CISAPRIDE

Fetal Risk Summary

Cisapride, an oral gastrointestinal prokinetic agent, was withdrawn from the market in the United States in July 2000 because of the risk of serious cardiac arrhythmias and death. The drug is available only through an investigational, limited access program sponsored by the manufacturer.

In female rats, doses of ³40 mg/kg/day (25 times the maximum recommended human dose [MRHD]) impaired fertility by prolonging the breeding interval required for conception (1). Similar fertility impairment was observed at maturity in female rats exposed in utero to maternal doses of ³10 mg/kg/day. Cisapride was embryotoxic and fetotoxic at doses 12 and 100 times the MRHD in rabbits and rats, respectively (1). Intrauterine growth retardation and increased neonatal mortality were also observed.

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (2). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Cisapride was taken during the 1st trimester in 12 pregnancies. The outcomes of these pregnancies included 2 elective abortions, 1 lost to follow-up, and 10 normal, term babies (one set of twins). In two other cases, cisapride was taken during the 2nd and/or 3rd trimesters (2).

A 1997 prospective multicenter compared the pregnancy outcomes of 129 subjects who had taken cisapride during pregnancy with two groups of matched controls (3). Outcomes included major and minor malformations, birth weight (including birth weight <2500 g), live births (including premature births), spontaneous or induced abortions, fetal distress, and gestational age at birth. All of the subjects and controls had contacted one of 10 antenatal counseling services. The mean daily cisapride dose was 25 mg (range 5–120 mg), and the mean length of exposure was 4.6 weeks (range 0.14–41 weeks). Among 113 (87.6%) subjects who had taken cisapride during the 1st trimester, 88 (68.2%) had taken it during the period of organogenesis. There were no significant differences in outcomes between the subjects and controls (3).

In summary, cisapride is not an animal teratogen in two species, although embryo and fetal toxicity were observed at doses above the maximum human dose, and it does not appear to be a major human teratogen. However, the data are still too limited to adequately assess the safety of cisapride. Moreover, the studies lacked sensitivity to identify minor anomalies because of the absence of standardized examinations. Late appearing major defects may also have been missed due to the timing of the questionnaires.

Breast Feeding Summary

Cisapride is excreted into human milk (4). Ten women in the immediate postpartum period (mean 1.2 days after delivery), who had elected not to breast-feed their infants, were administered the drug 20 mg orally every 8 hours for 4 days. Milk samples were collected on the 3rd and 4th days before and 1 hour after a dose. A single serum sample was obtained on the 4th day 1 hour after a dose. The mean milk concentrations just before a dose on days 3 and 4 were 4.2 ng/mL and 4.8 ng/mL, respectively, whereas on both days the mean concentrations in the 1-hour samples were 6.2 ng/mL. The serum level at this time was 137 ng/mL, yielding a milk:serum ratio of 0.063. The investigators estimated that a breast-feeding infant would have ingested 1 µg/kg/day of the drug, about 0.1% of the mother's dose, an amount 600 to 800 times lower than the usual therapeutic dose for an infant (4).

Although nursing infants were not involved in the above study, the American Academy of Pediatrics considers the drug to be compatible with breast feeding (5).

References

1. Product information. Propulsid. Janssen Pharmaceutical, 1994.
2. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
3. Bailey B, Addis A, Lee A, Sanghvi K, Mastroiacovo P, Mazzone T, Bonati M, Paolini C, Garbis H, Val T, De Souza CFM, Matsui D, Schechtman AS, Conover B, Lau M, Koren G. Cisapride use during human pregnancy. A prospective, controlled multicenter study. Dig Dis Sci 1997;42:1848–52.
4. Hofmeyr GJ, Sonnendecker EWW. Secretion of the gastrokinetic agent cisapride in human milk. Eur J Clin Pharmacol 1986;30:735–6.
5. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.