2.3)], which may reduce the efficacy of these substrates. Avoid concomitant use of LORBRENA with CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], LORBRENA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on LORBRENA use in pregnant women. Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of 100 mg once daily based on AUC (see Data). Advise a pregnant woman of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Preliminary embryo-fetal development studies investigating the administration of lorlatinib during the period of organogenesis were conducted in rats and rabbits. In rabbits, lorlatinib administration resulted in abortion and total loss of pregnancy at doses of 15 mg/kg (approximately 3 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 4 mg/kg (approximately 0.6 times the human exposure at the recommended dose of 100 mg) toxicities included increased post-implantation loss and malformations including rotated limbs, malformed kidneys, domed head, high arched palate, and dilation of the cerebral ventricles. In rats, administration of lorlatinib resulted in total loss of pregnancy at doses of 4 mg/kg (approximately 5 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 1 mg/kg (approximately equal to the human exposure at the recommended dose of 100 mg) there was increased post-implantation loss, decreased fetal body weight, and malformations including gastroschisis, rotated limbs, supernumerary digits, and vessel abnormalities.
8.2Lactation
Risk Summary
There are no data on the presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.
8.3Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating LORBRENA [see Use in Specific Populations (8.1)].
Contraception
LORBRENA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Females
Advise female patients of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENA and for at least 6 months after the final dose. Advise females of reproductive potential to use a non-hormonal method of contraception, because LORBRENA can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contracepti |
