Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to IMPAVIDO during pregnancy. Healthcare providers are encouraged to register patients by calling 1-866-588-5405.

Risk Summary

IMPAVIDO is contraindicated during pregnancy. Based on data from animal reproduction studies, IMPAVIDO may cause embryo-fetal toxicity when administered to pregnant women. There are no available data on IMPAVIDO use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal and/or fetal outcomes. If a woman becomes pregnant while being treated with IMPAVIDO, treatment should be discontinued and the patient should be counseled about the potential risk to the fetus.

Embryo-fetal toxicity, including death and fetal malformations, was observed in embryo-fetal studies in rats and rabbits administered oral miltefosine during organogenesis at doses that were respectively 0.06 and 0.2 times the maximum recommended human dose (MRHD) of 3.33 mg/kg/day. Numerous visceral and skeletal fetal malformations were observed in a fertility study in female rats administered miltefosine prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study in pregnant rats, miltefosine was administered in oral doses of 0.6, 1.2, 2.4, 6, 12, and 24 mg/kg/day during the period of organogenesis (Day 6 to Day 15 of gestation). Miltefosine dosages ≥ 1.2 mg/kg/day [0.06 times the MRHD based on body surface area (BSA) comparison] caused embryo-fetal toxicity including death and fetal malformations. Malformations included undeveloped cerebrum, hemorrhagic fluid filling the lumina of the skull, cleft palate and generalized edema. In an embryo-fetal development study in pregnant rabbits, miltefosine was administered in oral doses of 0.6, 1.2, 2.4, 6, 12, and 24 mg/kg/day during the period of organogenesis (Day 6 to Day 18 of gestation). Abortion and fetal resorption occurred with one dam receiving 2.4 mg/kg/day miltefosine (0.2 times the MRHD based on BSA comparison) and fetal resorptions occurred with all dams receiving ≥ 6.0 mg/kg/day miltefosine. In both rats and rabbits, there were no viable litters at miltefosine doses ≥ 6.0 mg/kg/day (0.3 or 0.6 times the MRHD based on BSA comparisons for rats and rabbits respectively).

In a separate fertility study in female rats, miltefosine was administered in oral doses of 2.15, 6.81, and 21.5 mg/kg for four weeks before mating and up to Day 7 of pregnancy. Miltefosine doses ≥ 6.81 mg/kg/day (0.3 times the MRHD based on BSA comparison) produced numerous visceral (misshapen cerebral structures, dilated ventricles filled with brown masses, misshapen spinal cord, misshapen and malpositioned eyes, hypophysis, and absent inner ear) and skeletal (cleft palate, dumbbell-shaped ossification of thoracic vertebral centers, markedly enlarged skull bones, and markedly dilated suturae) fetal malformations. [see Contraindications (4.1), Nonclinical Toxicology (13.1)].