INVOKANA (Page 5 of 9)

8.7 Hepatic Impairment

No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.

11 DESCRIPTION

INVOKANA® (canagliflozin) contains canagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin, the active ingredient of INVOKANA, is chemically known as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C24 H25 FO5 S∙1/2 H2 O and 453.53, respectively. The structural formula for canagliflozin is:

Chemical Structure

Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9.

INVOKANA is supplied as film-coated tablets for oral administration, containing 102 and 306 mg of canagliflozin in each tablet strength, corresponding to 100 mg and 300 mg of canagliflozin (anhydrous), respectively.

Inactive ingredients of the core tablet are croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, and microcrystalline cellulose. The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following excipients: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol/PEG, talc, and iron oxide yellow, E172 (100 mg tablet only).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG ), and thereby increases urinary glucose excretion (UGE).

Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure.

12.2 Pharmacodynamics

Following single and multiple oral doses of canagliflozin in patients with type 2 diabetes, dose-dependent decreases in the renal threshold for glucose (RTG ) and increases in urinary glucose excretion were observed. From a starting RTG value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RTG throughout the 24-hour period. Data from single oral doses of canagliflozin in healthy volunteers indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for doses up to 300 mg once daily. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 trials. The reductions in RTG led to increases in mean UGE of approximately 100 g/day in subjects with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin. In patients with type 2 diabetes given 100 to 300 mg once daily over a 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this trial, plasma glucose declined in a dose-dependent fashion within the first day of dosing. In single-dose trials in healthy and type 2 diabetic subjects, treatment with canagliflozin 300 mg before a mixed-meal delayed intestinal glucose absorption and reduced postprandial glucose.

Cardiac Electrophysiology

In a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover trial, 60 healthy subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose.

12.3 Pharmacokinetics

The 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 (2.2)].

Distribution

The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 83.5 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 administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O -glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.

Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O -glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.

Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.

Specific Populations

Renal Impairment

A single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.

Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60, and 15 to less than 30 mL/min/1.73 m2 , respectively), but was similar for ESKD (N=8) subjects and healthy subjects.

Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The glucose lowering pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.2)].

Canagliflozin was negligibly removed by hemodialysis.

Hepatic Impairment

Relative to subjects with normal hepatic function, the 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)].

Pharmacokinetic 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 the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)].

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 7: 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
AUC inf for drugs given as a single dose and AUC 24h for drugs given as multiple doses

See Drug Interactions (7.1) for the clinical relevance of the following:

Rifampin

600 mg QD for 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 QD for 6 days

0.91(0.88; 0.94)

0.92(0.84; 0.99)

Hydrochlorothiazide

25 mg QD for 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 BID for 3 days

300 mg QD for 17 days

1.21(1.16; 1.25)

1.13(1.00; 1.28)

Table 8: 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
AUC inf for drugs given as a single dose and AUC 24h 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 followed by 0.25 mg QD for 6 days

300 mg QD for 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 QD for 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 QD for 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)

Hydrochlorothiazide

25 mg QD for 35 days

300 mg QD for 7 days

Hydrochlorothiazide

0.99(0.95; 1.04)

0.94(0.87; 1.01)

Metformin

2,000 mg

300 mg QD for 8 days

Metformin

1.20(1.08; 1.34)

1.06(0.93; 1.20)

Simvastatin

40 mg

300 mg QD for 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 QD for 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)

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