, additional vessel on the aortic arch, small eyes, diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory lung lobe, extra/rudimentary 13th ribs, misshapen hyoid bone, bent hyoid bone alae, and reduced number of phalanges in the pollex; there was not an increased incidence of embryo-fetal mortality.
Letrozole increased preimplantation loss when administered to female rats at doses approximately 0.01 times the maximum recommended human dose on a mg/m2 basis. Administration of letrozole during organogenesis at this level of exposure resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals; it was also teratogenic, causing fetal domed head and cervical/centrum vertebral fusion. When administered at the same exposure level to pregnant rabbits, increased resorptions, increased post-implantation loss and decreased numbers of live fetuses occurred; fetal anomalies included incomplete ossification of the skull, sternebrae, and fore-and hind legs.
Counsel patients about the reproductive risk and contraception requirements during ribociclib; letrozole treatment. Both drugs can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception (resulting in less than 1% pregnancy rates) during and for at least 3 weeks after treatment with ribociclib; letrozole. Females of reproductive potential should undergo pregnancy testing prior to initiation of ribociclib; letrozole. Women who become pregnant while receiving ribociclib; letrozole should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of ribociclib; letrozole on human fertility, male and female infertility has been observed in animal studies.
MECHANISM OF ACTION
Ribociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor. CDK 4 and 6 are activated when binding to D-cyclins. Cyclin D1 and CDK 4/6 are downstream of signaling pathways that lead to cellular proliferation; the cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle, reducing cell proliferation in breast cancer cell lines. In a rat xenograft model with human tumor cells, inhibition of pRb phosphorylation by ribociclib monotherapy decreased tumor volumes. The combination of ribociclib and an antiestrogen agent such as letrozole inhibited tumor growth more than either agent alone in studies using patient-derived estrogen receptor positive breast cancer xenograft models.
Letrozole is a nonsteroidal inhibitor of aromatase, the enzyme that catalyzes the final step in estrogen production. In postmenopausal women, the primary source of circulating estrogen is from the conversion of adrenal estrogens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase; letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline, with maximal suppression within 2 to 3 days. Letrozole competitively binds to the heme of the cytochrome P450 subunit of aromatase, decreasing |
