Published: November 2000
Publications
Indication Changes for Cisapride
Prescriber Update 20: 7–11
November 2000
Medsafe Editorial Team
The indications for cisapride (Prepulsid) in New Zealand have been limited to the following:
Adults
For the treatment of:
- severe reflux oesophagitis where other treatment, including acid suppression with proton pump inhibitors, has failed; and
- gastroparesis;
where the diagnosis has been made or confirmed by a specialist physician or surgeon.
Children
Use should be restricted to children with severe gastro-oesophageal reflux, where the diagnosis has been made or confirmed by a specialist physician or surgeon.
The changes involve narrowing of the indications and placing the proviso of diagnosis by a specialist physician or surgeon on use.
The risk of rare QT-prolongation and torsade de pointes with cisapride, which is the reason for limiting the indications, can be reduced by observing the maximum recommended dose (40mg daily for adults). To further reduce the risk, cisapride is contraindicated:
- with substances which inhibit cytochrome P450 3A4;
- with other agents which prolong the QT-interval;
- in patients with predisposing factors for arrhythmia or pre-existing QT-prolongation; and
- in patients with hepatic failure.
The purpose of requiring diagnosis by a specialist is to minimise the risk to the patient by achieving careful weighing of the patient's risk of QT-prolongation with cisapride, with exclusion of patients with contraindications, and consideration of the risks and benefits of all therapies, prior to use.
Cisapride use restricted in several
countries
QT-prolongation with cisapride is rare
Diagnosis to be made by a specialist physician or surgeon
Avoid cisapride with interacting medicines or predisposing
conditions
References
Cisapride use restricted in several countries
Several countries have taken steps to restrict the use of cisapride (Prepulsid), because of the risk of QT-prolongation and death from torsade de pointes, although these events are very rare. In New Zealand, the available data, including epidemiological studies and case reports, have been reviewed by the Medicines Adverse Reactions Committee.
QT-prolongation with cisapride is rare
Two epidemiological studies have found that the risk of QT-prolongation with cisapride is very small. One study1 used the linked databases of the Canadian Province of Saskatchewan and the United Kingdom General Practice Research Database, including a total of some 36,000 cisapride users. The rate of arrhythmia with recent cisapride use was found to be 1.1 per 1000 person-years versus 0.6 per 1000 for non-recent use. A key result of this study was the observation that the relative risk of serious arrhythmias with cisapride fell from 1.6 (95% CI 0.9-2.9) to 1.0 (0.3-3.7) when adjustment was made for predisposing factors which increase the risk (see below). This result suggests that there may be little increase in risk when predisposing factors are eliminated.
A prescription event monitoring study2 conducted by the Drug Safety Research Unit in Southampton included 13,000 users of cisapride and found a rate of arrhythmias of 0.4 cases per 1000 patients.
Rate high in US with high maximum dosage and non-specific indications
The rate of reports of QT-prolongation with cisapride has been higher in
the US than in other parts of the world, and cisapride is now available
only under a special access scheme in the US. In New Zealand only one report
of (non-fatal) arrhythmias with cisapride has been received. The patient
was taking the interacting agents grapefruit juice and quinine. Usage differences
may account for the differences in the experience of the safety of cisapride
between the US and New Zealand.
- In New Zealand the maximum recommended dose is 40mg per day and in the US it is 80mg.
- In New Zealand a paediatric indication with paediatric dosage instructions is approved. Hence, there is a paediatric oral suspension with dosing pipette available. In the US there is no paediatric indication or paediatric-specific preparation.
- The adult indication in the US permits use for a broad range of conditions, but even prior to the current change the approved indication in New Zealand was quite specific.
- Cisapride is funded only on a specialist endorsement in New Zealand.
Diagnosis to be made by a specialist physician or surgeon
On the basis of these data, the indications for cisapride have been narrowed in New Zealand on the advice of the Medicines Adverse Reactions Committee, and with the agreement of the New Zealand Society of Gastroenterology. The new indications are as follows:
Adults
For the treatment of:
- severe reflux oesophagitis where other treatment, including acid suppression with proton pump inhibitors, has failed; and
- gastroparesis;
where the diagnosis has been made or confirmed by a specialist physician or surgeon.
Children
Use should be restricted to children with severe gastro-oesophageal reflux, where the diagnosis has been made or confirmed by a specialist physician or surgeon.
With the changes, the indications have been narrowed and the proviso of diagnosis of the condition by a specialist physician or surgeon has been placed on use. Note, in particular, that cisapride is no longer approved for the treatment of constipation, and mention of this indication has been deleted from the Dosage and Administration section of the data sheet.3
The proviso of diagnosis by a specialist physician or surgeon is to ensure that the initial prescription is preceded by careful weighing of the patient's risk of developing clinically significant QT-prolongation with cisapride against the expected benefits of this and alternative therapy, and exclusion of patients with contraindications (see below).
Avoid cisapride with interacting medicines or predisposing conditions
In addition to observing the maximum daily dose and using lower doses if these are effective, the risk of QT-prolongation is reduced if cisapride is contraindicated in the following circumstances:4
- With use of agents inhibiting metabolism by cytochrome P450 3A4: macrolide antibiotics (erythromycin, clarithromycin, etc), azole antifungals (ketoconazole, itraconazole, fluconazole, etc), protease inhibitors (ritonavir, indinavir, etc), nefazodone and grapefruit juice.
- With use of agents which may prolong the QT-interval: quinine, terfenadine, some antiarrhythmic medicines (e.g. amiodarone, quinidine, flecainide, sotalol), tricyclic antidepressants (e.g. amitriptyline, etc) and some antipsychotic agents (phenothiazines, haloperidol, risperidone).
- In patients with a history of QT-prolongation, ventricular arrhythmia, torsade de pointes, and those with risk factors for arrhythmia, such as second or third degree atrioventricular block, clinically significant heart disease, uncorrected electrolyte disturbances and renal or respiratory failure.
- In patients with hepatic failure.
Cardiac arrhythmias with cisapride are an adverse reaction of current concern. Please report all cases to the Centre for Adverse Reactions Monitoring, P O Box 913, Dunedin.
References
- Walker AM, Szneke P, Weatherby LB, et al. The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada. Am J Med 1999;107:356-62.
- Wager E, Tooley PJH, Pearce GL, et al. A comparison of two cohort studies evaluating the safety of cisapride: prescription-event monitoring and a large phase IV study. Eur J Clin Pharmacol 1997;52:87-94.
- Prepulsid data sheet.
- Medsafe Editorial Team. Cisapride and arrhythmias. Prescriber Update No.19, Feb 2000, p.22-3.
