Antilipemic Agent (Miscellaneous)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest High Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of lomitapide in human pregnancy have been located. The animal data suggest risk, but the absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. The manufacturer classifies the drug as contraindicated because of the toxicity observed in three animal species.
FETAL RISK SUMMARY
Lomitapide is an oral synthetic lipid-lowering agent that directly binds and inhibits microsomal triglyceride transfer protein. It is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein (LDL) apheresis where available, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. It is extensively metabolized by the liver to inactive metabolites. The drug is highly (99.8%) bound to plasma protein and the mean terminal half-life is about 40 hours (1).
Reproduction studies have been conducted in rats, rabbits, and ferrets. In rats, oral doses that were ≥2 times the human exposure at the maximum recommended human dose of 60 mg based on AUC (MRHD-AUC) given from gestation day 6 through organogenesis caused fetal malformations. The defects included umbilical hernia, gastroschisis, imperforate anus, alterations in heart shape and size, limb malrotations, skeletal malformations of the tail, and delayed ossification of cranial, vertebral and pelvic bones. When given from gestation day 7 through termination of nursing on lactation day 20, systemic exposures that were equivalent to the human exposure at the MRND-AUC were associated with malformations. Increased pup mortality occurred at 4 times the MRHD-AUC. In rabbits, exposures up to 3 times the MRHD based on BSA (MRHD-BSA) from gestational day 6 through organogenesis were not associated with adverse effects. However, exposures that were ≥6 times the MRHD-BSA resulted in embryo–fetal death. In ferrets given the drug from gestation day 12 through organogenesis, exposures that were <1–5 times the human exposure at the MRHD-AUC were associated with maternal toxicity and fetal malformations. Defects included umbilical hernia, medially rotated or short limbs, absent or fused digits on paws, cleft palate, open eye lids, low-set ears, and kinked tail (1).
In a 2-year dietary carcinogenicity study in mice, lomitapide caused significant increases of liver adenomas and small intestine carcinomas in males and combined adenomas and carcinomas in females. In 2-year studies in rats, there were no statistically significant drug-related increases in tumor incidences. Various assays for mutagenicity were negative. The drug had no effects on fertility in male and female rats at exposures up to 4–5 times the MRHD-AUC (1).
It is not known if lomitapide crosses the human placenta. The molecular weight (about 790) and high plasma protein binding suggest that exposure of the embryo–fetus will be limited, but the long terminal half-life might allow the drug to cross.
BREASTFEEDING SUMMARY
No reports describing the use of lomitapide during human lactation have been located. The molecular weight (about 790) and high (99.8%) plasma protein binding suggest that excretion of the drug into breast milk will be limited, but the long terminal half-life (about 40 hours) might allow excretion of the drug into milk. The effect of the exposure on a nursing infant is unknown. The potential for tumorigenicity in a mouse study suggests that the drug should not be used during breastfeeding. However, if a mother receiving the drug chooses to breastfeed, the infant should be monitored for the most common (incidence ≥28%) adverse effect seen in adults. These effects include diarrhea, nausea, vomiting, dyspepsia, and abdominal pain (1).
Reference
1.Product information. Juxtapid. Aegerion Pharmaceuticals, 2012.