Invokamet Xr Drug Information

Generic name: CANAGLIFLOZIN AND METFORMIN HYDROCHLORIDE

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Uses of Invokamet Xr

and INVOKAMET XR are a combination of canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. 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 in adults with type 2 diabetes mellitus and established cardiovascular disease. End-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria.

Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. INVOKAMET INVOKAMET is a combination of canagliflozin and metformin HCl immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. INVOKAMET XR INVOKAMET XR is a combination of canagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

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 .

Dosage & Administration of Invokamet Xr

Not treated with either canagliflozin or metformin HCl	Total daily dosage is canagliflozin 100 mg and metformin HCl 1,000 mg
Metformin HCl For patients taking an evening dosage of metformin HCl extended-release tablets, skip the last dose before starting INVOKAMET or INVOKAMET XR the following morning.	Total daily dosage is canagliflozin 100 mg and the nearest appropriate total daily dosage of metformin HCl
Canagliflozin	The same total daily dosage of canagliflozin and a total daily dosage of metformin HCl 1,000 mg
Canagliflozin and metformin HCl	The same total daily dosage of canagliflozin and the nearest appropriate total daily dosage of metformin HCl

Side Effects of Invokamet Xr

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. Canagliflozin has been evaluated in clinical trials in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Additionally, canagliflozin has been studied in clinical trials in adult patients with type 2 diabetes mellitus who also have heart failure or chronic kidney disease.

The overall safety profile of canagliflozin was consistent across the studied indications. Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Placebo-Controlled Trials for Glycemic Control Canagliflozin The data in Table 3 are derived from four 26-week placebo-controlled trials where canagliflozin was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 adult patients to canagliflozin and a mean duration of exposure to canagliflozin of 24 weeks with 1,275 patients exposed to a combination of canagliflozin and metformin HCl.

Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin HCl was 2,138 mg (SD 337.3) for the 1,275 patients in the three placebo-controlled metformin HCl add-on trials. The mean age of the population was 56 years and 2% were older than 75 years of age.

Fifty percent (50%) of the population was male and 72% were White, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA 1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m 2 ). Table 3 shows common adverse reactions associated with the use of canagliflozin.

These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg. Table 3: Adverse Reactions from Pool of Four 26−Week Placebo-Controlled Trials Reported in ≥ 2% of Canagliflozin-Treated Adult Patients The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin HCl, metformin HCl and sulfonylurea, or metformin HCl and pioglitazone. Adverse Reaction Placebo N=646 Canagliflozin 100 mg N=833 Canagliflozin 300 mg N=834 Note: Percentages were weighted by trials.

Trial weights were proportional to the harmonic mean of the three treatment sample sizes. Urinary tract infections Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. 3.8% 5.9% 4.4% Increased urination Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. 0.7% 5.1% 4.6% Thirst Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. 0.1% 2.8% 2.4% Constipation 0.9% 1.8% 2.4% Nausea 1.6% 2.1% 2.3% N=312 N=425 N=430 Female genital mycotic infections Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. 2.8% 10.6% 11.6% Vulvovaginal pruritus 0.0% 1.6% 3.2% N=334 N=408 N=404 Male genital mycotic infections Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. 0.7% 4.2% 3.8% Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Canagliflozin and Metformin HCl The incidence and type of adverse reactions in the three 26-week placebo-controlled metformin HCl tablets add-on trials in adults, representing a majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 3. There were no additional adverse reactions identified in the pooling of these three placebo-controlled trials that included metformin HCl tablets relative to the four placebo-controlled trials. In a trial in adults with canagliflozin as initial combination therapy with metformin HCl , an increased incidence of diarrhea was observed in the canagliflozin and metformin HCl combination groups (4.2%) compared to canagliflozin or metformin HCl monotherapy groups (1.7%). Placebo-Controlled Trial in Diabetic Nephropathy The occurrence of adverse reactions for canagliflozin was evaluated in patients participating in CREDENCE, a trial in adult patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day . These data reflect exposure of 2,201 adult patients to canagliflozin and a mean duration of exposure to canagliflozin of 137 weeks.

The rate of lower limb amputations associated with the use of canagliflozin 100 mg relative to placebo was 12.3 vs 11.2 events per 1,000 patient-years, respectively, with 2.6 years mean duration of follow-up. The incidence of hypotension was 2.8% and 1.5% on canagliflozin 100 mg and placebo, respectively. Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes The occurrence of adverse reactions for canagliflozin was evaluated in adult patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R. The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 adult patients to canagliflozin) were consistent with those listed in Table 3. Percentages were weighted by trials.

Trial weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) was 3.0%, 3.8%, and 4.2% of adult patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.

Five patients experienced serious adverse reactions of hypersensitivity with canagliflozin, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, 2 patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated.

Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Other adverse reactions occurring more frequently on canagliflozin than on comparator were: Lower Limb Amputation An increased risk of lower limb amputations associated with canagliflozin was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively . The amputation data for CANVAS and CANVAS-R are shown in Tables 4 and 5, respectively.

Table 4: Amputations in the CANVAS Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=1,441 Canagliflozin 100 mg N=1,445 Canagliflozin 300 mg N=1,441 Canagliflozin (Pooled) N=2,886 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

Patients with an amputation, n (%) 22 50 45 95 Total amputations 33 83 79 162 Amputation incidence rate (per 1,000 patient-years) 2.8 6.2 5.5

Hazard Ratio (95% CI) -- 2.24 2.01 2.12 Table 5: Amputations in

the CANVAS-R Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=2,903 Canagliflozin 100 mg (with up-titration to 300 mg) N=2,904 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation.

Patients with an amputation, n (%) 25 45 Total amputations 36 59 Amputation incidence rate (per 1,000 patient-years) 4.2

Hazard Ratio (95% CI) -- 1.80 Renal Cell Carcinoma

In the CANVAS trial in adults (mean duration of follow-up of 5.7 years) , the incidence of renal cell carcinoma was 0.15% (2/1,331) and 0.29% (8/2,716) for placebo and canagliflozin, respectively, excluding patients with less than 6 months of follow-up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to canagliflozin could not be established due to the limited number of cases. Volume Depletion-Related Adverse Reactions Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume.

In clinical trials for glycemic control, treatment with canagliflozin was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in adult patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ), and age 75 years and older (Table 6) . Table 6: Adult Patients with at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control) Baseline Characteristic Comparator Group Includes placebo and active-comparator groups % Canagliflozin 100 mg % Canagliflozin 300 mg % Overall population 1.5% 2.3% 3.4% 75 years of age and older Patients could have more than 1 of the listed risk factors 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m 2 2.5% 4.7% 8.1% Use of loop diuretic 4.7% 3.2% 8.8% Falls In a pool of nine clinical trials in adults with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment.

Genital Mycotic Infections In the pool of four placebo-controlled clinical trials in adults for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents.

In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively. In the pool of four placebo-controlled clinical trials in adults, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis.

Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo) and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively. In the pooled analysis of 8 randomized trials in adults evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis.

Hypoglycemia In canagliflozin glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control in adults , episodes of hypoglycemia occurred at a higher rate when canagliflozin was co-administered with insulin or sulfonylureas (Table 7). Table 7: Incidence of Hypoglycemia Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population in Randomized Clinical Trials of Glycemic Control in Adults Monotherapy (26 weeks) Placebo (N=192) Canagliflozin 100 mg (N=195) Canagliflozin 300 mg (N=197) Overall 5 7 6 In Combination with Metformin HCl (26 weeks) Placebo + Metformin HCl (N=183) Canagliflozin 100 mg + Metformin HCl (N=368) Canagliflozin 300 mg + Metformin HCl (N=367) Overall 3 16 17 Severe Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) 0 1 1 In Combination with Metformin HCl (18 weeks) Phase 2 clinical trial with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin HCl) Placebo (N=93) Canagliflozin 100 mg (N=93) Canagliflozin 300 mg (N=93) Overall 3 4 3 In Combination with Metformin HCl + Sulfonylurea (26 weeks) Placebo + Metformin HCl + Sulfonylurea (N=156) Canagliflozin 100 mg + Metformin HCl + Sulfonylurea (N=157) Canagliflozin 300 mg + Metformin HCl + Sulfonylurea (N=156) Overall 24 43 47 Severe 1 1 0 In Combination with Metformin HCl + Pioglitazone (26 weeks) Placebo + Metformin HCl + Pioglitazone (N=115) Canagliflozin 100 mg + Metformin HCl + Pioglitazone (N=113) Canagliflozin 300 mg + Metformin HCl + Pioglitazone (N=114) Overall 3 3 6 In Combination with Insulin (18 weeks) Placebo (N=565) Canagliflozin 100 mg (N=566) Canagliflozin 300 mg (N=587) Overall 208 279 285 Severe 14 10 16 In Combination with Insulin and Metformin HCl (18 weeks) Subgroup of patients (N=287) from insulin subtrial on canagliflozin in combination with metformin HCl and insulin (with or without other antiglycemic agents) Placebo (N=145) Canagliflozin 100 mg (N=139) Canagliflozin 300 mg (N=148) Overall 66 58 70 Severe 4 1 3 Bone Fracture In the CANVAS trial in adults , the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities.

Metformin HCl The most common adverse reactions (5% or greater incidence) due to initiation of metformin HCl in adults are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of adult patients. Laboratory and Imaging Tests Increases in Serum Creatinine and Decreases in eGFR Initiation of canagliflozin causes an increase in serum creatinine and decrease in estimated GFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes.

Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury . The acute effect on eGFR reverses after treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with canagliflozin. Increases in Serum Potassium In a pooled population of adult patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m 2 ), increases in serum potassium to greater than 5.4 mEq/L and 15% above occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with canagliflozin 100 mg, and 1.3% of patients treated with canagliflozin 300 mg.

In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers. In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed in adult patients treated with canagliflozin 100 mg relative to placebo.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C) In the pool of four glycemic control placebo-controlled trials in adults, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups.

Dose-related increases in non-HDL-C with canagliflozin were observed in adults. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.

Increases in Hemoglobin In the pool of four placebo-controlled trials in adults of glycemic control, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin above the upper limit of normal.

Decreases in Bone Mineral Density Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) . At 2 years, adult patients randomized to canagliflozin 100 mg and canagliflozin 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both canagliflozin doses and 0.4% at the distal forearm for patients randomized to canagliflozin 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to canagliflozin 100 mg was 0%. Clinical Trials in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Canagliflozin Canagliflozin was administered to 84 pediatric patients in a double-blind, placebo-controlled trial of 171 pediatric patients aged 10 to 17 years with a mean exposure to canagliflozin of 48.3 weeks . At baseline, background therapies included metformin monotherapy (46%), metformin and insulin (29%), diet and exercise only (14%), and insulin monotherapy (11%). Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% identified as Hispanic or Latino ethnicity.

The mean baseline eGFR was 157.3 mL/min/1.73 m 2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. The safety profile of pediatric patients treated with canagliflozin was similar to that observed in adults with type 2 diabetes mellitus. Metformin HCl In clinical trials with metformin HCl immediate-release tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.

Postmarketing Experience Additional adverse reactions have been identified during post-approval use of

canagliflozin and/or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Canagliflozin Metabolism and Nutrition Ketoacidosis Renal and Urinary Acute Kidney Injury Immune System Anaphylaxis Skin and Subcutaneous Tissue Angioedema Infections Urosepsis and Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's gangrene) Metformin HCl Hepatobiliary Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Warnings & Cautions for Invokamet Xr

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 or INVOKAMET XR. In INVOKAMET or 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 is dialyzable, with a clearance of up to 170 mL/min 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 or 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: 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. 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 . 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). 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.

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.

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, INVOKAMET or INVOKAMET XR significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of INVOKAMET or INVOKAMET XR. INVOKAMET or INVOKAMET XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis.

There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET or INVOKAMET XR. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected.

Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET or INVOKAMET XR ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis.

If ketoacidosis is suspected, discontinue INVOKAMET or INVOKAMET XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET or INVOKAMET XR. Withhold INVOKAMET or INVOKAMET XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKAMET or INVOKAMET XR and seek medical attention immediately if signs and symptoms occur.

Lower Limb Amputation

An increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET or INVOKAMET XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. 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 4 and 5, respectively . 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. Counsel patients about the importance of routine preventative foot care.

Monitor patients receiving INVOKAMET or INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET or INVOKAMET XR if these complications occur.

Volume Depletion Canagliflozin can cause intravascular volume contraction which may sometimes manifest

as symptomatic hypotension or acute transient changes in creatinine . There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET or INVOKAMET XR in patients with one or more of these characteristics, assess and correct volume status.

Monitor for signs and symptoms of volume depletion after initiating therapy.

Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving canagliflozin. Treatment with INVOKAMET or INVOKAMET XR increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated .

Hypoglycemia with

Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET or INVOKAMET XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Reports of necrotizing fasciitis of

the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with INVOKAMET or INVOKAMET XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET or INVOKAMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

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 . Monitor and treat appropriately.

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 or INVOKAMET XR; treat and monitor until signs and symptoms resolve . 5.10 Bone Fracture An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in adult patients using canagliflozin in the CANVAS trial . Consider factors that contribute to fracture risk prior to initiating INVOKAMET or INVOKAMET XR . 5.11 Vitamin B 12 Levels In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.

Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2- to 3-year intervals in patients on INVOKAMET or INVOKAMET XR and manage any abnormalities.

Drug Interactions with Invokamet Xr

Table 8: Clinically Significant Drug Interactions with INVOKAMET or INVOKAMET XR Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET or INVOKAMET XR may increase the risk for lactic acidosis.
Intervention: Consider more frequent monitoring of these patients.
Examples: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) Drugs That Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 / multidrug and toxin extrusion inhibitors could increase systemic exposure to metformin and may increase the risk for lactic acidosis.
Intervention: Consider the benefits and risks of concomitant use.
Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism.
Intervention: Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR.
UGT Enzyme Inducers Clinical Impact: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET or INVOKAMET XR.
Intervention: For patients with eGFR 60 mL/min/1.73 m 2 or greater, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET or INVOKAMET XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control. For patients with eGFR less than 60 mL/min/1.73 m 2, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg .
Examples: Rifampin, phenytoin, phenobarbital, ritonavir Insulin or Insulin Secretagogues Clinical Impact: The risk of hypoglycemia is increased when INVOKAMET or INVOKAMET XR is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention: Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
Intervention: When such drugs are administered to a patient receiving INVOKAMET or INVOKAMET XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET or INVOKAMET XR, monitor for hypoglycemia.
Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.
Digoxin Clinical Impact: Canagliflozin increases digoxin exposure .
Intervention: Monitor patients taking INVOKAMET or INVOKAMET XR with concomitant digoxin for a need to adjust the dosage of digoxin.
Lithium Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention: Monitor serum lithium concentration more frequently during INVOKAMET or INVOKAMET XR initiation and dosage changes. Drug/Laboratory Test Interference Positive Urine Glucose Test Clinical Impact: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests.
Intervention: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
Intervention: Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use See full prescribing information for additional drug interactions and information on interference of INVOKAMET and INVOKAMET XR with laboratory tests.

Pregnancy Safety for Invokamet Xr

Pregnancy 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.

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. 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 . 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 Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl was used during pregnancy.

However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Canagliflozin Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC. Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis.

This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively. Canagliflozin and Metformin HCl No adverse developmental effects were observed when canagliflozin and metformin HCl were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2,000 mg clinical doses of canagliflozin and metformin HCl based on AUC.

Pediatric Use of Invokamet Xr

Pediatric Use The safety and effectiveness of INVOKAMET and INVOKAMET XR as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of INVOKAMET and INVOKAMET XR for this indication is supported by evidence from a 52-week double-blind, placebo-controlled trial of canagliflozin in 171 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and in a pediatric pharmacokinetic study . The safety profile of pediatric patients treated with canagliflozin was similar to that observed in adults with type 2 diabetes mellitus. The use of INVOKAMET and INVOKAMET XR for this indication is also supported by evidence from adequate and well-controlled trials of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical trial using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, and pharmacokinetic data with metformin HCl extended-release tablets in adults.

In the clinical trial with pediatric patients receiving metformin HCl immediate-release tablets, adverse reactions with metformin HCl immediate-release tablets were similar to those described in adults. The safety and effectiveness of INVOKAMET or INVOKAMET XR for glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients under 10 years of age. The safety and effectiveness of INVOKAMET or INVOKAMET XR have not been established in pediatric patients to reduce the risk of: major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in patients 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 patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.

Contraindications for Invokamet Xr

or INVOKAMET XR is contraindicated in patients with: Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) . Acute or chronic metabolic acidosis, including diabetic ketoacidosis . Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema . Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) Metabolic acidosis, including diabetic ketoacidosis Serious hypersensitivity reaction to canagliflozin or metformin HCl

Overdosage Information for Invokamet Xr

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl use has been established. Lactic acidosis has been reported in approximately 32% of metformin HCl overdose cases . In the event of an overdose with INVOKAMET or INVOKAMET XR, contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

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.

Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom INVOKAMET or INVOKAMET XR overdosage is suspected.

Clinical Studies of Invokamet Xr

Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

The effectiveness of INVOKAMET and INVOKAMET XR have been established in clinical trials with canagliflozin in combination with metformin HCl alone, metformin HCl and sulfonylurea, metformin HCl and sitagliptin, metformin HCl and a thiazolidinedione (i.e., pioglitazone), and metformin HCl and insulin (with or without other anti-hyperglycemic agents). The efficacy of canagliflozin 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. 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 1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin HCl extended-release alone.

Table 13: Results from 26-Week Active-Controlled Clinical Trial of Canagliflozin Alone or Canagliflozin as Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus Intent-to-treat population Efficacy Parameter Metformin HCl extended-release (N=237) Canagliflozin 100 mg (N=237) Canagliflozin 300 mg (N=238) Canagliflozin 100 mg + Metformin HCl extended-release (N=237) Canagliflozin 300 mg + Metformin HCl extended-release (N=237) HbA 1C (%) Baseline (mean) 8.81 8.78 8.77 8.83 8.90 Change from baseline (adjusted mean) There were 121 patients without week 26 efficacy data. Analyses addressing missing data gave consistent results with the results provided in this table. -1.30 -1.37 -1.42 -1.77 -1.78 Difference from canagliflozin 100 mg (adjusted mean) (95% CI) Least squares mean adjusted for covariates including baseline value and stratification factor -0.40 Adjusted p=0.001 (-0.59, -0.21) Difference from canagliflozin 300 mg (adjusted mean) (95% CI) -0.36 (-0.56, -0.17) Difference from metformin HCl extended-release (adjusted mean) (95% CI) -0.46 (-0.66, -0.27) -0.48 (-0.67, -0.28) Percent of patients achieving HbA 1C < 7% 38 34 39 47 Adjusted p<0.05 51 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 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 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. Table 14: Results from 26-Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl 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 + Metformin HCl (N=183) Canagliflozin 100 mg + Metformin HCl (N=368) Canagliflozin 300 mg + Metformin HCl (N=367) HbA 1C (%) Baseline (mean) 7.96 7.94 7.95 Change from baseline (adjusted mean) -0.17 -0.79 -0.94 Difference from placebo (adjusted mean) (95% CI) Least squares mean adjusted for baseline value and stratification factors -0.62 p<0.001 (-0.76, -0.48) -0.77 (-0.91, -0.64) Percent of patients achieving HbA 1C < 7% 30 46 58 Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 173 Change from baseline (adjusted mean) 2 -27 -38 Difference from placebo (adjusted mean) (95% CI) -30 (-36, -24) -40 (-46, -34) 2-hour Postprandial Glucose (mg/dL) Baseline (mean) 249 258 262 Change from baseline (adjusted mean) -10 -48 -57 Difference from placebo (adjusted mean) (95% CI) -38 (-49, -27) -47 (-58, -36) Body Weight Baseline (mean) in kg 86.7 88.7 85.4 % change from baseline (adjusted mean) -1.2 -3.7 -

Difference from placebo (adjusted mean) (95% CI) -2.5 (-3.1, -1.9) -2.9 (-3.5

-2.3) 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 1C from baseline compared to glimepiride when added to metformin HCl therapy. Canagliflozin 300 mg provided a greater reduction from baseline in HbA 1C compared 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.

Table 15: Results from 52–Week Clinical Trial Comparing Canagliflozin to Glimepiride in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy Efficacy Parameter Canagliflozin 100 mg + Metformin HCl (N=483) Canagliflozin 300 mg + Metformin HCl (N=485) Glimepiride (titrated) + Metformin HCl (N=482) HbA 1C (%) Baseline (mean) 7.78 7.79 7.83 Change from baseline (adjusted mean) -0.82 -0.93 -0.81 Difference from glimepiride (adjusted mean) (95% CI) Least squares mean adjusted for baseline value and stratification factors -0.01 Canagliflozin + metformin HCl is considered non-inferior to glimepiride + metformin HCl because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. (-0.11, 0.09) -0.12 (-0.22, -0.02) Percent of patients achieving HbA 1C < 7% 54 60 56 Fasting Plasma Glucose (mg/dL) Baseline (mean) 165 164 166 Change from baseline (adjusted mean) -24 -28 -18 Difference from glimepiride (adjusted mean) (95% CI) -6 (-10, -2) -9 (-13, -5) Body Weight Baseline (mean) in kg 86.8 86.6 86.6 % change from baseline (adjusted mean) -4.2 -4.7

Difference from glimepiride (adjusted mean) (95% CI) -5.2 p<0.001 (-5.7, -4.7) -5.7

(-6.2, -5.1) Figure 1: Mean HbA 1C Change 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) Figure 1 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 2 and 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 2 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 HbA 1C (p<0.001) compared to placebo when added to metformin HCl and sitagliptin (see Table 16 ). Table 16: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Sitagliptin in Adults with Type 2 Diabetes Mellitus Efficacy Parameter Placebo + Metformin HCl and Sitagliptin (N=108 To preserve the integrity of randomization, all randomized patients were included in the analysis. The patient who was randomized once to each arm was analyzed on canagliflozin. ) Canagliflozin + Metformin HCl and Sitagliptin (N=109 ) HbA 1C (%) Baseline (mean) 8.40 8.50 Change from baseline (adjusted mean) -0.03 -0.83 Difference from placebo (adjusted mean) (95% CI) Early treatment discontinuation before week 26, occurred in 11.0% and 24.1% of canagliflozin and placebo patients, respectively. Estimated using a multiple imputation method modeling a "wash-out" of the treatment effect for patients having missing data who discontinued treatment.

Missing data was imputed only at week 26 and analyzed using ANCOVA. -0.81 p<0.001 (-1.11; -0.51) Percent of patients achieving HbA 1C < 7% Patients without week 26 efficacy data were considered as non-responders when estimating the proportion achieving HbA 1C< 7%. 9 28 Fasting Plasma Glucose (mg/dL) Estimated using a multiple imputation method modeling a "wash-out" of the treatment effect for patients having missing data who discontinued treatment. A mixed model for repeated measures was used to analyze the imputed data. Baseline (mean) 180 185 Change from baseline (adjusted mean) -3 -28 Difference from placebo (adjusted mean) (95% CI) -25 (-39; -11) 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 1C 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 HCl and sulfonylurea (see Table 17 ). Table 17: Results from 26–Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Sulfonylurea 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 + Metformin HCl and Sulfonylurea (N=156) Canagliflozin 100 mg + Metformin HCl and Sulfonylurea (N=157) Canagliflozin 300 mg + Metformin HCl and Sulfonylurea (N=156) HbA 1C (%) Baseline (mean) 8.12 8.13 8.13 Change from baseline (adjusted mean) -0.13 -0.85 -1.06 Difference from placebo (adjusted mean) (95% CI) Least squares mean adjusted for baseline value and stratification factors -0.71 p<0.001 (-0.90, -0.52) -0.92 (-1.11, -0.73) Percent of patients achieving HbA 1C < 7% 18 43 57 Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 173 168 Change from baseline (adjusted mean) 4 -18 -31 Difference from placebo (adjusted mean) (95% CI) -22 (-31, -13) -35 (-44, -25) Body Weight Baseline (mean) in kg 90.8 93.5 93.5 % change from baseline (adjusted mean) -0.7 -2.1 -

Difference from placebo (adjusted mean) (95% CI) -1.4 (-2.1, -0.7) -2.0 (-2.7

-1.3) 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 1C reduction 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.

Table 18: Results from 52−Week Clinical Trial Comparing Canagliflozin to Sitagliptin in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy Efficacy Parameter Canagliflozin 300 mg + Metformin HCl and Sulfonylurea (N=377) Sitagliptin 100 mg + Metformin HCl and Sulfonylurea (N=378) HbA 1C (%) Baseline (mean) 8.12 8.13 Change from baseline (adjusted mean) -1.03 -0.66 Difference from sitagliptin (adjusted mean) (95% CI) Least squares mean adjusted for baseline value and stratification factors -0.37 Canagliflozin + metformin HCl + sulfonylurea is considered non-inferior to sitagliptin + metformin HCl + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. (-0.50, -0.25) Percent of patients achieving HbA 1C < 7% 48 35 Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 164 Change from baseline (adjusted mean) -30 -6 Difference from sitagliptin (adjusted mean) (95% CI) -24 (-30, -18) Body Weight Baseline (mean) in kg 87.6 89.6 % change from baseline (adjusted mean) -2.5

Difference from sitagliptin (adjusted mean) (95% CI) -2.8 p<0.001 (-3.3, -2.2) Figure

2: Mean HbA 1C Change 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) Figure 2 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 1C less 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.

Table 19: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Pioglitazone 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 + Metformin HCl and Pioglitazone (N=115) Canagliflozin 100 mg + Metformin HCl and Pioglitazone (N=113) Canagliflozin 300 mg + Metformin HCl and Pioglitazone (N=114) HbA 1C (%) Baseline (mean) 8.00 7.99 7.84 Change from baseline (adjusted mean) -0.26 -0.89 -1.03 Difference from placebo (adjusted mean) (95% CI) Least squares mean adjusted for baseline value and stratification factors -0.62 p<0.001 (-0.81, -0.44) -0.76 (-0.95, -0.58) Percent of patients achieving HbA 1C < 7% 33 47 64 Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 164 Change from baseline (adjusted mean) 3 -27 -33 Difference from placebo (adjusted mean) (95% CI) -29 (-37, -22) -36 (-43, -28) Body Weight Baseline (mean) in kg 94.0 94.2 94.4 % change from baseline (adjusted mean) -0.1 -2.8 -

Difference from placebo (adjusted mean) (95% CI) -2.7 (-3.6, -1.8) -3.7 (-4.6

-2.8) 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.

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 . Table 20: Results from 18–Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Insulin ≥ 30 Units/Day 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 + Metformin HCl + Insulin (N=145) Canagliflozin 100 mg + Metformin HCl + Insulin (N=139) Canagliflozin 300 mg + Metformin HCl + Insulin (N=148) HbA 1C (%) Baseline (mean) 8.15 8.20 8.22 Change from baseline (adjusted mean) 0.03 -0.64 -0.79 Difference from placebo (adjusted mean) (95% CI) Least squares mean adjusted for baseline value and stratification factors -0.66 p≤0.001 (-0.81, -0.51) -0.82 (-0.96, -0.67) Percent of patients achieving HbA 1C < 7% 9 19 p≤0.01 29 Fasting Plasma Glucose (mg/dL) Baseline 163 168 167 Change from baseline (adjusted mean) 1 -16 -24 Difference from placebo (adjusted mean) (97.5% CI) -16 (-28, -5) -25 (-36, -14) Body Weight Baseline (mean) in kg 102.3 99.7 101.1 % change from baseline (adjusted mean) 0.0 -1.7 -

Difference from placebo (adjusted mean) (97.5% CI) -1.7 (-2.4, -1.0) -2.7 (-3.4

-2.0)

Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with

Type 2 Diabetes Mellitus 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 1C was ≥7.0% and eGFR ≥60 mL/min/1.73m 2 were 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 1C at 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 2 were 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 1C from 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.

Table 21: Results at Week 26 in a Placebo-Controlled Trial of Canagliflozin in Combination with Metformin HCl and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Modified intent-to-treat set (All randomized and treated patients with baseline HbA 1C measurement). Efficacy Parameter Placebo (N=87) Canagliflozin (N=84) HbA 1C (%) Baseline (mean) 8.3

Change from baseline Multiple imputation using retrieved dropout approach with 1,000 iterations

for missing data (canagliflozin N=7 (8.3%), placebo N=7 (8.1%) for HbA 1C and canagliflozin N=9 (10.7%), placebo N=7 (8.1%) for FPG). Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value, baseline age stratum (< 15 years vs 15 to < 18 years) and baseline antihyperglycemic agent (AHA) background (i.e., diet and exercise only, metformin monotherapy, insulin monotherapy, or combination of insulin and metformin). 0.34 -0.38 Difference from placebo 95% CI -0.73 (-1.26, -0.19) P-value=0.008 (two-sided) FPG (mg/dL) Baseline (mean) 156.5

Change from baseline 17.29 -8.22 Difference from placebo 95% CI -25.51 (-49.55

-1.47) Not evaluated for statistical significance, not part of sequential testing procedure. 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. Table 22: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl versus Placebo in Pediatric Patients Pediatric patients mean age 13.8 years (range 10–16 years) with Type 2 Diabetes Mellitus Metformin HCl Placebo p-value FPG Baseline Change at Final Visit (n=37) 162.4 -42.9 (n=36) 192.3 21.4 <0.001 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.

Canagliflozin Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic

Cardiovascular Disease Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD). The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double-blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population). The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigator's discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases. A total of 10,134 adult patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks (223 weeks in CANVAS and 94 weeks in CANVAS-R). Approximately 78% of the trial population was White, 13% was Asian, and 3% was Black or African American.

The mean age was 63 years and approximately 64% were male. The mean HbA 1C at baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported a past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m 2. At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin HCl (77%), insulin (50%), and sulfonylurea (43%). At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g.

At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti-thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial. For the primary analysis, a stratified Cox proportional hazards model was used to test for non-inferiority against a pre-specified risk margin of 1.3 for the hazard ratio of MACE. In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86. Refer to Table 23. Vital status was obtained for 99.6% of patients across the trials.

The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3. Table 23: Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the Integrated Analysis of CANVAS and CANVAS-R Trials in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Intent-To-Treat Analysis Set Placebo N=4,347 (%) Canagliflozin N=5,795 (%) Hazard ratio (95% CI) Stratified Cox-proportional hazards model with treatment as a factor and stratified by the trial and by prior CV disease Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) P-value for superiority (2-sided) = 0.0158, Number and percentage of first events, Due to pooling of unequal randomization ratios, Cochran-Mantel-Haenszel weights were applied to calculate percentages, 426 585 0.86 Non-fatal myocardial infarction, 159 215 0.85 Non-fatal Stroke, 116 158 0.90 Cardiovascular Death, 185 268 0.87 Figure 3: Time to First Occurrence of MACE Figure 3

Canagliflozin Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria

Canagliflozin is indicated to reduce the risk of 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 ˃ 300 mg/day. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) was a multinational, randomized, double-blind, placebo-controlled trial comparing canagliflozin with placebo in adult patients with type 2 diabetes mellitus, an eGFR ≥ 30 to < 90 mL/min/1.73 m 2 and albuminuria (urine albumin/creatinine ˃ 300 to ≤ 5,000 mg/g) who were receiving standard of care including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The primary objective of CREDENCE was to assess the efficacy of canagliflozin relative to placebo in reducing the composite endpoint of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or CV death. Patients were randomized to receive canagliflozin 100 mg (N=2,202) or placebo (N=2,199) and treatment was continued until the initiation of dialysis or renal transplantation.

The median follow-up duration for the 4,401 randomized subjects was 137 weeks. Vital status was obtained for 99.9% of subjects. The population was 67% White, 20% Asian, and 5% Black or African American; 32% were of Hispanic or Latino ethnicity.

The mean age was 63 years and 66% were male. At randomization, the mean HbA 1C was 8.3%, the median urine albumin/creatinine was 927 mg/g, the mean eGFR was 56.2 mL/min/1.73 m 2, 50% had prior CV disease, and 15% reported a history of heart failure. The most frequent antihyperglycemic agents (AHA) medications used at baseline were insulin (66%), biguanides (58%), and sulfonylureas (29%). Nearly all subjects (99.9%) were on ACEi or ARB at randomization, approximately 60% were taking an anti-thrombotic agent (including aspirin), and 69% were on a statin.

The primary composite endpoint in the CREDENCE trial was the time to first occurrence of ESKD (defined as an eGFR < 15 mL/min/1.73 m 2, initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death. Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint based on a time-to-event analysis (see Figure 4 ). The treatment effect reflected a reduction in progression to ESKD, doubling of serum creatinine and cardiovascular death as shown in Table 24 and Figure 4. There were few renal deaths during the trial. Canagliflozin 100 mg also significantly reduced the risk of hospitalization for heart failure.

Table 24: Analysis of Primary Endpoint (including the Individual Components) and Secondary Endpoints from the CREDENCE Trial in Adults with Diabetic Nephropathy and Albuminuria Placebo canagliflozin Endpoint N=2,199 (%) Event Rate Event rate per 100 patient-years. N=2,202 (%) Event Rate HR Hazard ratio (canagliflozin compared to placebo), 95% CI and p-value are estimated using a stratified Cox proportional hazards model including treatment as the explanatory variable and stratified by screening eGFR (≥ 30 to < 45, ≥ 45 to < 60, ≥ 60 to < 90 mL/min/1.73 m 2). HR is not presented for renal death due to the small number of events in each group. (95% CI) Intent-To-Treat Analysis Set (time to first occurrence) The individual components do not represent a breakdown of the composite outcomes, but rather the total number of subjects experiencing an event during the course of the trial. Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death) 340 6.1 245 4.3 0.70 P-value <0.0001 ESKD 165 2.9 116 2.0 0.68 Doubling of serum creatinine 188 3.4 118 2.1 0.60 Renal death 5 0.1 2

CV death 140 2.4 110 1.9 0.78 CV death or hospitalization for

heart failure 253 4.5 179 3.1 0.69 P-value <0.001 CV death, non-fatal myocardial infarction or non-fatal stroke 269 4.9 217 3.9 0.80 P-value <0.02 Non-fatal myocardial infarction 87 1.6 71 1.3 0.81 Non-fatal stroke 66 1.2 53 0.9 0.80 Hospitalization for heart failure 141 2.5 89 1.6 0.61 ESKD, doubling of serum creatinine or renal death 224 4.0 153 2.7 0.66 The Kaplan-Meier curve (Figure 4) shows time to first occurrence of the primary composite endpoint of ESKD, doubling of serum creatinine, renal death, or CV death. The curves begin to separate by Week 52 and continue to diverge thereafter. Figure 4: CREDENCE: Time to First Occurrence of the Primary Composite Endpoint Figure 4

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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