Limitations of Use

INVOKAMET XR is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

2.1 Recommended Dosage

• Individualize the starting dose of INVOKAMET XR (canagliflozin and metformin hydrochloride extended-release), taken once-daily with the morning meal, based on the effectiveness and tolerability of the patient's current regimen:

  –

  In patients currently not treated with either canagliflozin or metformin, initiate therapy with two INVOKAMET XR tablets, each tablet containing canagliflozin 50 mg and metformin 500 mg [see Clinical Studies (14.1)].

  –

  In patients on metformin, switch to two INVOKAMET XR tablets, where two tablets equal a starting dose of canagliflozin 100 mg daily and the patient's current total daily dose (or nearest appropriate) of metformin.

  –

  In patients on canagliflozin, switch to two INVOKAMET XR tablets, where two tablets equal the patient's current total daily dose of canagliflozin and a starting dose of metformin 1000 mg daily.

  –

  In patients already treated with canagliflozin and metformin, switch to two INVOKAMET XR tablets containing the same total daily dose of canagliflozin and the same, or nearest appropriate, total daily dose of metformin.

• In patients that require additional glycemic control that are taking a total daily dose of canagliflozin 100 mg, the INVOKAMET XR dose can be increased to canagliflozin 300 mg once daily [see Dosage Forms and Strengths (3) and Clinical Studies (14.1)].
• The dose of metformin should be gradually escalated to reduce the gastrointestinal side effects due to metformin [see Dosage Forms and Strengths (3) and Clinical Studies (14.1)].
• Patients taking an evening dose of metformin XR should skip their last dose before starting INVOKAMET XR the following morning.
• In patients with volume depletion not previously treated with canagliflozin, correct this condition before initiating INVOKAMET XR [see Warnings and Precautions (5.3), Use in Specific Populations (8.5, 8.6), and Patient Counseling Information (17)].
• Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of metformin 2000 mg and canagliflozin 300 mg in patients with an eGFR of 60 mL/min/1.73 m2 or greater [see Dosage and Administration (2.2)].

2.2 Recommended Dosage for Patients with Renal Impairment

• Assess renal function before initiating INVOKAMET XR and periodically thereafter.
• INVOKAMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.4)].
• Limit the dose of INVOKAMET XR to two tablets, each tablet containing canagliflozin 50 mg, in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.

2.3 Concomitant Use with UDP-Glucuronosyl Transferase (UGT) Enzyme Inducers

If an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET XR, consider increasing the dose of canagliflozin to a total daily dose of 300 mg once daily in patients currently tolerating INVOKAMET XR with 100 mg canagliflozin once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control [see Drug Interactions (7.2)].

Consider another antihyperglycemic agent in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer.

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1)].

2.5 Important Administration Instructions

• Take INVOKAMET XR tablets once daily with the morning meal.
• INVOKAMET XR must be swallowed whole and never crushed, cut, or chewed [see Patient Counseling Information (17)].

5.1 Lactic Acidosis

There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET XR. In INVOKAMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

5.2 Lower Limb Amputation

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. In CANVAS, canagliflozin-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, canagliflozin-treated patients and placebo-treated patients had 7.5 and 4.2 amputations per 1000 patients per year, respectively. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively [see Adverse Reactions (6.1)].

Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.

Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.

Before initiating INVOKAMET XR, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET XR if these complications occur.

5.3 Hypotension

Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET XR [see Adverse Reactions (6.1)] particularly in patients with eGFR less than 60 mL/min/1.73 m2, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKAMET XR in patients with one or more of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.

5.4 Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. INVOKAMET XR is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

Patients treated with INVOKAMET XR who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with INVOKAMET XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, INVOKAMET XR should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating INVOKAMET XR consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with INVOKAMET XR consider monitoring for ketoacidosis and temporarily discontinuing INVOKAMET XR in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

5.5 Acute Kidney Injury and Impairment in Renal Function

Canagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.3)] and can cause renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving canagliflozin; some reports involved patients younger than 65 years of age.

Before initiating INVOKAMET XR, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing INVOKAMET XR in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue INVOKAMET XR promptly and institute treatment.

Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKAMET XR [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of INVOKAMET XR and monitored periodically thereafter. Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR below 60 mL/min/1.73 m2. INVOKAMET XR is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

5.6 Hyperkalemia

Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk of developing hyperkalemia [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Monitor serum potassium levels periodically after initiating INVOKAMET XR in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

5.7 Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].

5.8 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin

5.9 Genital Mycotic Infections

Canagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.

5.10 Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of INVOKAMET XR; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1, 6.2)].

5.11 Bone Fracture

An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Consider factors that contribute to fracture risk prior to initiating INVOKAMET XR [see Adverse Reactions (6.1)].

5.12 Vitamin B12 Levels

In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decreases, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (less than 1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measure hematologic parameters on an annual basis in patients on INVOKAMET XR and investigate and treat if abnormalities occur. Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to developing subnormal vitamin B12 levels, and routine serum vitamin B12 measurement at 2- to 3-year intervals is recommended in these patients.

5.13 Increases in Low-Density Lipoprotein (LDL-C)

Dose-related increases in LDL-C occur with canagliflozin [see Adverse Reactions (6.1)]. Monitor LDL-C and treat if appropriate after initiating INVOKAMET XR.

5.14 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKAMET XR [see Adverse Reactions (6.1)].

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of canagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7.1 Drug Interactions with Metformin

7.2 Drug Interactions with Canagliflozin

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

8.4 Pediatric Use

Safety and effectiveness of INVOKAMET XR in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET XR is not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1)]

Canagliflozin

There were no reports of overdose during the clinical development program of canagliflozin.

Metformin

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)].

Canagliflozin

Canagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin 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 C24H25FO5S∙1/2 H2O and 453.53, respectively. The structural formula for canagliflozin is:

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

Metformin Hydrochloride

Metformin hydrochloride is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is chemically known as 1,1-Dimethylbiguanide hydrochloride and its molecular formula and weight are C4H11N5 ∙ HCl and 165.62, respectively. The structural formula for metformin hydrochloride is:

Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

INVOKAMET XR

INVOKAMET XR is supplied as film-coated tablets for oral administration. Each 50 mg/500 mg tablet and 50 mg/1,000 mg tablet contains 51 mg of canagliflozin equivalent to 50 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin hydrochloride. Each 150 mg/500 mg tablet and 150 mg/1,000 mg tablet contains 153 mg of canagliflozin equivalent to 150 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin hydrochloride.

System Components and Performance

INVOKAMET XR is an oral fixed-dose combination tablet of canagliflozin for immediate-release and metformin hydrochloride for extended-release. Each bilayer tablet is compressed from two separate granulates, one for each active ingredient of the tablet, and finished with a film-coating. The metformin HCl extended-release layer is based on a polymer matrix which controls the drug release by passive diffusion through the swollen matrix in combination with tablet erosion.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Drug-Drug Interactions

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Canagliflozin as Initial Combination Therapy with Metformin

A total of 1186 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 study to evaluate the efficacy and safety of initial therapy with canagliflozin in combination with metformin XR. The median age was 56 years, 48% of patients were men, and the mean baseline eGFR was 87.6 mL/min/1.73 m2. 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 11). The metformin XR dose was initiated at 500 mg/day for the first week of treatment and then increased to 1000 mg/day. Metformin XR or matching placebo was up-titrated every 2–3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1500 to 2000 mg/day, as tolerated; about 90% of patients reached 2000 mg/day.

At the end of treatment, canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin XR resulted in a statistically significant greater improvement in HbA1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin XR alone.

14.2 Canagliflozin as Add-on Combination Therapy with Metformin

A total of 1284 patients with type 2 diabetes inadequately controlled on metformin 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 study to evaluate the efficacy and safety of canagliflozin in combination with metformin. The mean age was 55 years, 47% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin dose (N=1009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin dose or patients on metformin in combination with another antihyperglycemic agent (N=275) were switched to metformin 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.

At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C 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 when added to metformin (see Table 12). 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.

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

A total of 1450 patients with type 2 diabetes inadequately controlled on metformin 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 study to evaluate the efficacy and safety of canagliflozin in combination with metformin.

The mean age was 56 years, 52% of patients were men, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin 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 study to 6 or 8 mg), administered once daily as add-on therapy to metformin.

As shown in Table 13 and Figure 1, at the end of treatment, canagliflozin 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin therapy. Canagliflozin 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: −0.22; −0.02). As shown in Table 13, treatment with canagliflozin 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.

Figure 1: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

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

A total of 217 patients with type 2 diabetes inadequately controlled on the combination of metformin (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 study to evaluate the efficacy and safety of canagliflozin in combination with metformin and sitagliptin. The mean age was 57 years, 58% of patients were men, 73% of patients were Caucasian, 15% were Asian, and 12% were Black or African-American. The mean baseline eGFR was 90 mL/min/1.73 m2 and the mean baseline BMI was 32 kg/m2. 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 and sitagliptin. Patients with a baseline eGFR of 70 mL/min/1.73 m2 or 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 HbA1C (p<0.001) compared to placebo when added to metformin and sitagliptin.

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

A total of 469 patients with type 2 diabetes inadequately controlled on the combination of metformin (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 study to evaluate the efficacy and safety of canagliflozin in combination with metformin and sulfonylurea. The mean age was 57 years, 51% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin 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 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 and sulfonylurea.

At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and sulfonylurea. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less 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 and sulfonylurea (see Table 15).

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

A total of 755 patients with type 2 diabetes inadequately controlled on the combination of metformin (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 study to compare the efficacy and safety of canagliflozin 300 mg versus sitagliptin 100 mg in combination with metformin and sulfonylurea. The mean age was 57 years, 56% of patients were men, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin 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 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 and sulfonylurea.

As shown in Table 16 and Figure 2, at the end of treatment, canagliflozin 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin 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 HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

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

A total of 342 patients with type 2 diabetes inadequately controlled on the combination of metformin (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 study to evaluate the efficacy and safety of canagliflozin in combination with metformin and pioglitazone. The mean age was 57 years, 63% of patients were men, and the mean baseline eGFR was 86 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin 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 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 and pioglitazone.

At the of end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and pioglitazone. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin and pioglitazone (see Table 17). 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.

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

A total of 1718 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 substudy of a cardiovascular study 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 and ≥ 30 units/day of insulin over 18 weeks.

In this subgroup, the mean age was 61 years, 67% of patients were men, and the mean baseline eGFR was 81 mL/min/1.73 m2. Patients on metformin 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 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 and insulin. The mean daily insulin dose at baseline was 93 units, which was similar across treatment groups.

At the of end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and insulin. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 18). 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 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 study, which is consistent with the expected increase of hypoglycemia when an agent not associated with hypoglycemia is added to insulin [see Warnings and Precautions (5.8) and Adverse Reactions (6.1)].

Storage and Handling

Keep out of reach of children.

Store at 68–77°F (20–25°C); excursions permitted between 59°F and 86°F (15°C and 30°C) [see USP Controlled Room Temperature]. Store and dispense in the original container. Storage in a pill box or pill organizer is allowed for up to 30 days.