Antineoplastic (Hormone)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of exemestane in human pregnancy have been located. The animal data suggest moderate risk. The antineoplastic is indicated for postmenopausal women with breast cancer who have been treated with tamoxifen for 2–3 years. The drug prevents the conversion of androgens to estrogen. Because estrogen is required to maintain pregnancy, exemestane is contraindicated in pregnancy.
FETAL RISK SUMMARY
Exemestane is an oral steroidal aromatase inactivator that binds irreversibly to the enzyme, thus preventing conversion of androgens to estrogen both in pre- and postmenopausal women. It is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received 2–3 years of tamoxifen and are changed to exemestane for completion of a total of 5 consecutive years of adjuvant hormonal therapy. The drug is extensively metabolized in inactive or minimally active compounds. Plasma protein binding to albumin and α1-acid glycoprotein is 90%. The mean terminal half-life is about 24 hours (1).
Reproduction studies have been conducted in rats and rabbits. When rats were given a daily dose that was about 1.5 times the recommended human daily dose based on BSA (RHDD) from 14 days before mating to day 15 or 20 of gestation, an increase in placental weight was observed. At doses about ≥8 times the RHDD, prolonged gestation, abnormal or difficult labor, increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were observed. No malformations were observed with doses that were about 320 times the RHDD. Exemestane and its metabolites crossed the rat placenta at doses about equal to the RHDD resulting in approximately equal concentrations in maternal and fetal blood. In rabbits, daily doses given during organogenesis that were about 70 times the RHDD caused a decrease in placental weight. At about 210 times the RHDD, abortions, an increase in resorptions, and a decrease in fetal body weight occurred but no increase in malformations occurred (1,2).
A 2-year carcinogenicity study in mice resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both males and females, and an increased incidence of renal tubular adenomas in males. The doses used in male and female mice produced plasma AUC levels that were 34 and 75 times the AUC in postmenopausal patients at the recommended clinical dose. No evidence of carcinogenicity was observed in a separate study with rats. The drug was not mutagenic in two assays and was not clastogenic in an in vivo assay. In fertility studies, untreated female rats showed reduced fertility when mated with male rats given doses of exemestane that were ≥200 times the RHDD (1,2).
It is not known if exemestane or its metabolites cross the human placenta. The molecular weight (about 296) and long elimination half-life suggest that exposure of the embryo and/or fetus to the parent drug and metabolites will occur.
BREASTFEEDING SUMMARY
No reports describing the use exemestane during human lactation have been located. The molecular weight (about 296) and long elimination half-life (about 24 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. However, because the drug prevents conversion of androgens to estrogen, breastfeeding is contraindicated if the woman is receiving exemestane.
References
1.Product information. Aromasin. Pharmacia & Upjohn Company, 2008.
2.Beltrame D, di Salle E, Giavini E, Gunnarsson K, Brughera M. Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits. Reprod Toxicol 2001;195–213.