PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
Only two reports describing the use of fenofibrate in human pregnancy has been located. Although the near absence of human pregnancy experience prevents an assessment of the risk, the combined animal data are reason for concern if this drug is used for prolonged periods in pregnancy. As with other antilipemic agents, there is apparently no benefit in otherwise healthy women from the use of fenofibrate during gestation. However, fenofibrate may be of benefit to treat or prevent hyperlipidemia-associated pancreatitis. If used during pregnancy, the woman should be informed of the limited human data.
FETAL RISK SUMMARY
Fenofibrate is a prodrug that is rapidly hydrolyzed by esterases after oral administration to the active metabolite, fenofibric acid. The active metabolite is further metabolized to inactive metabolites. Fenofibric acid is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia. Fenofibric acid is extensively bound to serum protein (about 99%) and has an elimination half-life of 20 hours (1,2).
Reproduction studies have been conducted in pregnant rats and rabbits (1,2). The drug was embryocidal and teratogenic in pregnant rats given 7–10 times the maximum recommended human dose based on BSA (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 postimplantation 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 seven 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). Embryocidal effects were also observed in rabbits. Doses 9 and 18 times the MRHD caused abortions in 10% and 25% of the dams, respectively. At 18 times the MRHD, 7% of the fetuses died (1,2).
Fenofibrate had no mutagenic potential in four different tests, but the drug 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 (1,2). Some of these tumors (pancreatic acinar adenomas and testicular interstitial cell tumors) were also seen in a second strain of rats at lower doses (1,2).
It is not known if fenofibrate or fenofibric acid crosses the human placenta. Fenofibrate is rapidly metabolized and is not detected in the plasma (1,2). The molecular weight of the metabolite, fenofibric acid (about 319), and the prolonged elimination half-life suggest that the drug will cross, but the high serum protein binding should limit the amount available for transfer to the embryo or fetus.
A 2011 case report described the use of fenofibrate in the 3rd trimester (3). A 30-year-old G4P1SAB2 woman with adequately treated hypothyroidism presented at 32 weeks’ gestation with hypertriglyceridemia-associated pancreatitis. Diet alone did not control her dyslipidemia and she was started on an unspecified dose of fenofibrate. Recurrence of pancreatitis was prevented and at 35 weeks’ gestation she gave birth spontaneously to a healthy, 2452-g male infant with Apgar scores of 8 and 9, presumably at 1 and 5 minutes (3).
A 30-year-old woman with high triglyceride levels was started on fenofibrate 267 mg/day (4). One year later, an unplanned pregnancy was diagnosed at 8 weeks’ gestation and the drug was stopped. At 36 weeks, a cesarean section delivered a healthy 3200-g (75th percentile) male infant with Apgar scores of 7, 9, and 10 at 1, 5, and 10 minutes, respectively. No congenital anomalies were found and the infant was healthy at 1 year of age (4).
No reports describing the use of fenofibrate in human lactation have been located. The relative 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 breastfeed because of potential toxicity in a nursing infant.
1.Product information. Tricor. Abbott Laboratories, 2001.
2.Product information. Lofibra. GATE Pharmaceuticals, 2004.
3.Whitten AE, Lorenz RP, Smith JM. Hyperlipidemia-associated pancreatitis in pregnancy managed with fenofibrate. Obstet Gynecol 2011;117:517–9.
4.Sunman H, Canpolat U, Sahiner L, Aytemir K. Use of fenofibrate during the first trimester of an unplanned pregnancy in a patient with hypertriglyceridemia. Ann Pharmacother 2012;46:e5. doi:10.1345/aph.1Q626.