FENOFIBRATE

Fetal Risk Summary

Fenofibrate is a prodrug that is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid. Fenofibric acid produces reductions in total cholesterol, low-density liproprotein cholesterol, apolipoprotein B, total triglycerides, and triglyceride rich lipoprotein. It is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia (1).

Reproduction studies have been conducted in pregnant rats and rabbits (1). The drug was embryocidal and teratogenic in pregnant rats given 7 to 10 times the maximum recommended human dose on a body surface area basis (MRHD). At 9 times the MRHD given before and throughout gestation to rats, reproductive toxicity included delayed parturition in 100% of the dams, a 60% increase in post-implantation loss with a decrease in litter size, reduced birth weight, an increase in spina bifida, and decreased pup survival (40% at birth, 4% during neonatal period, and 0% to weaning). Similar findings were observed at 7 times the MRHD given from day 15 of gestation through weaning. When pregnant rats were dosed at 10 times the MRHD during organogenesis, an increased incidence of congenital malformations was observed, including domed head/hunched shoulders/rounded body/abnormal chest, kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra foramen in palatine, misshapen vertebrae, and supernumerary ribs (1). In pregnant rabbits, doses 9 and 18 times the MRHD resulted in increased rates of abortions at both doses and fetal death at the highest dose (1).

Although not mutagenic, fenofibrate was carcinogenic in rats, significantly increasing the incidence of liver carcinoma, pancreatic carcinoma and adenomas, and benign testicular interstitial cell tumors in a dose-related manner (1). Some of these tumors (pancreatic acinar adenomas and testicular interstitial cell tumors) were also seen in a second strain of rats at lower doses (1).

It is not known if fenofibrate or fenofibric acid cross the human placenta. Fenofibrate is rapidly metabolized and is not detected in the plasma (1). The molecular weight of the metabolite, fenofibric acid (about 319), however, is low enough that transfer to the fetus should be expected.

Breast Feeding Summary

No reports describing the use of fenofibrate in human lactation have been located. The relatively low molecular weight of the active metabolite (about 319) suggests that it is excreted into breast milk. Although the effect of this exposure on a nursing infant is unknown, women taking fenofibrate should probably not breast feed because of the carcinogenicity observed in rats.

Reference