Propulsid®
(cisapride)
Tablets/Suspension
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
Warning: Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation,
torsades de points, and QT prolongation have been reported in patients taking PROPULSID® 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® is contraindicated in patients taking any of these drugs. (See
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS).
PROPULSID® (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-piperidinyl]-2- methoxybenzamide monohydrate. its emprical formula is C23H29CIFN3O4 · H2O. The
molecular weight is 483.97 and the structural formula is:
Cisapride as the monohydrate is a white to slightly beige ordorless 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 one mg of cisapride.
PROPULSID® 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 1 mg/mL of cisapride. The
inactive ingredients in the tablets are collodial silicon dioxide, lactose monohydrate, magnesium
sterate, microcrystalline cellulose, polysorbate 20, providone, and starch (com). The 20 mg
tablets also contain FD&C; Blue No.2 aluminum lake. The inactive ingredients in the
suspension are hydroxpropyl methylcellulose, methylparaben, microcrystalline cellulose and
carboxymethylcellulose sodium, polysorbate 20, propylparaben, sodium chloride, sorbitol, and
water. The 1 mg suspension also contains artificial cherry cream flavor and FD&C; Red No. 40.
Pharmacoinetics
PROPULSID®: is rapidly absorbed after oral administration: peak plasma concentrations are
reached to 1 to 1.5 hours after dosing. The absolute bioavailability of PROPULSID® is 35-40%.
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 lesser degree the extent,
of PROPULSID® tablet absorption.(This has not been established for the suspension)
PROPULSID® binds to an extent of 97.5 – 98% to plasma proteins, mainly to albumin. The
volume of distribution of PROPULSID® is about 180 L, indicating extensive tissue distribution.
The plasma clearance of PROPULSID® is about 100 mL/min. The mean terminal half-life
reported for PROPULSID® ranges from 6 to 12 hours; 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® is extensively metabolized; unchanged drug
accounts for less than 10% 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) were in the same order
as after single dosing. There is some evidence that the degree of accumulation of PROPULSID®
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.
Pharmacodyamics
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-HT) 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 LESP of <10 mm Hg, cisapride
dose-dependenly increased the strength of esophageal peristalsis and more than doubled LESP,
raising it to normal values. The increase in LESP was partially reversed by atopine, 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 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) significant 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 Trials
Clinical trials have shown that cisapride can reduce the symptoms of noctumal heartburn
associated with gastroesophageal reflux disease. Two placebocontrolled 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 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.
PROPULSID®: (cisapride) is indicated for the symptomatic treatment of patients with noctumal
heartburn due to gastroesophageal reflux disease.
Concomitant administration of NIZORAL® (ketoconazole) tablets, SPORANOX® (itraconazole)
capsules, MONISTAT® i.vtm (miconazole), fluconazole, erythromycin, clarithromycin, or TAO®
(troleandomycin) capsules with PROPULSID® is contraindicated (See WARNINGS and
PRECAUTIONS:Drug interactions).
PROPLSID®:(cisapride) should not be used in patients in whom an increase in gastroinestinal
motility could be harmful, e.g in the presence of gastrointestinal hemorrhage, mechanical
obstruction, perforation. PROPULSID® is contraindicated in patients with known sensitivity or
intolerance to the drug.
PROPULSID®:undergoes metabolism mainly by the hepatic cytochrome p450 3A4 isoenzyme.
Drugs which inhibit this enzyme such as ketoconazole, itraconazole, miconazole, clairithromycin,
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; 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.
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®.
Although PROPULSID® (cisparide) does not affect psychomotor function nor does it induce sedation or drowsiness when used alone, patients should be advised that the sedative effects of benzodiazapines and of alcohol may be accelerated by PROPULSID®.
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® 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®.
The acceleration of gastric emptying by PROPULSID® 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; 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 alter the start and discontinuation
of PROPULSID® therapy, with an appropriate adjustment of the anticogulant dose, if necessary.
Cimetidine coadministration leads to an increased peak plasma concentration and AUC of
PROPULSID®; there is no effect of PROPULSID® absorption when it is coadministered with
ranitidine. The gastrointestinal absorption of cimetidine and ranitidine is accelerated when they
are coadministered with PROPULSID®.
Carcinogenesis, mutagenesis, impairment of fertility: in a twenty-five month oral carcinogencity
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 nineteen month oral
carcinogencity 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, 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
day and higher prolonged the breeding maximum recommended human dose on a mg/m2basis).
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 (F), of the female rats (F) 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 (F).
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/ basis and 14 times the maximum recommended human
dose of a mg/m2 basis) and 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 concentration approximately one
twentieth of those observed in plasma. Caution should be exercised when PROPULSID® 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 PROPULSID® metabolism. (see CONTRAINDICTATION,
WARNING, PRECAUTIONS: 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.
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% of patients treated with PROPULSID® (cisapride) and at least as
often on PROPULSID® as on placebo. The percent of patients who discontinued treatment is
displayed in parenthesis.
The following adverse events also reported in more than 1% of PROPULSID® patients were more
frequently reported on placebo: dizziness, vomiting, pharyngitis, chest pain, fatique, back pain
depression, dehydration, and myalgia.
Diarrhea, abdominal pain, constipation, flatulence and rhinitis all occurred more frequently in
patients using 20 mg of PROPULSID® than in patients using 10 mg.
Additional adverse experiences reported to occur in 1% 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 extapyamidal effects, tachycardia, elevated liver enzymes, hepatitis,
thrombocytopenia, leukopenia, aplastic anemia, pancytopenia, and granulocytopenia. The
relationship PROPULSID® to the event was not clear in these cases.
There have been rare cases of sinus tachycardia reported. Rechallenge precipitated relapse in
some for those patients.
Rare cases of cardiac arrhythmias, including ventricular arrhythmias, torsades de points, 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 causual relationship to PROPULSID® has not been established.
Reports of overdosage with PROPULSID® (cisapride) include an adult who took 540 mg and 2
hours experienced retching, borborygmi, flatulence, stool frequency and urinary frequency.
A one-month-old male infant received 2 mg/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 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, 160 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.
5 mL (1 teaspoon) suspension = 5 mg.
Adults: Initiate therapy with one 10 mg tablet of PROPULSID® or 10 mL of the suspension 4 times
daily at least 15 minutes before meals and at bed time. 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.
PROPULSID® tablets are provided as scored white tablets debossed “Janssen” and P/10
containing the equivalent of 10 mg of cisapride in blister packages 100 (NDC 50458-430-01) and
in bottles of 100 (NDC 50458-43-10) and 500 (NDC 50458-440-10).
PROPULSID® Suspension is provided as a bright pink homogeneous suspension containing 1mL
of cisapride in 16 oz. bottles containing 450 mL (NDC 50458-50-45)
Store at room temperature (59 -86 degrees F/15 -30 degrees C). Protect the tablets from moisture. The 20 mg tablets should also be
protected from light.
Revised January 1995, September 1995
U.S. Patent No. 4,962,115
Printed in U.S.A.
© Janssen Pharmaceutica, Inc. 1995
7502607