Prepulsid (Cisapride)

PREPULSID®

Janssen-Ortho

Cisapride Monohydrate

Gastrointestinal Prokinetic Agent

Action And Clinical Pharmacology: Cisapride is a gastrokinetic drug whose activity is considered to be due to enhancement of the physiological release of acetylcholine at the myenteric plexus.

Cisapride increases esophageal peristaltic activity and lower esophageal sphincter tone, thereby decreasing reflux of gastric contents into the esophagus and improving esophageal clearance. Gastric and duodenal emptying are also enhanced by cisapride as a consequence of increased gastric and duodenal contractility and antroduodenal coordination. Cisapride decreases duodenogastric reflux. It also enhances intestinal propulsive activity and improves both small and large bowel transit.

Cisapride lacks cholinomimetic effects and, therefore, does not increase basal or pentagastrin-induced gastric acid secretion. In vitro studies with animal tissues have shown that cisapride is a serotonin (5-HT4) receptor agonist.

Pharmacokinetics: Following oral administration in man, cisapride is rapidly and completely absorbed. Peak plasma levels are attained within 1 or 2 hours. Plasma levels proportionally increase with oral doses from 5 to 20 mg. At steady-state, morning predose plasma levels and evening peak levels fluctuate between 10 to 20 ng/mL and 30 to 60 ng/mL respectively for 5 mg cisapride t.i.d., and between 20 to 40 ng/mL and 50 to 100 ng/mL for 10 mg t.i.d. The elimination half-life is 10 hours. Pharmacokinetics and steady-state levels are unrelated to the duration of treatment.

Cisapride is metabolized mainly by the cytochrome P450 3A4 enzyme. Cisapride undergoes extensive first-pass metabolism in the liver and in the gut wall. The main metabolic pathways are oxidative N-dealkylation and aromatic hydroxylation. The excretion of cisapride occurs mainly as metabolites in approximately the same amounts in urine and in feces. The excretion in maternal milk is limited.

Cisapride is extensively bound to plasma proteins (97.5%), mainly to albumin.

Indications And Clinical Uses: The symptomatic management of gastrointestinal motility disorders including: gastroesophageal reflux disease; gastroparesis, idiopathic or associated with diabetic neuropathy; and intestinal pseudo-obstruction.

Also for the prophylaxis of gastroesophageal reflux disease.

Contra-Indications: The concomitant oral or parenteral use of the following potent cytochrome P450 3A4 inhibiting drugs may lead to elevated cisapride blood levels and is contraindicated.

Antifungals: oral or i.v. fluconazole, itraconazole, ketoconazole.

Antibiotics: oral or i.v. erythromycin, clarithromycin.

Protease Inhibitors: ritonavir, indinavir (in vitro studies suggest that saquinavir is only a weak inhibitor).

Antidepressants: nefazodone.

Cisapride is also contraindicated for patients with: history of prolonged electrocardiographic QT intervals; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; uncorrected electrolyte disorders (hypokalemia, hypomagnesemia or in patients who might experience rapid reduction of plasma potassium such as those administered potassium-wasting diuretics and/or insulin in acute settings); 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 and terfenadine.

The preceding lists of drugs are not comprehensive.

Cisapride is contraindicated in prematurely born infants (born at gestational age of less than 36 weeks), from 0 through 3 months after the delivery date.

Cisapride is contraindicated in patients with known sensitivity or intolerance to the drug.

Cisapride is contraindicated whenever gastrointestinal stimulation might be dangerous, i.e., gastrointestinal hemorrhage, mechanical obstruction or perforation. (See also Warnings and Precautions, Drug Interactions.)

Manufacturers’ Warnings In Clinical States: 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. Cisapride is contraindicated in patients taking any of these drugs. Some of these contraindicated drugs are listed in the Contraindications section. 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. 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. Some of these events have been fatal.

Cisapride is contraindicated in patients with the following risk factors for cardiac arrhythmia: uncorrected electrolyte disturbances (hypokalemia, hypomagnesemia such as seen in patients taking potassium-wasting diuretics, severe dehydration, vomiting, malnutrition, or in patients who might experience a rapid reduction of plasma potassium, such as insulin administered in acute settings), renal failure (particularly when on chronic dialysis), chronic obstructive pulmonary disease, respiratory failure, conditions associated with QT prolongation (such as congenital long QT syndrome, idiopathic QT prolongation, QT prolongation associated with diabetes mellitus, combination with medications known to prolong the QT interval), prolonged QT interval at baseline and history of significant cardiac disease (including serious ventricular arrhythmia, torsades de pointes, second or third degree AV block, congestive heart failure, ischemic heart disease and sinus node dysfunction).

Additionally, 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 but not limited to quinidine and procainamide) and Class III (such as but not limited to amiodarone and sotalol); tricyclic antidepressants (such as but not limited to amitriptyline); certain tetracyclic antidepressants (such as but not limited to maprotiline); certain antipsychotic medications (such as but not limited to certain phenothiazines); astemizole and terfenadine should also be avoided.

The preceding lists of drugs are not comprehensive.

Potential benefits should be weighed against risks prior to the administration of cisapride to patients who have, or may develop prolongation of cardiac conduction intervals, particularly QTc. In addition, patients with or suspected of having the above risk factors should be evaluated prior to the administration of cisapride. An ECG should be considered as part of this evaluation to exclude a prolonged QT interval.

(See also Contraindications and Precautions, Drug Interactions.)

Precautions: General: Before initiating therapy with cisapride, organic disease such as gastrointestinal hemorrhage, mechanical obstruction or perforation should be excluded by the physician.

Drug Interactions: The main metabolic pathway of cisapride is through cytochrome P450 3A4. In some cases where serious cardiac arrhythmias 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 QT prolongation. Therefore, the use of such drugs is contraindicated. Examples of these drugs include the following:

Antifungals: oral or i.v. fluconazole, itraconazole, ketoconazole.

Antibiotics: oral or i.v. erythromycin, clarithromycin.

Protease Inhibitors: ritonavir, indinavir (in vitro studies suggest that saquinavir is only a weak inhibitor).

Antidepressants: nefazodone.

Additionally, 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 but not limited to quinidine and procainamide) and Class III (such as but not limited to amiodarone and sotalol); tricyclic antidepressants (such as but not limited to amitriptyline); certain tetracyclic antidepressants (such as but not limited to maprotiline); certain antipsychotic medications (such as but not limited to certain phenothiazines); astemizole and terfenadine should also be avoided.

The preceding lists of drugs are not comprehensive.

(See also Contraindications, Warnings and Adverse Effects.)

Since cisapride accelerates gastric emptying, the absorption from the stomach of other concomitantly administered drugs may be diminished whereas absorption of drugs from the small bowel may be accelerated.

In the case of drugs that require careful individual titration, such as anticonvulsants, it may be useful to monitor the plasma levels of such drugs when cisapride is given concomitantly.

In patients receiving anticoagulants, the coagulation times may increase. It is advisable to check the coagulation time within the first few days after the initiation and termination of cisapride therapy, with appropriate adaptation of the anticoagulant dose, if necessary.

Although cisapride does not affect psychomotor function, nor does it induce sedation or drowsiness when used alone, the sedative effects of benzodiazepines and of alcohol may be enhanced by cisapride.

The beneficial effects of cisapride on gastrointestinal motility are largely antagonized by anticholinergic drugs.

The oral bioavailability of cisapride increases slightly when used concomitantly with cimetidine or ranitidine; this is not considered to be clinically significant.

Patients With Hepatic or Renal Insufficiency: Because of the importance of the liver and kidneys in the metabolism and excretion of cisapride, the daily dose should be halved in patients with hepatic or renal insufficiency (see Dosage).

Geriatrics: Steady-state plasma levels of cisapride are generally higher than those of younger patients, due to a moderate prolongation of the elimination half-life. Initial therapeutic doses are similar to those used in younger patients but afterwards this dose can be adjusted depending on the therapeutic effects or possible side effects.

The rate of common adverse experiences in patients greater than 65 years of age in clinical trials was similar to that in younger adults.

Pregnancy: In a large population study in humans, cisapride has shown no increase in fetal anomalies. However, the anticipated therapeutic benefits should be weighed against potential hazards before giving cisapride during pregnancy, especially during the first trimester.

Lactation: Although the excretion of cisapride in human breast milk is minimal, it is advisable to discontinue breast-feeding while taking cisapride.

Adverse Reactions: The most frequent side effects encountered are gastrointestinal in nature: diarrhea and abdominal discomfort. Most side effects are transient and rarely necessitate discontinuation of therapy.

Gastrointestinal (9.9%): diarrhea (5.1%), abdominal pain/cramps (2.1%), nausea, abdominal distention, constipation, borborygmi, flatulence, increased appetite (all
CNS (3.3%): headache (1.6%), mental disorders, sedation, fatigue, sleep disorders (all
Dermatological (0.9%): rash, pruritus (each
Cardiovascular (0.6%): orthostatic hypotension, palpitations, tachycardia, hot flushes (all
Genitourinary (0.5%): mastalgia, menstrual disorder, dose-related pollakiuria, urinary incontinence (all
Musculoskeletal (0.3%): back pain, heaviness in limbs (
Miscellaneous: vertigo/dizziness (1.2%), blurred vision (0.2%).

Postmarketing Reports: In addition, other side effects, such as edema (unspecified) and hemorrhoids have been observed during cisapride therapy. The relationship to the drug is unclear. Cases of hypersensitivity including rash, pruritus and urticaria, bronchospasm, and mild and transient headache or lightheadedness have been reported occasionally

Rare cases of cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported. Most of these patients had been receiving multiple other medications and had pre-existing cardiac disease or risk factors for arrhythmias.

Exceptional cases of reversible liver function abnormalities, with or without cholestasis, have been reported. Hyperprolactinemia which may cause gynecomastia and galactorrhea have also been reported; however, in large-scale surveillance studies the incidence.

There are isolated reports of CNS effects, i.e., convulsive seizures and extrapyramidal effects. (See also Contraindications – Warnings and Precautions, Drug Interactions.)

Symptoms And Treatment Of Overdose: Symptoms: The symptoms that occur most frequently after overdosing are abdominal cramping and increased stool frequency. Rare cases of QT prolongation and ventricular arrhythmia have been reported.

Treatment: In case of overdosage, the administration of activated charcoal and close observation of the patient are recommended. It is recommended that patients be evaluated for possible QT prolongation and for factors that can predispose to the occurrence of torsades de pointes, such as electrolyte disturbances (especially hypokalemia or hypomagnesemia) and bradycardia.

Dosage And Administration: The tablets and oral suspension should be taken with a beverage. The suspension should be shaken before use. The recommended doses should not be exceeded.

Adults: Gastroesophageal Reflux Disease: Symptomatic Management: 5 to 10 mg 3 to 4 times daily, 15 minutes before meals and at bedtime or 20 mg twice daily, before breakfast and at bedtime.

Prophylaxis: 10 mg twice daily, before breakfast and at bedtime or 20 mg once daily, at bedtime. In patients with severe disease, it may be necessary to increase the dose to a maximum of 20 mg twice daily.

Gastroparesis and Pseudo-obstruction: The usual dose is 10 mg, 3 to 4 times daily, 15 minutes before meals and at bedtime. Although improvement will usually be obtained within the first weeks of treatment, maximal effect may not be seen until the patient has completed 8 to 12 weeks of continuous therapy.

Patients with Hepatic or Renal Insufficiency: Because of the importance of the liver and kidneys in the metabolism and excretion of cisapride, the daily dose should be halved in patients with hepatic or renal insufficiency.

Geriatrics: Therapeutic doses in the elderly are similar to those used in younger adults; however, because of a moderate prolongation of the elimination half-life, the steady-state plasma levels tend to be higher. More careful titration to the lowest effective dose may be necessary.

Availability And Storage: Tablets: 5 mg: Each white, circular, biconvex, half-scored tablet, inscribed © on the scored side and JANSSEN on the other side, contains: cisapride 5 mg as cisapride monohydrate. Nonmedicinal ingredients: colloidal anhydrous silica, lactose, magnesium stearate, maize starch, microcrystalline cellulose, polysorbate 20 and polyvidone K90. Bisulfites-, gluten- and tartrazine-free. HDPE bottles of 100 and 500.

10 mg: Each white, circular, biconvex, half-scored tablet, inscribed ± on the scored side and JANSSEN on the other side, contains: cisapride 10 mg as cisapride monohydrate. Nonmedicinal ingredients: colloidal anhydrous silica, lactose, magnesium stearate, maize starch, microcrystalline cellulose, polysorbate 20 and polyvidone K90. Bisulfites-, gluten- and tartrazine-free. HDPE bottles of 500.

20 mg: Each light blue, oval, biconvex, unscored tablet, inscribed with on one side and JANSSEN on the other, contains: cisapride 20 mg as cisapride monohydrate. Nonmedicinal ingredients: colloidal anhydrous silica, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, maize starch, microcrystalline cellulose, polysorbate 20 and polyvidone K90. Bisulfites-, gluten- and tartrazine-free. HDPE bottles of 250.

Suspension: Each mL of white, cherry-cream-flavored suspension contains: cisapride 1 mg as cisapride monohydrate. Nonmedicinal ingredients: cherry-cream flavor, hypromellose 2910, methyl parahydroxybenzoate, microcrystalline cellulose and sodium carmellose, polysorbate 20, propyl parahydroxybenzoate, purified water, sodium chloride and sucrose. Sodium:

Store at room temperature (15 to 30°C). Protect from moisture and light. (Shown in Product Recognition Section)

PREPULSID® Janssen-Ortho Cisapride Monohydrate Gastrointestinal Prokinetic Agent

Connected Diseases :

Gastro-Esophageal Reflux Disease (GERD)

General Illness Information Common Name: Hiatus hernia, Gastro-esophageal reflux disease, GERD Medical Term: Gastro-esophageal reflux disease. Description: Reflux of stomach and duodenal contents into the…

Gastrointestinal Tract Disorders

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