Antineoplastic (mTOR Inhibitor)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Only two reports describing the use of everolimus in human pregnancy have been located and, in both cases, normal infant outcomes occurred. Severe embryo toxicities, in the absence of maternal toxicity, were observed in one animal species at exposures much lower than those occurring in humans taking the recommended dose. The limited human pregnancy experience prevents a full assessment of the embryo–fetal risk. The manufacturer advices women of childbearing potential to use an effective method of contraception during treatment and for up 8 weeks after ending treatment (1). If a woman becomes pregnant while receiving everolimus, she should be advised of the potential for embryo–fetal harm.
FETAL RISK SUMMARY
Everolimus is a mTOR inhibitor (mammalian target of rapamycin) that is available as oral tablets. It is indicated for the treatment of various cancers and for prophylaxis of organ rejection in kidney and liver transplantation. The other agent in this subclass is temsirolimus. After oral absorption, everolimus is metabolized to relatively inactive metabolites. Plasma protein binding is about 74% and the mean elimination half-life is about 30 hours (1, 2). Everolimus is a derivative of sirolimus (see Sirolimus) (3). Reproduction studies have been conducted in rats and rabbits. Oral doses given to rats before mating and through organogenesis resulted in increased resorptions, preimplantation and postimplantation loss decreased number of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. The embryo–fetal toxicities occurred at about 4% of the exposure (AUC) in patients receiving the recommended human dose (RHD) of 10 mg/day and in the absence of maternal toxicity. In a prenatal and postnatal study with rats, no adverse effects on delivery or lactation or maternal toxicity were noted at a dose that was about 10% of the RHD based on BSA. However, this dose was associated with a slight reduction in pup body weight and survival, but no drug-related effects on offspring development were observed. In rabbits, embryotoxicity as evident as an increase in resorptions occurred at a dose that was about 1.6 times the RHD based on BSA. However, maternal toxicity also was evident (1).
Two-year studies for carcinogenicity in mice and rats were negative, as were multiple assays for genotoxic and mutagenic effects. Everolimus caused infertility in male rats that was partially reversible when the drug exposure was stopped. In female rats, the increases in preimplantation loss suggested that the drug may reduce female fertility (1).
It is not known if everolimus crosses the human placenta. The molecular weight (about 958), moderate plasma protein binding, and long elimination half-life suggest that the drug will cross to the embryo–fetus.
In a 2011 case report, a woman with a kidney transplant conceived while receiving everolimus (4). The pregnancy was discovered at 12 weeks’ gestation. Because of worsening renal function, proteinuria, and severe hypertension during week 30, a cesarean section was performed to deliver a 1.280-kg healthy female infant with an Apgar score of 10. No congenital anomalies were noted. The infant had normal growth without detectable disorders at 12 months of age (4).
A 2012 case report described the pregnancy outcome of a woman who had received a kidney transplant 4 years before conceiving (5). The woman received everolimus, cyclosporine, and corticosteroids throughout pregnancy. At term, she gave birth to a healthy, 3.020-kg infant with an initial Apgar score of 9. The child was in good health at 3 years of age (5).
BREASTFEEDING SUMMARY
No reports describing the use of everolimus during human lactation have been located. The molecular weight (about 958), moderate (about 74%) plasma protein binding, and long (about 30 hours) elimination half-life suggest that the drug will be excreted into breast milk. Based on animal data, the concentration in milk may exceed the maternal plasma concentration. The effect of this exposure on a nursing infant is unknown. However, marked toxicity has been observed in adults, such as gastrointestinal disorders (stomatitis, diarrhea, nausea, vomiting), infections, anorexia, respiratory (cough, dyspnea, epistaxis, pneumonitis), skin and subcutaneous disorders, headache, and other toxicities.
References
1.Product information. Afinitor. Novartis Pharmaceuticals, 2012.
2.Product information. Zortress. Novartis Pharmaceuticals, 2013.
3.Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715–29.
4.Veroux M, Corona D, Veroux P. Pregnancy under everolimus-based immunosuppression. Trans Int 2011;24:e115–7.
5.Carta P, Caroti L, Zanazzi M. Pregnancy in a kidney transplant patient treated with everolimus. Am J Kidney Dis 2012;60:329.