Antilipemic Agent
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of ezetimibe in human pregnancy have been located. Although the animal data suggest low risk, the lack of human pregnancy experience prevents an assessment of the risk this agent presents to the embryo and fetus. Generally, discontinuing treatment of hypercholesterolemia during pregnancy is not thought to put the mother at risk. If treatment during pregnancy is mandated, ezetimibe appears to be a better choice than treatment with HMG-CoA reductase inhibitors (i.e., “statins” are contraindicated) or the fibric acid derivative fenofibrate.
FETAL RISK SUMMARY
Ezetimibe selectively inhibits the intestinal absorption of cholesterol and related phytosterols. It is indicated, either alone or in combination with HMG-CoA reductase inhibitors, as adjunctive therapy to diet for the reduction of cholesterol and triglycerides in patients with primary hypercholesterolemia. Ezetimibe is extensively metabolized in the small intestine and liver and both the parent compound and the metabolite are pharmacologically active. In addition, both are highly bound (>90%) to plasma proteins and have an elimination half-life of about 22 hours (1,2).
Reproduction studies have been conducted in rats and rabbits. In rats, there was no evidence of impaired fertility or embryolethal effects at doses up to about 10 times the human exposure at 10 mg/day based on AUC for total ezetimibe (HD). At the highest dose, increased incidences of skeletal abnormalities (extra pair of thoracic ribs, unossified cervical vertebral centra, and shortened ribs) were noted. In rabbits, doses up to about 150 times the HD did not cause embryolethal effects, but an increased incidence of extra thoracic ribs was observed (1,2).
No evidence of carcinogenicity was observed in mice and rats administered high doses over a 2-year period. There was also no evidence of mutagenic, clastogenic, or genotoxic effects with various other assays (1,2).
It is not known if ezetimibe or its active metabolite crosses the human placenta. The parent compound does cross the rat and rabbit placentas (1,2). The molecular weight (about 409 for the parent compound) and prolonged elimination half-life suggest that passage to the human embryo and/or fetus will occur, but the high plasma protein binding should limit the transfer.
BREASTFEEDING SUMMARY
No reports describing the use of ezetimibe during human lactation have been located. The molecular weight (about 409 for the parent compound) and the prolonged elimination half-life (about 22 hours) for both ezetimibe and its active metabolite suggest that the drug and/or its metabolite will be excreted into breast milk. However, the high plasma protein binding (>90%) should limit the amount excreted. The effect on a nursing infant from this exposure is unknown. If ezetimibe is taken during lactation, the nursing infant should be closely observed for adverse effects that are commonly seen in adults (e.g., headache, diarrhea, pharyngitis, sinusitis, arthralgia).
References
1.Product information. Zetia. Merck/Schering-Plough Pharmaceuticals, 2004.
2.Product information. Zetia. Schering, 2004.