INVOKAMET XR (canagliflozin 150 mg metformin hydrochloride 1000 mg) Dailymed

2 Dosage And Administration

• Individualize starting dose based on the patient's current regimen and renal function ( 2.2, 2.3, 2.4)
• 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 component ( 2.4)
• INVOKAMET: one tablet, twice daily with meals, recommended starting dose of canagliflozin is 50 mg twice daily and metformin HCl 500 mg twice daily ( 2.2)
• INVOKAMET XR: two tablets, once daily with the morning meal. Swallow whole. Never crush, cut, or chew ( 2.2)
• Canagliflozin dose can be increased to a total daily dose of 300 mg in patients tolerating 100 mg who have an eGFR of 60 mL/min/1.73 m ²or greater and require additional glycemic control. Do not exceed a total daily canagliflozin dose of 300 mg ( 2.2)
• Gradually escalate metformin HCl dose to reduce the gastrointestinal side effects while not exceeding a total daily dose of 2,000 mg ( 2.3)
• Assess renal function before initiating and as clinically indicated ( 2.1, 2.3)
• Dose adjustment for patients with renal impairment may be required ( 2.4)
• See full prescribing information for INVOKAMET and INVOKAMET XR dosage modifications due to drug interactions. ( 2.5)
• May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.6)
• Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting ( 2.7)

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 (2.4)and Warnings and Precautions (5.1, 5.4), Contraindications (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 Dosage Overview

INVOKAMET

Take one tablet of INVOKAMET orally twice daily with meals [see Dosage and Administration (2.3)] .

INVOKAMET XR

Take two tablets of INVOKAMET XR orally once daily with the morning meal [see Dosage and Administration (2.3)] . Swallow each tablet whole and never crush, cut, or chew.

2.3 Recommended Dosage and Administration

Individualize the starting dose of INVOKAMET or INVOKAMET XR based on the patient's current regimen and renal function [see Dosage and Administration (2.4)] . Table 1 presents the recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient's current regimen. For the available strengths of the canagliflozin and metformin components in INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3) .

Table 1: Recommended Starting Dosage Based on the Patient's Current Regimen

Current Regimen	INVOKAMET Recommended Dosage Administered as one tablet, orally, twice daily with meals	INVOKAMET XR Recommended Dosage Administered as two tablets, orally, once daily with the morning meal
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

INVOKAMET

Canagliflozin may be increased to the maximum recommended dosage of 150 mg twice daily in patients tolerating 50 mg twice daily and metformin may be increased to the maximum recommended dosage of 1,000 mg twice daily, with gradual escalation to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1)].

INVOKAMET XR

Canagliflozin may be increased to the maximum recommended dosage of 300 mg once daily in patients tolerating 100 mg once daily and metformin may be increased to the maximum recommended dosage of 2,000 mg once daily, with gradual escalation to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1)].

2.4 Recommended Dosage for Patients with Renal Impairment

• 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 component.
• Table 2 provides dosage recommendations for patients with renal impairment, based on eGFR [see Use in Specific Populations (8.6)and Clinical Studies (14.3)].

Table 2: Recommended Dosage in Patients with Renal Impairment

Estimated Glomerular Filtration Rate [eGFR (mL/min/1.73 m 2)]	Recommended Dosage
eGFR 45 to less than 60	The maximum recommended dosage of canagliflozin is 100 mg daily.
eGFR 30 to less than 45	Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR. The maximum recommended dosage of canagliflozin is 100 mg daily.
eGFR less than 30	Contraindicated. If eGFR falls below 30 during treatment; discontinue INVOKAMET or INVOKAMET XR [see Contraindications (4)] .

2.5 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 ²or 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 recommended dosage of canagliflozin is 300 mg daily.
• 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.

2.6 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)] .

2.7 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)].

• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INVOKAMET or INVOKAMET XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting ( 5.2)
• Lower Limb Amputation: Monitor patients for infection or ulcers of lower limb and discontinue if these occur ( 5.3)
• Volume Depletion: May result in acute kidney injury. Before initiating, assess and correct volume status in patients with renal impairment, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy ( 5.4)
• Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated ( 5.5)
• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Consider a lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia when used in combination ( 5.6)
• Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment ( 5.7)
• Genital Mycotic Infections: Monitor and treat if indicated ( 5.8)
• Hypersensitivity Reactions: Discontinue and monitor until signs and symptoms resolve ( 5.9)
• Bone Fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET or INVOKAMET XR ( 5.10)
• Vitamin B ₁₂Deficiency : Metformin HCl may lower vitamin B ₁₂levels. Measure hematological parameters annually and vitamin B ₁₂at 2- to 3-year intervals and manage any abnormalities ( 5.11)

5.1 Lactic Acidosis

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

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET 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 [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)].

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

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

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

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

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

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

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

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

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

5.2 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 [see Clinical Pharmacology (12.2)] ; 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 [see Dosage and Administration (2.7)] .

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.

5.3 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 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 [see Adverse Reactions (6.1)] .

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

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

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.

5.4 Volume Depletion

Canagliflozin can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)] . 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.

5.5 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 [see Adverse Reactions (6)] .

5.6 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 [see Adverse Reactions (6.1)] . 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.

5.7 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.

5.8 Genital Mycotic Infections

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

5.9 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 [see Contraindications (4)and Adverse Reactions (6.1, 6.2)] .

5.10 Bone Fracture

An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin in the CANVAS trial [see Clinical Studies (14.2)] . Consider factors that contribute to fracture risk prior to initiating INVOKAMET or INVOKAMET XR [see Adverse Reactions (6.1)] .

5.11 Vitamin B Levels

In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B ₁₂levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B ₁₂absorption 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 ₁₂supplementation. Certain individuals (those with inadequate vitamin B ₁₂or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B ₁₂levels. Measure hematologic parameters on an annual basis and vitamin B ₁₂at 2- to 3-year intervals in patients on INVOKAMET or INVOKAMET XR and manage any abnormalities [see Adverse Reactions (6.1)].

6 Adverse Reactions

The following important adverse reactions are also discussed elsewhere in the labeling:

• Lactic Acidosis [see Boxed Warningand 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 ₁₂Deficiency [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.

Pool of Placebo-Controlled Trials for Glycemic Control

Canagliflozin

The data in Table 3 is 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 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 _1Cof 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 Studies Reported in ≥ 2% of Canagliflozin-Treated 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 studies. Study 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, 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 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 study in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day [see Clinical Studies (14.3)] . These data reflect exposure of 2,201 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 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 patients to canagliflozin) were consistent with those uled in Table 3. Percentages were weighted by studies. Study 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 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 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 (14.2)] . The amputation data for CANVAS and CANVAS-R are shown in Tables 4 and 5, respectively .

Table 4: CANVAS Amputations

	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: CANVAS-R Amputations

	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 (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.2)] , 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 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 (8.5and 8.6)] .

Table 6: 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 uled 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 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 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, 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 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 [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 populationin Randomized Clinical Studies of Glycemic Control

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 study 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 substudy 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 [see Clinical Studies (14.2)] , 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 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 ₁₂levels was observed in approximately 7% of 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 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 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, 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. 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 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, 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%.

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

Ketoacidosis

Acute Kidney Injury

Anaphylaxis, Angioedema

Urosepsis and Pyelonephritis

Necrotizing Fasciitis of the Perineum (Fournier's gangrene)

Metformin HCl

Cholestatic, hepatocellular, and mixed hepatocellular liver injury