he geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin.
These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment [see Use in Specific Populations (8.7)].
Pharmacokinetics Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race
Based on the population PK analysis with data collected from 1526 subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)].
Pediatric
Studies characterizing the pharmacokinetics of canagliflozin in pediatric patients have not been conducted.
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp.
Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2.
In Vivo Assessment of Drug Interactions
Table 5: Effect of Co−Administered Drugs on Systemic Exposures of Canagliflozin Co-Administered Drug Dose of Co-Administered Drug * Dose of Canagliflozin * Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect=1.0
AUC †(90% CI) Cmax (90% CI)
QD = once daily; BID = twice daily
* Single dose unless otherwise noted
AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses
See Drug Interactions (7.1) for the clinical relevance of the following:
Rifampin 600 mg QDfor 8 days 300 mg 0.49(0.44; 0.54) 0.72(0.61; 0.84)
No dose adjustments of INVOKANA required for the following:
Cyclosporine 400 mg 300 mg QD for 8 days 1.23(1.19; 1.27) 1.01(0.91; 1.11)
Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QDfor 6 days 0.91(0.88; 0.94) 0.92(0.84; 0.99)
Hydrochlorothiazide 25 mg QDfor 35 days 300 mg QD for 7 days 1.12(1.08; 1.17) 1.15(1.06; 1.25)
Metformin 2,000 mg 300 mg QD for 8 days 1.10(1.05; 1.15) 1.05(0.96; 1.16)
Probenecid 500 mg BIDfor 3 days 300 mg QD for 17 days 1.21(1.16; 1.25) 1.13(1.00; 1.28)
QD = once daily; BID = twice daily
* Single dose unless otherwise noted
AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses
Table 6: Effect of Canagliflozin on Systemic Exposure of Co-Administered Drugs Co-Administered Drug Dose of Co-Administered Drug * Dose of Canagliflozin * Geometric Mean Ratio(Ratio With/Without Co-Administered Drug)No Effect = 1.0
AUC †(90% CI) Cmax (90% CI)
QD = once daily; BID = twice daily; INR = International Normalized Ratio
* Single dose unless otherwise noted
AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses
AUC0–12h
See Drug Interactions (7.2) for the clinical relevance of the following:
Digoxin 0.5 mg QD first day follow |
