 enzyme.
Human pharmacokinetic data indicate that oral ketoconazole potently 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 PROPULSID(R) and ketoconazole can result in prolongation of
the QT interval on the ECG.
In vitro data indicate that itraconazole, miconazole, fluconazole, erythromycin,
clarithromycin, and troleandomycin also markedly inhibit cytochrome P450 3A4
mainly responsible for the metabolism of cisapride.
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. Normalization of the QT interval after
cisapride was discontinued has been observed.
Concurrent administration of anticholinergic compounds would be expected to
compromise the beneficial effects of PROPULSID(R).
The acceleration of gastric emptying by PROPULSID(R) 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+ADs- if plasma
levels are being monitored, they should be reassessed.
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 PROPULSID(R) therapy, with an
appropriate adjustment of the anticoagulant dose, if necessary.
Cimetidine coadministration leads to an increased peak plasma concentration and
AUC of PROPULSID(R)+ADs- there is no effect on PROPULSID(R) absorption when it is
coadministered with ranitidine. The gastrointestinal absorption of cimetidine
and ranitidine is accelerated when they are coadministered with PROPULSID(R).
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: In a twenty-five 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 M(squared) 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/M(squared)) on a body surface area basis. In a nineteen 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/M(squared) 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/M(squared) 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
justifies the potential risk to the fetus.
NURSING MOTHERS: Cisapride is excreted in human milk at concentrations
approximately one twentieth of those observed in plasma. Caution should be
exercised when PROPULSID(R)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 PROULSID(R)'s metabolism in the infant. (See CONTRAINDICATIONS,
WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS).
PEDIATRIC USE: Safety and effectiveness in children have not been established.
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 adverse experiences in patients greater than 65 years of age was
similar to that in younger adults.
DRUG INTERACTIONS:
Cisapride is metabolized mainly via the cytochrome P450 3A4 enzyme.
Human pharmacokinetic data indicate that oral ketoconazole potently 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 suggest that
coadministration of PROPULSID(R) and ketoconazole can result in prolongation of
the QT interval on the ECG.
In vitro data suggest that itraconazole, miconazole, fluconazole, erythromycin,
clarithromycin, and troleandomycin also markedly inhibit cythochrome P450 3A4
mainly responsible for the metabolism of cisapride.
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. Normalization of the QT interval after
cisapride was discontinued has been observed.
Concurrent administration of anticholinergic compounds would be expected to
compromise the beneficial effects of PROPULSID(R).
The acceleration of gastric emptying by PROPULSID(R) 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+ADs- if plasma
levels are being monitored, they should be reassessed.
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 PROPULSID(R) therapy, with an
appropriate adjustment of the anticoagulant dose, if necessary.
Cimetidine coadministration leads to an increased peak plasma concentration and
AUC of PROPULSID(R)+ADs- there is no effect on PROPULSID(R) absorption when it is
coadministered with ranitidine. The gastrointestinal absorption of cimetidine
and ranitidine is accelerated when they are coadministered with PROPULSID(R).
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
In the U.S. clinical trial population of 1728 patients (comprising 506 with
gastroesophageal reflux disorders, and the remainder with other motility
disorders) the following adverse experiences were reported in more than 1+ACU- of
patients treated with PROPULSID(R) (cisapride) and at least as often on
PROPULSID(R) as on placebo. The percent of patients who discontinued treatment
is displayed in parentheses.
SYSTEM/ADVERSE EVENT PROPULSID(R) PLACEBO
N+AD0-1042 N+AD0-686
Central +ACY- Peripheral
Nervous Systems
Headache 19.3+ACU- (1.1+ACU-) 17.1+ACU- (0.4+ACU-)
Gastrointestinal
Diarrhea 14.2 (0.7) 10.3 (0.1)
Abdominal pain 10.2 (1.2) 7.7 (0.9)
Nausea 7.6 (1.0) 7.6 (0.3)
Constipation 6.7 (0.1) 3.4 (0.0)
Flatulence 3.5 (0.4) 3.1 (0.4)
Dyspepsia 2.7 (0.1) 1.0 (0.0)
Respiratory System
Rhinitis 7.3 (0.1) 5.7 (0.1)
Sinusitis 3.6 (0.0) 3.5 (0.0)
Coughing 1.5 (0.2) 1.2 (0.0)
Resistance Mechanism
Viral infection 3.6 (0.2) 3.2 (0.0)
Upper respiratory
tract infection 3.1 (0.0) 2.8 (0.0)
Body As A Whole
Pain 3.4 (0.0) 2.3 (0.0)
Fever 2.2 (0.1) 1.5 (0.0)
Urinary System
Urinary tract infection 2.4 (0.0) 1.9 (0.0)
Micturition frequency 1.2 (0.1) 0.6 (0.0)
Psychiatric
Insomnia 1.9 (0.3) 1.3 (0.4)
Anxiety 1.4 (0.1) 1.0 (0.1)
Nervousness 1.4 (0.2) 0.7 (0.0)
Skin +ACY- Appendages
Rash 1.6 (0.0) 1.6 (0.3)
Pruritus 1.2 (0.1) 1.0 (0.0)
Musculoskeletal System
Arthralgia 1.4 (0.1) 1.2 (0.0)
Vision
Abnormal vision 1.4 (0.2) 0.3 (0.0)
Reproductive, Female
Vaginitis 1.2 (0.0) 0.9 (0.0)
The following adverse events also reported in more than 1+ACU- of PROPULSID(R)
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 PROPULSID(R) than in patients using
10 mg.
Additional adverse experiences reported to occur in 1+ACU- 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 foreign marketing experience,
there have been rare reports of seizures and extrapyramidal effects,
tachycardia, elevated liver enzymes, hepatitis, thrombocytopenia, leukopenia,
aplastic anemia, pancytopenia, and granulocytopenia. The relationship of
PROPULSID(R) to the event was not clear in these cases.
There have been rare cases of sinus tachycardia reported. Rechallenge
precipitated relapse in some of those patients.
Rare cases of cardiac arrhythmias, including ventricular tachycardia,
ventricular fibrillation, torsades de pointes and QT prolongation, in some cases
resulting in death, have been reported. Most of these patients had been
receiving multiple other medications and had pre-existing cardiac disease or
risk factors for arrhythmias. A causal relationship to PROPULSID(R) has not been
established.
OVERDOSAGE:
Reports of overdosage with PROPULSID(R) (cisapride) include an adult who took
540 mg and for 2 hours experienced retching, borborygmi, flatulence, stool
frequency and urinary frequency. A one-month-old male infant received 2mg/kg of
cisapride, 10 times the prescribed dose, four 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.
Treatment should include gastric lavage and/or activated charcoal, close
observation and general supportive measures.
In instances of overdose, patients should be evaluated for possible QT
prolongation and for factors that can predispose to the occurrence of
ventricular arrhythmias, including torsades de pointes.
Single oral doses of cisapride at 4000 mg/kg, 160mg/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.
DOSAGE AND ADMINISTRATION:
5 mL (1 teaspoon) suspension+AD0-5 mg.
ADULTS: Initiate therapy with one 10 mg tablet of PROPULSID(R) (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.
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.