flozin * 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)
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
13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis
Carcinogenicity was eva luated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose).
Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical study, LH did not increase in males treated with canagliflozin.
Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical studies have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg.
Mutagenesis
Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats.
Impairment of Fertility
Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation |
