E-drug: Update on Cisapride
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In the U.K.
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Cisapride will be withdrawn from marketing in the UK
from 28th July 2000, until further notice. Cisapride
can prolong the QT interval, which may lead to life
threatening ventricular arrhythmias. This risk can be
increased by certain underlying medical conditions and
concomitant use of medicines that prolong the QT
interval, inhibit the metabolism of cisapride or
produce electrolyte imbalance. Despite previous
action by the CSM, cisapride continues to be
co-prescribed with contraindicated medication and
serious cardiovascular reactions, including fatalities
continue to be reported. Therefore the CSM has
advised that the risks of cisapride outweigh the
benefits. The CSM has advised that all treatment with
cisapride should be stopped and patients changed to
alternative treatment as necessary. Unlicensed use in
children should also be stopped. Pharmacists are
advised that prescriptions for cisapride should not be
dispensed from receipt of the MCA letter and patients
should be referred back to their doctor. All stocks
of products containing cisapride are to be quarantined
and returned to supplier.
In France
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In France, Prepulsid� has been the subject of
attentive monitoring for several years because of the
many drug interactions and cardiac adverse effects.
This monitoring led to several modifications of
information with sending of a letter to health
professionals in 1995, 1996 and 1997. The cardiac
adverse effects reported with Prepulsid� are
rate/rhythm disorders, can be serious but of rare
frequency and generally occur in the presence of risk
factors such as association with drugs that induce
long QT or drugs that inhibit the metabolism of
cisapride, overdoses, bradycardia, electrolytic
disorders... The Food and Drug Administration
announced on 23 March that the Janssen laboratory
would withdraw Prepulsid� from the United States
market, as of July 14 2000. However, the laboratory
will continue to dispense Prepulsid� for patients who
present clinical criteria defined within the framework
of a protocol.
Within the European Union, the reevaluation of the
benefit-risk of Prepulsid� is under way and must lead
in a few months to a common decision, with either
limited regulation or a withdrawal of the product.
In the interim, the reevaluation of all the safety and
effectiveness data led Afssaps to register Prepulsid�
on list I of poisonous substances and to restrict the
therapeutic indications :
In adults, because of limited effectiveness, risk of
cardiac adverse effects and existence of therapeutic
alternatives, the benefit-risk ratio was regarded as
negative in the treatment of gastro-esophageal reflux
and esophagitis. The indication for Prepulsid� in the
adult was thus restricted to treatment of symptomatic
gastroparesy proven objectively (preferably by
isotopic
measurement of gastric draining) in the event of
failure of other drug treatment.
In new-borns, infants and children up to 36 months, in
the absence of satisfactory therapeutic alternatives,
the benefit-risk ratio was regarded as positive in the
treatment of complicated gastro-esophageal reflux -
respiratory pathology or ORL, - ulcerated esophagitis
or - growth disorders, in the event of resistance to
the usual treatment (thickening of the food-drug
treatment). Moreover, the headings
Contra-indications, Warnings and Precautions for use,
Drug Interactions and Adverse effects were modified.
A newsletter accompanied by the new legal cites will
be addressed by Janssen to doctors and pharmacists.
In Germany
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The Federal Institute for Medicines and Medical
Products (BfArM) ordered the immediate suspension of
permission for Cisapride for one year. At the same
time the BfArM asked the medicine speciality committee
of the European Medicines agency in London to make a
global evaluation of cisapride-containing medications
and to submit in addition a justified appraisal as
basis for a European commission decision.
The crucial reason for this measure is the justified
suspicion that cisapride caused or endangered patients
with heartbeat disturbances. These rarely occur
according to current knowledge, however can be
life-threatening. There are only estimates of the
actual frequency of this side effect in patients with
and without endangering factors. Both in Germany and
in other countries such serious heartbeat disturbances
occurred and were in some cases deadly. Based on the
present level of knowledge it is assumed that the risk
of such heartbeat disturbances is increased
particularly for patients with certain heart
illnesses. Such heartbeat disturbances also occur in
some cases without additional risk factors being
present.
From Germany since the first permission in 1990
altogether 30 cases of suspicion of cardiac side
effects were announced up to now. In 13 cases
it was ventricular heartbeat disturbances, which were
deadly in four cases; in four other cases
life-threatening heartbeat disturbances of the type
Torsade de pointes occurred, however without death;
and in one case a sudden cardiac death occurred. The
causal connection of these side effects with the use
of cisapride is distinctly convincing.
Results from electrophysiological investigations of
the effects of cisapride on heart muscle cells support
the suspicion that cisapride could be causally
responsible for the serious heartbeat disturbances in
humans.
With the decision over suspending the permission,
cisapride-containing medications are not available any
longer for treatment, and patients are no longer
exposed to the described risk. The pharmaceutical
entrepreneur, Janssen Cilag GmbH, has the possibility
of executing meaningful investigations of the
effectiveness and safety of cisapride and of
submitting current data on the frequency of heartbeat
disturbances that can be attributed to cisapride.