Invokana canagliflozin 300 mg Tablet, Film Coated, 720-count — NDC 55154-1426-8 (Billing 55154-1426-08)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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 (RT G ), 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.

12.2Pharmacodynamics Following single and multiple oral doses of canagliflozin in adult patients with type 2 diabetes, dose-dependent decreases in RT G and increases in urinary glucose excretion were observed. From a starting RT G value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RT G 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 RT G 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 RT G led to increases in mean UGE of approximately 100 g/day in patients 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 RT G 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 patients, 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 adult 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.

12.3Pharmacokinetics 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 T max ) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma C max and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg.

The apparent terminal half-life (t 1/2 ) 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

83.5L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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 (RT G ), 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.

12.3Pharmacokinetics 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 T max ) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma C max and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg.

The apparent terminal half-life (t 1/2 ) 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

83.5L, 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 Pediatric Patients The pharmacokinetics and pharmacodynamics of canagliflozin were investigated in pediatric patients aged 10 years and older with type 2 diabetes mellitus. Oral administration of canagliflozin at 100 mg and 300 mg resulted in exposures and responses consistent with those found in adult patients. Patients with Renal Impairment A single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in adult subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.

Renal impairment did not affect the C max of canagliflozin. Compared to healthy adult subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m 2 ), 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 m 2 , 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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Following single and multiple oral doses of canagliflozin in adult patients with type 2 diabetes, dose-dependent decreases in RT G and increases in urinary glucose excretion were observed. From a starting RT G value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RT G 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 RT G 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 RT G led to increases in mean UGE of approximately 100 g/day in patients 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 RT G 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 patients, 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 adult 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.

14 CLINICAL STUDIES

14.1Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus INVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin HCl, sulfonylurea, metformin HCl and sulfonylurea, metformin HCl and sitagliptin, metformin HCl and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other anti-hyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin HCl and sulfonylurea, and a sulfonylurea (glimepiride), both as add-on combination therapy with metformin HCl.

INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment. Monotherapy A total of 584 adult patients with type 2 diabetes inadequately controlled on diet and exercise participated in a 26-week double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA. The mean age was 55 years, 44% of patients were male, and the mean baseline eGFR was 87 mL/min/1.73 m 2 .

Patients taking other antihyperglycemic agents (N=281) discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, placebo run-in period. Patients not taking oral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily for 26 weeks.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA 1C (p<0.001 for both doses) compared to placebo. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo (see Table 10 ). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 10: Results from 26-Week Placebo-Controlled Clinical Trial with INVOKANA as Monotherapy in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy Efficacy Parameter Placebo (N=192) INVOKANA 100 mg (N=195) INVOKANA 300 mg (N=197) HbA 1C (%) Baseline (mean) 7.97 8.06

8.01Change from baseline (adjusted mean) 0.14 -0.77 -1.03 Difference from placebo (adjusted mean) (95% CI) Least squares mean adjusted for baseline value and stratification factors -0.91 p<0.001 (-1.09; -0.73) -1.16 (-1.34; -0.99) Percent of Patients Achieving HbA 1C < 7% 21 45 62 Fasting Plasma Glucose (mg/dL) Baseline (mean) 166 172 173 Change from baseline (adjusted mean) 8 -27 -35 Difference from placebo (adjusted mean) (95% CI) -36 (-42; -29) -43 (-50; -37) 2-hour Postprandial Glucose (mg/dL) Baseline (mean) 229 250 254 Change from baseline (adjusted mean) 5 -43 -59 Difference from placebo (adjusted mean) (95% CI) -48 (-59.1; -37.0) -64 (-75.0; -52.9) Body Weight Baseline (mean) in kg 87.5 85.9 86.9 % change from baseline (adjusted mean) -0.6 -2.8 -3.9 Difference from placebo (adjusted mean) (95% CI) -2.2 (-2.9; -1.6) -3.3 (-4.0; -2.6) Add-on Combination Therapy with Metformin HCl A total of 1,284 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl.

The mean age was 55 years, 47% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m 2 . Patients already on the required metformin HCl dose (N=1,009) were randomized after… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity was evaluated 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 trial, LH did not increase in males treated with canagliflozin. Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed at 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 at 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 trials 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 sites, and smaller litter sizes) at the highest dosage administered.