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Cisapride


Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Synonyms: Cisaprid; Cisaprida; Cisapridas; Cisapridum; Ciszaprid; R-51619; Sisapridi
BAN: Cisapride
USAN: Cisapride
INN: Cisapride [rINN (en)]
INN: Cisaprida [rINN (es)]
INN: Cisapride [rINN (fr)]
INN: Cisapridum [rINN (la)]
INN: Цизаприд [rINN (ru)]
Chemical name: cis-4-Amino-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidyl}-2-methoxybenzamide monohydrate
Molecular formula: C23H29ClFN3O4,H2O =484.0
CAS: 81098-60-4 (anhydrous cisapride)
ATC code: A03FA02
Read code: y028d

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Cisapnde Monohydrate Cisapride BP 2008). A white or almost white powder it exhibits polymorphism. Practically insoluble in water soluble in dichloromethane freely soluble in dimethylformamide sparingly soluble in methyl alcohol. Protect from light.

Cisapride Tartrate

Drug Approvals

(British Approved Name Modified, rINNM)

Synonyms: Cisaprid-tartarát; Cisaprida, tartrato de; Cisapridi Tartras; Cisaprido tartratas; Cisapridtartrat; Ciszaprid-tartarát; Sisapriditartraatti
BAN: Cisapride Tartrate [BANM]
INN: Cisapride Tartrate [rINNM (en)]
INN: Tartrato de cisaprida [rINNM (es)]
INN: Cisapride, Tartrate de [rINNM (fr)]
INN: Cisapridi Tartras [rINNM (la)]
INN: Цизаприда Тартрат [rINNM (ru)]
Molecular formula: C27H35ClFN3O10 =616.0

Pharmacopoeias. In Europe

European Pharmacopoeia, 6th ed. (Cisapride Tartrate). A white or almost white powder. It exhibits polymorphism. Slightly soluble in water and in methyl alcohol very slightly soluble in alcohol freely soluble in dimethylformamide. Protect from light.

Adverse Effects

The most commonly reported adverse effects with cisapride are gastrointestinal disturbances including abdominal cramps, borborygmi, and diarrhoea. Headache and lightheadedness may also occur. Hypersensitivity (including rash, pruritus, and bronchospasm), convulsions, extrapyramidal effects, and increased urinary frequency, have occasionally been reported. Cases of arrhythmia, including ventricular tachycardia, ventricular fibrillation, torsade de pointes, and QT interval prolongation have occurred rarely fatalities have resulted, and have led to severe restrictions on its use (see Effects on the Heart, below). There have been a few cases of disturbances in liver function among patients receiving cisapride.

Incidence of adverse effects. A comparison of data from prescription-event monitoring in over 13 000 recipients of cisapride and from a further 9726 recipients involved in a controlled study showed that diarrhoea, in about 2 to 4% of patients, was the commonest adverse effect reported. Other relatively common adverse effects were headache, abdominal pain, nausea and vomiting, and constipation, all in around 1 to 1.5% of patients. There were 46 reports in the prescription-event monitoring data of increased urinary frequency (plus a further 20 among the controlled study patients), and 5 reports of arrhythmias.

Effects on the heart. Seven reports of cardiac effects associated with cisapride were submitted to the WHO Programme for International Drug Monitoring between 1989 and 1991. They included palpitations in 4, tachycardia and hypertension in 1, and extrasystole in 2. Subsequent reports implicated cisapride in the development of prolonged QT interval and torsade de pointes or ventricular fibrillation or both. By December 1999 the FDA had received 341 reports of heart rhythm abnormalities associated with cisapride use, including 80 reports of deaths. Most patients were either receiving other drugs known to impair cisapride metabolism (see Interactions, below) or had other factors predisposing to arrhythmias. In the light of earlier reports of cardiac effects and of evidence for a direct effect of cisapride on the heart at therapeutic concentrations, in 1998 the UK CSM contra-indicated the use of cisapride in patients receiving drugs that could inhibit cisapride metabolism or that prolong the QT interval, as well as in patients with a history of QT interval prolongation, ventricular arrhythmia, or torsade de pointes, or other risk factors for arrhythmia (see Precautions, below). Neonates (especially of low gestational age) are vulnerable to cisapride-induced QT interval prolongation, and the CSM also specifically contra-indicated use in premature neonates and noted that there were insufficient data to support use in children up to the age of 12. Other studies have also noted a prolongation of QT interval in children. However, some commentators have questioned the general contra-indication in prematurity, and one retrospective analysis estimated the rate of serious adverse events such as arrhythmia in premature newborns to be less than 1 in 11 000, excluding those cases related to concurrent treatment with a contra-indicated drug or to overdose. Conversely, others emphasise the lack of objective evidence of benefit for cisapride in most paediatric indications. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition has published recommendations on the use of cisapride in paediatric gastro-oesophageal reflux disease, including that the total daily dose of cisapride should rarely exceed 800 micrograms/kg, and that ECG monitoring should be performed before and after 3 days of treatment in certain groups such as premature infants.

The use of cisapride has also been the subject of warnings and restrictions in other countries. In the USA, prescribing information was amended in January 2000 to recommend that all patients should receive an ECG before beginning cisapride therapy and extending the contra-indications to use the drug was subsequently withdrawn from general supply, remaining available only in severely restricted cases. In July 2000 cisapride was also withdrawn completely from the UK market. In Europe, the European Commission decided that cisapride-containing products could be maintained with restricted indications all patients given cisapride should be enrolled in either a study or registry of clinical safety, or a study of clinical effectiveness. Despite a withdrawal of cisapride from general supply, a retrospective cohort study in South Korea found that it was still in use there up to 2 years later in many instances cisapride had been given with contra-indicated drugs, which was associated with an increase in the risk of all-cause mortality.

Effects on the respiratory system. Chest tightness, wheezing, and a fall in peak flow rate occurred in a patient with severe brittle asthma after taking cisapride 10 mg. Four other cases of bronchospasm associated with cisapride were discussed in a subsequent report in 2 of these cases symptoms resolved on withdrawal and recurred on rechallenge.

Effects on the urinary tract. There had been 12 cases of urinary disturbances associated with use of cisapride reported to the Australian Adverse Drug Reactions Advisory Committee between March 1991 and July 1993. Five reports were of urinary incontinence, 8 involved frequency, and individual reports involved cystitis, hesitancy, and urinary retention. The majority of the cases involved women, and most patients were elderly.

Precautions

Cisapride should not be used when stimulation of muscular contractions might adversely affect gastrointestinal conditions as in gastrointestinal haemorrhage, obstruction, perforation, or immediately after surgery. Cisapride is contra-indicated in the following patients:

• those receiving potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 such as macrolide antibacterials, azole antifungals, HIV-protease inhibitors, or nefazodone (see also Interactions, below)

• those taking other drugs that predispose to electrolyte disturbances or that prolong the QT interval

• those with a personal or family history of QT interval prolongation

• those with a history of ventricular arrhythmia or torsade de pointes

Furthermore, it should not be given to those with other risk factors for arrhythmia including:

• clinically significant heart disease

• uncorrected electrolyte disturbances (particularly hypokalae-mia and hypomagnesaemia)

• renal failure

• respiratory failure

Use is also contra-indicated in premature infants for up to 3 months after birth.

Cisapride should be used with caution and in reduced doses in patients with hepatic or renal impairment. All patients should have their ECG, serum electrolytes, and renal function monitored before and during treatment.

Care should be taken not to exceed the recommended dose.

Breast feeding. No adverse effects have been observed in breast-fed infants whose mothers were receiving cisapride, and the American Academy of Pediatrics considers that it is therefore usually compatible with breast feeding.

Interactions

Cisapride is metabolised by the cytochrome P450 isoenzyme C YP3A4. Use with drugs that significantly inhibit this enzyme is contra-indicated as it may result in increased plasma concentrations of cisapride and hence a greater risk of QT interval prolongation and ventricular arrhythmias. Examples of such drugs include the azole antifungals ketoconazole, fluconazole, itraconazole, and miconazole the macrolide antibacterials troleandomycin, azithromycin, erythromycin, and clarithromycin the NNRTIs delavirdine and efavirenz and the HIV-protease inhibitors. Nefazodone may interact similarly. Cisapride should not be used in patients receiving other medication known to prolong the QT interval, including quinine or halofantrine, terfenadine, astemizole, certain antiarrhythmics such as amiodarone or quinidine, some antidepressants such as amitriptyline, phenothiazine antipsychotics, and sertindole. Cimetidine may enhance cisapride bioavailability. Grapefruit juice also increases the bioavailability of cisapride and they should not be taken together. In addition, drugs such as potassium-sparing diuretics, or insulin in acute settings, can result in altered electrolyte balance, and use with cisapride may also increase the risk of arrhythmias.

Antimuscarinics and possibly opioid analgesics may antagonise the gastrointestinal effects of cisapride. Because cisapride increases intestinal motility it may affect the absorption of other drugs, either diminishing absorption from the stomach or enhancing absorption from the small intestine. Prothrombin times may be increased in some patients receiving oral anticoagulants, and the effects of alcohol and some other CNS depressants may be enhanced.

Cardiovascular drugs. Near syncope and a prolonged QT interval occurred in a patient taking cisapride and diltiazem Diltiazem may have inhibited the metabolism of cisapride. For mention of cisapride possibly reducing the absorption of digoxin.

H2-antagonists. Cimetidine but not ranitidine has been reported to enhance the bioavailability of oral cisapride, possibly by inhibition of cisapride metabolism (cimetidine is an inhibitor of the cytochrome P450 isoenzyme CYP3A4). Cisapride conversely increases the rate of absorption and decreases the oral bioavailability of both cimetidine and ranitidine.

Pharmacokinetics

Cisapride is readily absorbed from the gastrointestinal tract, with peak plasma concentrations achieved 1 to 2 hours after an oral dose. It undergoes extensive first-pass metabolism in the liver and gut wall, resulting in an absolute bioavailability of 35 to 40%. The main metabolic pathways are oxidative N-dealkylation by the cytochrome P450 isoenzyme CYP3A4, producing the major metabolite norcisapride, and aromatic hydroxylation. More than 90% of a dose is excreted as metabolites in the urine and faeces in about equal amounts. A small amount is distributed into breast milk. The elimination half-life is about 10 hours. Cisapride is about 98% bound to plasma proteins.

Uses and Administration

Cisapride is a substituted benzamide used for its prokinetic properties. It stimulates gastrointestinal motility, probably by increasing the release of acetylcholine in the gut wall at the level of the myenteric plexus, increases the resting tone of the lower oesophageal sphincter, and increases the amplitude of lower oesophageal contractions. Gastric emptying is accelerated and the mouth-to-caecum transit time is reduced. Colonic peristalsis is also increased which decreases colonic transit time. Cisapride apparently lacks antidopaminergic effects (unlike metoclopramide, p. 1747, to which it is chemically related) or direct parasympathomimetic activity and it does not affect prolactin release or gastric secretion. It is reported to be an agonist at serotonin-4 (5-HT4) receptors.

Cisapride has been used mainly in the treatment of gastro-oesophageal reflux disease, in disorders associated with decreased gastric motility, and in non-ulcer dyspepsia. However, as mentioned under Effects on the Heart, above, its use is severely restricted by its propensity to cause cardiac arrhythmias, and it has been withdrawn completely in many countries, including the UK.

Cisapride is given as the monohydrate, but doses are calculated in terms of the anhydrous substance. Cisapride monohydrate 10.39 mg is equivalent to about lOmg of anhydrous cisapride. It is taken orally 15 to 30 minutes before a meal and at bedtime, if necessary. Where still licensed, a usual oral dose is 5 to 10 mg three to four times daily up to a maximum daily dose of 40 mg. For discussion of dosage and use in children, see below. Doses of cisapride should be reduced in patients with hepatic or renal impairment (see below).

Administration in children. Where still licensed, neonates, infants, and children have been given cisapride 200 micrograms/kg orally three or four times daily up to a maximum daily dose of 800 micrograms/kg. However, there are particular safety concerns over the use of cisapride in children because of the risk of cardiac arrhythmias (see Effects on the Heart, above). Special care is needed in neonates and cisapride is contra-indicated in premature neonates for 3 months after birth due to the increased risk of QT interval prolongation in this patient group.

Its efficacy has also been questioned and a systematic review of the use of cisapride in children found no clear evidence that cisapride had a statistically significant effect in reducing symptoms of gastro-oesophageal reflux disease compared with placebo.

Administration in hepatic or renal impairment. In patients with hepatic impairment the dose of cisapride should be half the usual dose, followed by adjustment depending on clinical response. In cases where renal impairment is not considered to contra-indie ate the use of cisapride, a similar reduction in dose has been recommended.

Preparations

Proprietary Preparations

Argentina: Cisap Cispride Digenormotil Etacril Fabrapride Kinetizine-H Prepulsid-H Pulsar Regalisa

Australia: Prepulsid

Austria: Prepulsid

Belgium: Prepulsid

Brazil: Prepulsid

Czech Republic: Prepulsid

Denmark: Prepulsid

Finland: Prepulsid

France: Prepulsid

Hong Kong: Prepulsid

Hungary: Coordinax

India: Alipride Cisalone Gastro

Indonesia: Acpulsi Disflux Ethiprid Guarposid Priclesia Stimulit

Ireland: Prepulsid

Israel: Prepulsid

Mexico: Aposada Cepriser Enteropride Eriken Expril Kinestase Maprilex Mavisid Nodrix Prepulsid Presistin Profercol Sapriken Unamol

The Netherlands: Prepulsid

Norway: Prepulsid

New Zealand: Prepulsid

Poland: Gasprid Gastronax

Portugal: Prepulsid

South Africa: Prepulsid

Spain: Arcasin Fisiogastrol Kelosal Prepulsid

Sweden: Prepulsid

Switzerland: Prepulsid

Thailand: Cipasid Cipride Cisapin Cisaride Esorid Metison Palcid Prepulsid Pri-De-Sid

Venezuela: Adamin Cisamod Isaprid Motilar

Multi-ingredient

Argentina: Digenormotil Plus Gastrimet Enzimatico Gastrimet Pulsar Enzimatico Pulsar Plus

India: Gastro MPS

Mexico: Ergex

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