Invokamet

Canagliflozin

Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

• Major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).
• End-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

Limitations of Use

INVOKAMET or INVOKAMET XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)] .

INVOKAMET and INVOKAMET XR

• INVOKAMET and INVOKAMET XR contain canagliflozin and metformin HCl. For the available strengths of the canagliflozin and metformin HCl components in INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3).
• Individualize the starting dosage of INVOKAMET or INVOKAMET XR based on the patient's current regimen as presented in Table 1 and based on renal function as presented in Table 2 [see Dosage and Administration (2.3] .

Recommended Dosage for Additional Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older

Risk Summary

Based on juvenile animal data showing adverse renal effects from canagliflozin, INVOKAMET or INVOKAMET XR is not recommended during the second and third trimesters of pregnancy.

Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5-times the 300 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin HCl was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data] .

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA 1C>7 and has been reported to be as high as 20–25% in women with a HbA 1C>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Data

Risk Summary

There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data] . However, there is insufficient information on the effects of metformin HCl on the breastfed infant and no available information on the effects of metformin HCl on milk production. Canagliflozin is present in the milk of lactating rats [see Data] . Since human kidney maturation occurs in uteroand during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKAMET or INVOKAMET XR is not recommended while breastfeeding.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants.

Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

INVOKAMET and INVOKAMET XR

Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET or INVOKAMET XR in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.4)and Warnings and Precautions (5.1, 5.4)] .

Canagliflozin

In 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin HCl [see Clinical Studies (14.1)] . Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1)and Adverse Reactions (6.1)]. Smaller reductions in HbA 1Cwith canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo).

Metformin HCl

Controlled clinical trials of metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin HCl should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)] .

Canagliflozin

The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m 2). These patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using canagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions (5.4)] .

Efficacy and safety trials with canagliflozin did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m 2[see Clinical Pharmacology (12.3)] .

Metformin HCl

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET or INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m 2) or in patients on dialysis [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Renal Impairment:The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)].

• Before initiating INVOKAMET or INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).
• INVOKAMET or INVOKAMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2[see Contraindications (4)] .
• Obtain an eGFR at least annually in all patients taking INVOKAMET or INVOKAMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions:The concomitant use of INVOKAMET or INVOKAMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast:Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET or INVOKAMET XR if renal function is stable.

Surgery and Other Procedures:Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.

INVOKAMET or INVOKAMET XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States:Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET or INVOKAMET XR.

Excessive Alcohol Intake:Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR.

Hepatic Impairment:Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of INVOKAMET or INVOKAMET XR in patients with clinical or laboratory evidence of hepatic disease.

Clinical Trials in Adults with Type 2 Diabetes Mellitus

Pool of Placebo-Controlled Trials for Glycemic Control

Laboratory and Imaging Tests

Clinical Trials in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus

Canagliflozin

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.

Metformin HCl

Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Canagliflozin

Following single and multiple oral doses of canagliflozin in adult patients with type 2 diabetes, dose-dependent decreases in RT Gand increases in urinary glucose excretion were observed. From a starting RT Gvalue of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RT Gthroughout 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 Gover 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 Gled 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. The 24-h mean RT Gat steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg. In patients with type 2 diabetes given 100 to 300 mg once daily over a 16-day dosing period, reductions in RT Gand 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.

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.

INVOKAMET

Administration of INVOKAMET 150 mg/1,000 mg fixed-dose combination with food resulted in no change in overall exposure of canagliflozin. There was no change in metformin AUC; however, the mean peak plasma concentration of metformin was decreased by 16% when administered with food. A delayed time to peak plasma concentration was observed for both components (a delay of 2 hours for canagliflozin and 1 hour for metformin) under fed conditions. These changes are not likely to be clinically meaningful.

INVOKAMET XR

After administration of INVOKAMET XR tablets with a high-fat breakfast, the peak (C max) and total (AUC) exposure of canagliflozin were not altered relative to dosing in the fasted state. However, the AUC of metformin increased by approximately 61% and C maxincreased by approximately 13%.

Absorption

Distribution

INVOKAMET and INVOKAMET XR

No animal studies have been conducted with the combined products in INVOKAMET or INVOKAMET XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on findings in studies with canagliflozin and metformin HCl individually.

Canagliflozin

Metformin HCl

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.

Fertility of male or female rats was unaffected by metformin HCl when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

Canagliflozin as Initial Combination Therapy with Metformin HCl Extended-Release

A total of 1,186 adult patients with type 2 diabetes inadequately controlled with diet and exercise participated in a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter trial to evaluate the efficacy and safety of initial therapy with canagliflozin in combination with metformin HCl extended-release. The median age was 56 years, 48% of patients were male, and the mean baseline eGFR was 87.6 mL/min/1.73 m 2. The median duration of diabetes was 1.6 years, and 72% of patients were treatment naïve. After completing a 2-week single-blind placebo run-in period, patients were randomly assigned for a double-blind treatment period of 26 weeks to 1 of 5 treatment groups (Table 13). The metformin HCl extended-release dose was initiated at 500 mg/day for the first week of treatment and then increased to 1,000 mg/day. Metformin HCl extended-release or matching placebo was up-titrated every 2–3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1,500 to 2,000 mg/day, as tolerated; about 90% of patients reached 2,000 mg/day.

At the end of treatment, canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin HCl extended-release resulted in a statistically significant greater improvement in HbA 1Ccompared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin HCl extended-release alone.

Canagliflozin as 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 canagliflozin 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 completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin HCl dose or patients on metformin HCl in combination with another antihyperglycemic agent (N=275) were switched to metformin HCl monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin HCl.

At the end of treatment, canagliflozin 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 when added to metformin HCl. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin HCl (see Table 14). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with canagliflozin 100 mg and 300 mg, respectively.

Canagliflozin Compared to Glimepiride, Both as Add-on Combination Therapy with Metformin HCl

A total of 1,450 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 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl.

The mean age was 56 years, 52% of patients were male, and the mean baseline eGFR was 90 mL/min/1.73 m 2. Patients tolerating maximally required metformin HCl dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin HCl monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride (titration allowed throughout the 52-week trial to 6 or 8 mg), administered once daily as add-on therapy to metformin HCl.

As shown in Table 15 and Figure 1, at the end of treatment, canagliflozin 100 mg provided similar reductions in HbA 1Cfrom baseline compared to glimepiride when added to metformin HCl therapy. Canagliflozin 300 mg provided a greater reduction from baseline in HbA 1Ccompared to glimepiride, and the relative treatment difference was -0.12% (95% CI: −0.22; −0.02). As shown in Table 15, treatment with canagliflozin 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.

Figure 1: Mean HbA 1CChange in Adults with Type 2 Diabetes Mellitus Treated with Canagliflozin or Glimepiride in Combination with Metformin HCl at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Canagliflozin as Add-on Combination Therapy with Metformin HCl and Sitagliptin

A total of 217 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 1,500 mg/day) and sitagliptin 100 mg/day (or equivalent fixed-dose combination) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and sitagliptin. The mean age was 57 years, 58% of patients were male, 73% of patients were White, 15% were Asian, and 12% were Black or African American. The mean baseline eGFR was 90 mL/min/1.73 m 2and the mean baseline BMI was 32 kg/m 2. The mean duration of diabetes was 10 years. Eligible patients entered a 2-week, single-blind, placebo run-in period and were subsequently randomized to canagliflozin 100 mg or placebo, administered once daily as add-on to metformin HCl and sitagliptin. Patients with a baseline eGFR of 70 mL/min/1.73 m 2or greater who were tolerating canagliflozin 100 mg and who required additional glycemic control (fasting finger stick 100 mg/dL or greater at least twice within 2 weeks) were up-titrated to canagliflozin 300 mg. While up-titration occurred as early as Week 4, most (90%) patients randomized to canagliflozin were up-titrated to canagliflozin 300 mg by 6 to 8 weeks.

At the end of 26 weeks, canagliflozin once daily resulted in a statistically significant improvement in HbA 1C(p<0.001) compared to placebo when added to metformin HCl and sitagliptin (see Table 16).

Canagliflozin as Add-on Combination Therapy with Metformin HCl and Sulfonylurea

A total of 469 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 51% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m 2. Patients already on the protocol-specified doses of metformin HCl and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo administered once daily as add-on to metformin HCl and sulfonylurea.

At the end of treatment, canagliflozin 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 when added to metformin HCl and sulfonylurea. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7.0%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and sulfonylurea (see Table 17).

Canagliflozin Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin HCl and Sulfonylurea

A total of 755 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52 week, double-blind, active-controlled trial to compare the efficacy and safety of canagliflozin 300 mg versus sitagliptin 100 mg in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 56% of patients were male, and the mean baseline eGFR was 88 mL/min/1.73 m 2. Patients already on protocol-specified doses of metformin HCl and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 300 mg or sitagliptin 100 mg as add-on to metformin HCl and sulfonylurea.

As shown in Table 18 and Figure 2, at the end of treatment, canagliflozin 300 mg provided greater HbA 1Creduction compared to sitagliptin 100 mg when added to metformin HCl and sulfonylurea (p<0.05). Canagliflozin 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with canagliflozin 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.

Figure 2: Mean HbA 1CChange in Adults with Type 2 Diabetes Mellitus Treated with Canagliflozin or Sitagliptin in Combination with Metformin HCl and Sulfonylurea at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Canagliflozin as Add-on Combination Therapy with Metformin HCl and Pioglitazone

A total of 342 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double--blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and pioglitazone. The mean age was 57 years, 63% of patients were male, and the mean baseline eGFR was 86 mL/min/1.73 m 2. Patients already on protocol-specified doses of metformin HCl and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin HCl and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and pioglitazone.

At the end of treatment, canagliflozin 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 when added to metformin HCl and pioglitazone. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and pioglitazone (see Table 19). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with canagliflozin 100 mg and 300 mg, respectively.

Canagliflozin as Add-on Combination Therapy with Insulin (With or Without Other Anti-Hyperglycemic Agents, Including Metformin HCl)

A total of 1,718 adult patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled subtrial of a cardiovascular trial to evaluate the efficacy and safety of canagliflozin in combination with insulin. Of these patients, a subgroup of 432 patients with inadequate glycemic control received canagliflozin or placebo plus metformin HCl and ≥ 30 units/day of insulin over 18 weeks.

In this subgroup, the mean age was 61 years, 67% of patients were male, and the mean baseline eGFR was 81 mL/min/1.73 m 2. Patients on metformin HCl in combination with basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 74% of these patients were on a background of metformin HCl and basal/bolus insulin regimen. After the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and insulin. The mean daily insulin dose at baseline was 93 units, which was similar across treatment groups.

At the end of treatment, canagliflozin 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 when added to metformin HCl and insulin. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 20). Statistically significant (p=0.023 for the 100 mg and p<0.001 for the 300 mg dose) mean change from baseline in systolic blood pressure relative to placebo was –3.5 mmHg and -6 mmHg with canagliflozin 100 mg and 300 mg, respectively. Fewer patients on canagliflozin in combination with metformin HCl and insulin required glycemic rescue therapy: 3.6% of patients receiving canagliflozin 100 mg, 2.7% of patients receiving canagliflozin 300 mg, and 6.2% of patients receiving placebo. An increased incidence of hypoglycemia was observed in this trial, which is consistent with the expected increase of hypoglycemia when an agent not associated with hypoglycemia is added to insulin [see Warnings and Precautions (5.6)and Adverse Reactions (6.1)] .

Glycemic Control Trial of Canagliflozin in Pediatric Patients Aged 10 years and Older with Type 2 Diabetes Mellitus

In a double-blind, placebo-controlled, parallel-group pediatric trial (NCT03170518), 171 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA 1C≥6.5% and ≤11.0%) were randomized to canagliflozin (84 patients) or placebo (87 patients) as add-on to diet and exercise, metformin HCl (≥1,000 mg per day or maximally tolerated dosage), insulin, or a combination of metformin HCl and insulin, for a total of 52-weeks. At Week 13, patients in the canagliflozin arm whose HbA 1Cwas ≥7.0% and eGFR ≥60 mL/min/1.73m 2were re-randomized to either continue on canagliflozin 100 mg orally once daily (n=16) or to up-titrate to 300 mg orally once daily (n=17).

At baseline, background therapies included diet and exercise only (14%), insulin monotherapy (11%), metformin HCl and insulin (29%), and metformin HCl monotherapy (46%). The mean HbA 1Cat baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2 years. The mean eGFR at baseline was 157.3 mL/min/1.73 m 2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. Patients with an eGFR less than 60 mL/min/1.73 m 2were not enrolled in the trial; no patients in the trial reached an eGFR < 60 mL/min/1.72m 2. The mean age was 14.3 years, 47% were under 15 years of age, and 68% were female. Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% were of Hispanic or Latino ethnicity. The mean BMI was 30.8 kg/m 2(range 18–57 kg/m 2) and the mean BMI Z-score was 1.84.

At Week 26, treatment with canagliflozin provided statistically significant improvement in HbA 1Cfrom baseline, compared with placebo (see Table 21).

The treatment effect with canagliflozin was consistent in the subgroup of patients with metformin with or without insulin as background therapy [adjusted mean change in HbA 1Crelative to placebo from baseline to Week 26 was –0.74% (95% CI -1.37, -0.11; p = 0.02)].

Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus

A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The results are displayed in Table 22.

Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively.