Children, infants
The safety and efficacy of ribociclib; letrozole in pediatric patients (adolescents, children, and infants) has not been established. Administration of letrozole to young (postnatal day 7) rats for 12 weeks at exposures below those achieved in adult patients receiving the recommended dose of 2.5 mg per day resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Hypertrophy of the hypophysis, testicular changes including degeneration of the seminiferous tubular epithelium, and atrophy of the female reproductive tract resulted in decreased fertility. Forty-two days after discontinuation of letrozole, histopathological changes were not reversible.
Pregnancy
Avoid use of ribociclib; letrozole during pregnancy and for at least 3 weeks after the last dose. The product label of letrozole (single ingredient) contraindicated use in pregnancy. Although there are no available human data, both ribociclib and letrozole can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving ribociclib; letrozole should be apprised of the potential hazard to the fetus.
When given to pregnant rats at exposures approximately 0.6 times what would be achieved at the recommended human dose, reduced maternal body weight gain and reduced fetal weights were accompanied by skeletal changes related to the lower fetal weights. Increased incidences of fetal abnormalities (malformations and external, visceral, and skeletal variants) as well as lower fetal weights occurred in rabbits treated at exposures of 1.5 times what would be achieved at the recommended human dose; there was no maternal toxicity at this dose. Fetal abnormalities included reduced/small lung lobes, additional vessel on the descending aorta, 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.
Contraception requirements, infertility, pregnancy testing, reproductive risk
Counsel patients about the reproductive risk and contraception requirements during ribociclib; letrozole treatment. Both drugs can be teratogenic if taken by the mother during preg |
