INVOKAMET

INVOKAMET ® (canagliflozin and metformin HCl immediate-release tablets) and INVOKAMET ® XR (canagliflozin and metformin HCl extended-release tablets) contain canagliflozin and metformin HCl. Canagliflozin Canagliflozin is an inhibitor of SGLT2, the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin is chemically known as (1 S )-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C 24 H 25 FO 5 S•1/2 H 2 O and 453.53, respectively. The structural formula for canagliflozin is: Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9. Chemical Structure Metformin HCl Metformin HCl is a biguanide chemically known as 1,1-Dimethylbiguanide HCl and its molecular formula and weight are C 4 H 11 N 5 ● HCl and 165.62, respectively. The structural formula for metformin HCl is: Chemical Structure INVOKAMET and INVOKAMET XR INVOKAMET or INVOKAMET XR are 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 HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively). 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 HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively). INVOKAMET contains the following inactive ingredients: croscarmellose sodium (E468), hypromellose, magnesium stearate (E572), and microcrystalline cellulose (E460[i]). The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide yellow (E172) (50 mg/1,000 mg and 150 mg/500 mg tablets only), iron oxide red (E172) (50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg tablets only), and iron oxide black (E172) (150 mg/1,000 mg tablets only). INVOKAMET XR contains the following inactive ingredients: croscarmellose sodium (E468), hydroxypropyl cellulose (E463), hypromellose, lactose anhydrous, magnesium stearate (E572) (vegetable-sourced), microcrystalline cellulose (E460[i]), polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only). The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), and iron oxide black (E172) (50 mg/1,000 mg and 150 mg/1,000 mg tablets only). INVOKAMET XR tablets provide canagliflozin for immediate-release and metformin HCl 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.

INVOKAMET 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 ( 1 ). 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 ( 1 ). 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 ( 1 ). Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus ( 1 ). 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 [see Warnings and Precautions (5.2) ] .

Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating ( 2.1 ). Individualize starting dose based on the patient's current regimen and renal function. See Table 1 in the full prescribing information for recommended starting dosages based on the current regimen ( 2.2 , 2.3 ). The maximum recommended total daily dosage is 300 mg of canagliflozin and 2,000 mg of metformin HCl ( 2.2 ). Initiation of INVOKAMET or INVOKAMET XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component ( 2.3 ). INVOKAMET: take one tablet orally twice daily with meals ( 2.2 ). INVOKAMET XR: take two tablets orally once daily with the morning meal. Swallow whole. Never crush, cut, or chew ( 2.2 ). Gradually escalate the dosage of metformin HCl in INVOKAMET or INVOKAMET XR to reduce the risk of gastrointestinal adverse reactions with metformin HCl ( 2.2 ). Dose adjustment for patients with renal impairment may be required ( 2.3 ). See full prescribing information for INVOKAMET and INVOKAMET XR dosage modifications due to drug interactions ( 2.4 ). May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.5 ). Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting ( 2.6 ). 2.1 Prior to Initiation of INVOKAMET or INVOKAMET XR Assess renal function before initiating INVOKAMET or INVOKAMET XR and as clinically indicated [see Dosage and Administration (2.3) , Contraindications (4) , and Warnings and Precautions (5.1 , 5.4) ]. In patients with volume depletion, correct this condition before initiating INVOKAMET or INVOKAMET XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5 , 8.6) ] . 2.2 Recommended Dosage and Administration INVOKAMET and INVOKAMET XR INVOKAMET and INVOKAMET XR contain canagliflozin and metformin HCl. For the available strengths of the canagliflozin and metformin HCl components in INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3) . Individualize the starting dosage of INVOKAMET or INVOKAMET XR based on the patient's current regimen as presented in Table 1 and based on renal function as presented in Table 2 [see Dosage and Administration (2.3 ] . INVOKAMET Take one tablet of INVOKAMET orally twice daily with meals. INVOKAMET XR Take two tablets of INVOKAMET XR orally once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. Table 1 presents the recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient's current regimen. Table 1: Recommended Starting Dosage Based on the Current Regimen Current Regimen INVOKAMET Recommended Dosage INVOKAMET XR Recommended Dosage 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 Recommended Dosage for Additional Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older INVOKAMET The dosage of canagliflozin in INVOKAMET may be increased to the maximum total daily dosage of 300 mg (150 mg orally twice daily) in patients tolerating a dosage of 100 mg (50 mg twice daily) of canagliflozin. The dosage of metformin HCl in INVOKAMET may be increased to the maximum total daily dosage of 2,000 mg (1,000 mg orally twice daily), with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ]. INVOKAMET XR The dosage of canagliflozin in INVOKAMET XR may be increased to the maximum total daily dosage of 300 mg orally once daily in patients tolerating a 100 mg once daily dosage of canagliflozin. The dosage of metformin HCl in INVOKAMET XR may be increased to the maximum total daily dosage of 2,000 mg once daily, with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ]. 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Initiation of INVOKAMET or INVOKAMET XR is not recommended in adults or pediatric patients aged 10 years and older with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin component. Table 2 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on eGFR [see Use in Specific Populations (8.6) and Clinical Studies (14.4) ]. Table 2: Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Estimated Glomerular Filtration Rate [eGFR (mL/min/1.73 m 2 )] Recommended Dosage of INVOKAMET or INVOKAMET XR For the dosing frequency of INVOKAMET and INVOKAMET XR, see Dosage and Administration (2.2). eGFR 45 to less than 60 The maximum total daily dosage of canagliflozin is 100 mg. eGFR 30 to less than 45 Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR. The maximum total daily dosage of canagliflozin is 100 mg. eGFR less than 30 Contraindicated. If eGFR falls below 30 during treatment; discontinue INVOKAMET or INVOKAMET XR [see Contraindications (4) ] . 2.4 Concomitant Use with UDP-Glucuronosyltransferase (UGT) Enzyme Inducers When co-administering INVOKAMET or INVOKAMET XR with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the total daily dosage of canagliflozin based on renal function [see Drug Interactions (7) ] : In patients with eGFR 60 mL/min/1.73 m 2 or greater, increase the total daily dosage of canagliflozin to 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. The maximum total daily dosage of canagliflozin is 300 mg. In patients with eGFR less than 60 mL/min/1.73 m 2 , increase the total daily dosage of canagliflozin to a maximum of 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. 2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of less than 60 mL/min/1.73 m 2 ; 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 or INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1) ] . 2.6 Temporary Interruption for Surgery Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ].

INVOKAMET or INVOKAMET XR is contraindicated in patients with: Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ] . Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2) ] . Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema [see Warnings and Precautions (5.9) and Adverse Reactions (6) ] . Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 ) Serious hypersensitivity reaction to canagliflozin or metformin HCl ( 4 )

The following important adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1 , 5.4) ] Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.2) ] Lower Limb Amputation [see Warnings and Precautions (5.3) ] Volume Depletion [see Warnings and Precautions (5.4) ] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.6) ] Necrotizing Fasciitis of the Perineum (Fournier's gangrene) [see Warnings and Precautions (5.7) ] Genital Mycotic Infections [see Warnings and Precautions (5.8) ] Hypersensitivity Reactions [see Warnings and Precautions (5.9) ] Bone Fracture [see Warnings and Precautions (5.10) ] Vitamin B 12 Deficiency [see Warnings and Precautions (5.11) ] Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination ( 6.1 ). Most common adverse reactions associated with metformin HCl (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. 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 [see Clinical Studies (14.1) ] , 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 [see Clinical Studies (14.4) ] . 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 [see Clinical Studies (14.3) ] . 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 (1.5) 50 (3.5) 45 (3.1) 95 (3.3) Total amputations 33 83 79 162 Amputation incidence rate (per 1,000 patient-years) 2.8 6.2 5.5 5.9 Hazard Ratio (95% CI) -- 2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38) 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 (0.9) 45 (1.5) Total amputations 36 59 Amputation incidence rate (per 1,000 patient-years) 4.2 7.5 Hazard Ratio (95% CI) -- 1.80 (1.10, 2.93) Renal Cell Carcinoma In the CANVAS trial in adults (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.3) ] , 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) [see Use in Specific Populations (8.5 and 8.6) ] . 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 [see Clinical Studies (14.1) ] , 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 [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) 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 [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) Severe [N (%)] 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 (0) 1 (0.3) 1 (0.3) 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 [N (%)] 3 (3.2) 4 (4.3) 3 (3.2) 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 [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Severe [N (%)] 1 (0.6) 1 (0.6) 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 [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) In Combination with Insulin (18 weeks) Placebo (N=565) Canagliflozin 100 mg (N=566) Canagliflozin 300 mg (N=587) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)] 14 (2.5) 10 (1.8) 16 (2.7) 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 [N (%)] 66 (45.5) 58 (41.7) 70 (47.3) Severe [N (%)] 4 (2.8) 1 (0.7) 3 (2.0) Bone Fracture In the CANVAS trial in adults [see Clinical Studies (14.3) ] , 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 [see Clinical Pharmacology (12.1) ] . 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 [see Use in Specific Populations (8.6) ]. 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) [see Clinical Studies (14.1) ] . 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 [see Clinical Studies (14.2) ] . 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. 6.2 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

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 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ]. 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 [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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 ( 7 ) Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use ( 7 ) See full prescribing information for additional drug interactions and information on interference of INVOKAMET and INVOKAMET XR with laboratory tests. ( 7 )

Storage and Handling Keep out of reach of children. Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30°C (59 °F to 86 °F) [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.