CILOSTAZOL

Fetal Risk Summary

Cilostazol, an antiplatelet agent, is an inhibitor of cellular phosphodiesterase III. It is indicated for the reduction of symptoms of intermittent claudication. The drug undergoes extensive hepatic metabolism. Two of the metabolites are active.

Reproduction studies have been conducted with cilostazol in rats and rabbits (1). No effects on fertility or mating performance were observed in male and female rats at oral doses up to 1000 mg/kg/day. The highest dose produced systemic exposures less than 1.5 times in males, and about 5 times in females, the human systemic exposure based on the area under the plasma concentration curve of unbound cilostazol at the maximum recommended human dose (AUC-MRHD). In pregnant rats, the 1000 mg/kg/day dose resulted in decreased fetal weights and an increased incidence of congenital malformations in the cardiovascular (ventricular septal, aortic arch, and subclavian artery defects), renal (renal pelvic dilation), and skeletal (14th rib; retarded ossification) systems. Increased incidences of ventricular septal defects and retarded ossification were also observed at 150 mg/kg/day. This same dose administered to rats in late pregnancy was associated with stillbirths and decreased birth weight. In pregnant rabbits, a dose of 150 mg/kg/day was associated with an increased incidence of retarded ossification of the sternum (1).

It is not known if cilostazol crosses the human placenta to the fetus. The molecular weight (about 369) is low enough that transfer to the fetus should be expected. Moreover, transfer of the two active metabolites may also occur.

In summary, no reports describing the use of cilostazol during human pregnancy have been located. The drug is teratogenic and toxic in two animal species, but the complete lack of human data prevents any assessment of the risk that cilostazol presents to a human fetus.

Breast Feeding Summary

No reports describing the use of cilostazol during human lactation have been located. The drug is excreted into the milk of lactating rats (1). This is consistent with the relatively low molecular weight (about 369) of the drug and excretion into human breast milk should be expected. The effect on a nursing infant from exposure to cilostazol in milk is unknown. Because of the potential for severe adverse effects, breast feeding while receiving cilostazol is not recommended.

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