oncentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.
8.3 Nursing Mothers
It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.3)].
8.4 Pediatric Use
Safety and effectiveness of KADCYLA have not been established in pediatric patients.
8.5 Geriatric Use
Of 495 patients who were randomized to KADCYLA in the randomized trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients ≥ 65 years old (n=138 across both treatment arms) the hazard ratios for progression-free survival (PFS) and Overall Survival (OS) were 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively.
Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)].
8.6 Females of Reproductive Potential
KADCYLA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving KADCYLA and for 6 months following the last dose of KADCYLA.
If KADCYLA is administered during pregnancy or if the patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].
8.7 Renal Impairment
No dedicated renal impairment trial for KADCYLA has been conducted. Based on the population pharmacokinetics, as well as analysis of Grade 3 or greater adverse drug reactions and dose modifications, dose adjustments of KADCYLA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited data available [see Clinical Pharmacology (12.3)].
8.8 Hepatic Impairment
In vitro studies in human liver microsomes indicates that DM1 is metabolized by CYP3A4/5. The influence of hepatic impairment on the pharmacokinetics of ado-trastuzumab emtansine conjugate has not been determined.
10 OVERDOSAGE
There is no known antidote for overdose of KADCYLA. In clinical trials, overdose of KADCYLA has been reported at approximately two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) a
