ed by 0.25 mg QD for 6 days 300 mg QDfor 7 days digoxin 1.20(1.12; 1.28) 1.36(1.21; 1.53)
No dose adjustments of co-administered drug required for the following:
Acetaminophen 1,000 mg 300 mg BID for 25 days acetaminophen 1.06‡(0.98; 1.14) 1.00(0.92; 1.09)
Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QDfor 6 days ethinyl estradiol 1.07(0.99; 1.15) 1.22(1.10; 1.35)
levonorgestrel 1.06(1.00; 1.13) 1.22(1.11; 1.35)
Glyburide 1.25 mg 200 mg QDfor 6 days glyburide 1.02(0.98; 1.07) 0.93(0.85; 1.01)
3-cis-hydroxy-glyburide 1.01(0.96; 1.07) 0.99(0.91; 1.08)
4-trans-hydroxy-glyburide 1.03(0.97; 1.09) 0.96(0.88; 1.04)
Hydrochloro-thiazide 25 mg QDfor 35 days 300 mg QDfor 7 days hydrochlorothiazide 0.99(0.95; 1.04) 0.94(0.87; 1.01)
Metformin 2,000 mg 300 mg QDfor 8 days metformin 1.20(1.08; 1.34) 1.06(0.93; 1.20)
Simvastatin 40 mg 300 mg QDfor 7 days simvastatin 1.12(0.94; 1.33) 1.09(0.91; 1.31)
simvastatin acid 1.18(1.03; 1.35) 1.26(1.10; 1.45)
Warfarin 30 mg 300 mg QDfor 12 days (R)-warfarin 1.01(0.96; 1.06) 1.03(0.94; 1.13)
(S)-warfarin 1.06(1.00; 1.12) 1.01(0.90; 1.13)
INR 1.00(0.98; 1.03) 1.05(0.99; 1.12
advertisementINVOKANA (Page 3 of 7)
By Janssen Pharmaceuticals, Inc. | Last revised: 31 March 2013
12.3 PharmacokineticsThe pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of INVOKANA, peak plasma concentrations (median Tmax ) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2 ) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg.
Absorption
The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, INVOKANA may be taken with or without food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA be taken before the first meal of the day [see Dosage and Administration (2.1)].
advertisementDistribution
The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 119 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
Metabolism
O -glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O -glucuronide metabolites.
CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.
Excretion
Following administration of a single oral [14 C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the admin |
