PERINDOPRIL

Fetal Risk Summary

Perindopril, a competitive inhibitor of angiotensin I–converting enzyme (ACE), is a prodrug that is hydrolyzed in vivo to the active agent, perindoprilat. The agent is used in the management of essential hypertension.

Reproduction studies have been conducted with perindopril in mice, rats, rabbits, and cynomolgus monkeys (1). No evidence of teratogenicity was observed in these species at doses 6, 670, 50, and 17 times, respectively, the maximum recommended human dose on a body surface area basis for a 50-kg adult (MRHD). At 6 times the MRHD in rats, no adverse effects on reproductive performance or fertility were observed in male and female rats (1).

It is not known if either perindopril or its metabolite, perindoprilat, crosses the human placenta to the fetus. The relatively low molecular weights of perindopril (about 368 for the free acid or 442 for the salt form) and perindoprilat (less than the prodrug) suggest that transfer to the fetus will occur.

No reports describing the use of perindopril during human pregnancy have been located. Although ACE inhibitors do not appear to cause embryo or fetal harm when used only during the 1st trimester, their use during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity. The mechanism of these adverse effects are thought to be related to fetal hypotension and decreased renal blood flow. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth retardation, prematurity, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial defor- mation, and pulmonary hypoplasia. Severe anuria and hypotension, that is resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to ACE inhibitors, including perindopril (see also Captopril and Enalapril). Newborn renal function and blood pressure should be closely monitored.

[*Risk Factor DM if used in the 2nd and 3rd trimesters.]

Breast Feeding Summary

No reports describing the use of the prodrug perindopril during human lactation have been located. Perindopril was excreted into the milk of lactating rats (1). The relatively low molecular weights of perindopril (about 368 for the free acid or 442 for the salt form) and its active metabolite, perindoprilat (molecular weight less than perindopril), are suggestive that both would be excreted into breast milk if present in the maternal circulation. The effects on a nursing infant from exposure to perindopril or perindoprilat in milk are unknown. However, other agents in this class are excreted into milk and, because the amounts are low and no adverse effects have been observed in nursing infants, are classified as compatible with breast feeding by the American Academy of Pediatrics (see also Captopril and Enalapril).

Reference