Antineoplastic (Proteasome Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of carfilzomib in human pregnancy have been located. The animal data suggest moderate risk, but the absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. The manufacturer states that the drug can cause fetal harm based on its mechanism of action and findings in animals.
FETAL RISK SUMMARY
Carfilzomib is an antineoplastic agent that is given IV on 2 consecutive days each week for 3 weeks, followed by a 12-day rest period before subsequent cycles are given. It is a proteasome inhibitor in the same class as bortezomib. Carfilzomib is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy. The drug is rapidly and extensively metabolized to inactive metabolites. Plasma protein binding averaged 97% and the parent drug is cleared from the systemic circulation with a half-life of ≤1 hour (1).
Reproduction studies have been conducted in rats and rabbits. No teratogenicity was observed in rats given doses of 0.5–2 mg/kg/day (comparison to the human dose not specified) during organogenesis. In pregnant rabbits, doses that were ≥20% of the recommended human dose of 27 mg/m2 based on BSA (RHD) caused an increase in preimplantation loss. At a maternal toxic dose (40% of the RHD), an increase in early resorptions and postimplantation loss and a decrease in fetal weight was observed (1).
Carcinogenicity studies have not been conducted with carfilzomib. The drug was not mutagenic in one assay, but clastogenic effects were observed in one of two assays. Although fertility studies have not been conducted, no effects on reproductive tissues were noted during 28-day repeat-dose toxicity studies in rats and monkeys or in 6-month rat and 9-month monkey chronic toxicity studies (1).
It is not known if carfilzomib crosses the human placenta. The molecular weight (about 720) suggests that the drug will cross the placenta. However, the rapid metabolism to inactive metabolites, high plasma protein binding, and short half-life in the systemic circulation suggest that exposure of the embryo–fetus will be limited.
BREASTFEEDING SUMMARY
No reports describing the use of carfilzomib during human lactation have been located. The molecular weight (about 720) suggests that the drug will be excreted into breast milk. However, the rapid metabolism to inactive metabolites, high plasma protein binding (97%), and short systemic circulation half-life (≤1 hour) in the systemic circulation suggest that exposure of a nursing infant will be limited. The effects of this potential exposure on a nursing infant are unknown. The most common (≥30%) adverse reactions in adults are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. If a woman receiving this drug is nursing, her infant should be closely monitored for these effects.
Reference
1.Product information. Kyprolis. Onyx Pharmaceuticals, 2012.