Hepatic Impairment: Afatinib is eliminated mainly by biliary/fecal excretion. Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of GILOTRIF. Subjects with severe (Child Pugh C) hepatic dysfunction have not been studied [see Use in Specific Populations (8.8)].

Body Weight, Gender, Age, and Race: Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.

Drug Interactions
Effect of P-gp Inhibitors and Inducers on Afatinib: The effect of ritonavir dosing time relative to a single oral dose of GILOTRIF was eva luated in healthy subjects taking 40 mg of GILOTRIF alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after GILOTRIF administration. The relative bioavailability for AUC0-∞ and Cmax of afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking GILOTRIF. In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of GILOTRIF, exposure to afatinib increased by 48% for AUC0-∞ and 39% for Cmax [see Drug Interactions (7)].

Pre-treatment with a potent inducer of P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC0-∞ ) and 22% (Cmax ) [see Drug Interactions (7)].

P-glycoprotein (P-gp): Based on in vitro data, afatinib is a substrate and an inhibitor of P-gp.

Breast Cancer Resistance Protein (BCRP): Based on in vitro data, afatinib is a substrate and an inhibitor of the transporter BCRP.

Effect of CYP450 Enzyme Inducers and Inhibitors on Afatinib: In vitro data indicated that drug-drug interactions with GILOTRIF due to inhibition or induction of CYP450 enzymes by concomitant medications are unlikely. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes. In humans, enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.

Effect of Afatinib on CYP450 Enzymes: Afatinib is not an inhibitor or an inducer of CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4) in cultured primary human hepatocytes. Therefore, afatinib is unlikely to affect the metabolism of other drugs that are substrates of CYP450 enzymes.
13  NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been conducted with afatinib.

A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. No mutagenic or genotoxic potential was identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as in the in vivo bone marrow micronucleus assa