Antineoplastic (Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of temsirolimus in human pregnancy have been located. The animal reproduction studies suggest risk, but the absence of human pregnancy experience prevents a full assessment of the embryo–fetal risk. The manufacturer recommends advising women of childbearing potential to avoid becoming pregnant during treatment and for 3 months after the last dose (1). The manufacturer also recommends that men be counseled on the potential effects of the drug on the fetus and sperm, and, if their partner is of childbearing potential, should use reliable contraception during treatment and for 3 months after the last dose (1). (See also Sirolimus.)
FETAL RISK SUMMARY
Temsirolimus is an antineoplastic agent indicated for the treatment of advanced renal cell carcinoma. It is a mTOR inhibitor (mammalian target of rapamycin) that is the same subclass as everolimus. Temsirolimus is given as an IV infusion over 30–60 minutes once weekly. The drug is metabolized to five metabolites. Sirolimus is the principal metabolite in humans. Plasma protein binding of sirolimus is about 92% but apparently is not known for the parent compound. The mean half-lives of temsirolimus and sirolimus are about 17 and 55 hours, respectively (1).
Reproduction studies have been conducted in rats and rabbits. Exposures after daily oral doses that produced embryo–fetal toxicity in rats and rabbits were about 0.04 and 0.12 times the AUC in cancer patients at the human recommended dose, respectively. Toxicity in the rat consisted of reduced fetal weight and reduced ossification, whereas in the rabbit it was reduced fetal weight, omphalocele, bifurcated sternebrae, notched ribs, and incomplete ossifications (1).
Carcinogenic studies have not been conducted with temsirolimus, but sirolimus was carcinogenic in mice and rats (see Sirolimus). Temsirolimus was not genotoxic in multiple assays. Fertility was impaired in male rats at doses that were about 0.2 times the human recommended IV dose (RHID). The effects observed were decreased number of pregnancies, decreased sperm concentration and motility, decreased reproductive organ weights, and testicular tubular degeneration. At about 2 times the RHID, fertility was absent. In female rats, an increased incidence of pre- and postimplantation losses was noted at an oral dose about 0.3 times the RHID (1).
It is not known if temsirolimus or sirolimus crosses the human placenta. The molecular weights of the two compounds, about 1030 and 914, respectively, are within the range for passive diffusion. In addition, the elimination half-lives will place the drug at the maternal–fetal interface for long periods.
BREASTFEEDING SUMMARY
No reports describing the use of temsirolimus during human lactation have been located. There also are no reports of the use of sirolimus, the active metabolite, during lactation (see Sirolimus). The molecular weights of the two compounds, about 1030 and 914, respectively, are low enough for excretion into breast milk. Moreover, the elimination half-lives, about 17 and 55 hours, respectively, suggest that both temsirolimus and sirolimus will be excreted. The effect of this exposure on a nursing infant is unknown. However, serious toxicity has been observed in adults, such as hypersensitivity reactions, including anaphylaxis, infections, interstitial lung disease, bowel perforation, renal failure, and abnormal wound healing.
Reference
1.Product information. Torisel. Wyeth Pharmaceuticals, 2007.