Invokamet

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL
  
  

  [see
  
  

  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 m²
    [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 m²; 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.

  ]
  
  

  .
  
  
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment
  
  

  [see
  
  

  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 m²
    [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 m²; 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.

  ]
  
  

  .
  
  
• Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information
  
  

  [see
  
  

  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 HClFor 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 m², 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 m2)]	Recommended Dosage of INVOKAMET or INVOKAMET XRFor 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)] .

  ,
  
  

  4 CONTRAINDICATIONS

  INVOKAMET or INVOKAMET XR is contraindicated in patients with:

  • Severe renal impairment (eGFR less than 30 mL/min/1.73 m²)
    [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 m²)
  • Metabolic acidosis, including diabetic ketoacidosis
  • Serious hypersensitivity reaction to canagliflozin or metformin HCl

  ,
  
  

  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 m²
    [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 m²; 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.

  ,
  
  

  7 DRUG INTERACTIONS

  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 m2or 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 m2, 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
  • 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.

  , and
  
  

  8.6 Renal Impairment

  Canagliflozin

  The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m²). These patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using canagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury

  [see Warnings and Precautions (5.4)]

  .

  Efficacy and safety trials with canagliflozin did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m²

  [see Clinical Pharmacology (12.3)]

  .

  Metformin HCl

  Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET or INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or in patients on dialysis

  [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

  ,
  
  

  8.7 Hepatic Impairment

  Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET or INVOKAMET XR is not recommended in patients with hepatic impairment

  [see Warnings and Precautions (5.1)].

  ]
  
  

  .
  
  
• If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended
  
  

  [see
  
  

  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 m²
    [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 m²; 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.

  ]
  
  

  .
  
  

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 INDICATIONS AND USAGE

  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 .

  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

  [see Warnings and Precautions (5.2)]

  .
  ).
  
• 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 INDICATIONS AND USAGE

  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 .

  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

  [see Warnings and Precautions (5.2)]

  .
  ).
  

Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus (

• Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating (
  
  
  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)]

  .
  ).
  
• Individualize starting dose based on the patient's current regimen and renal function. See
  
  

  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 HClFor 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

  in the full prescribing information for recommended starting dosages based on the current regimen (
  
  
  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 HClFor 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 m², 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 m2)]	Recommended Dosage of INVOKAMET or INVOKAMET XRFor 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)] .
  ).
  
• The maximum recommended total daily dosage is 300 mg of canagliflozin and 2,000 mg of metformin HCl (
  
  
  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 HClFor 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)].
  ).
  
• 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 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 m², 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 m2)]	Recommended Dosage of INVOKAMET or INVOKAMET XRFor 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)] .
  ).
  
• INVOKAMET: take one tablet orally twice daily with meals (
  
  
  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 HClFor 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)].
  ).
  
• INVOKAMET XR: take two tablets orally once daily with the morning meal. Swallow whole. Never crush, cut, or chew (
  
  
  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 HClFor 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)].
  ).
  
• 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 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 HClFor 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)].
  ).
  
• Dose adjustment for patients with renal impairment may be required (
  
  
  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 m², 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 m2)]	Recommended Dosage of INVOKAMET or INVOKAMET XRFor 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)] .
  ).
  
• See full prescribing information for INVOKAMET and INVOKAMET XR dosage modifications due to drug interactions (
  
  
  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 m²or 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 m², 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.
  ).
  
• May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (
  
  
  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 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart INVOKAMET or INVOKAMET XR if renal function is stable

  [see Warnings and Precautions (5.1)]

  .
  ).
  
• Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting (
  
  
  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 (canagliflozin and metformin HCl) tablets are available as follows:

INVOKAMET XR (canagliflozin and metformin HCl) extended-release tablets are available as follows:

• Pregnancy
  : Advise females of the potential risk to a fetus especially during the second and third trimesters (
  
  
  8.1 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

  [see Data].

  There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

  [see Clinical Considerations].

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

  [see Data]

  .

  The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA_1C>7 and has been reported to be as high as 20–25% in women with a HbA_1C>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

  Clinical Considerations

  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/m²) 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.
  )
  
• Lactation
  : Not recommended when breastfeeding (
  
  
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk

  [see Data]

  . However, there is insufficient information on the effects of metformin HCl on the breastfed infant and no available information on the effects of metformin HCl on milk production. Canagliflozin is present in the milk of lactating rats

  [see Data]

  . Since human kidney maturation occurs

  in utero

  and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

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

  Data

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

  Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
  )
  
• Females and Males of Reproductive Potential
  : Advise premenopausal females of the potential for an unintended pregnancy (
  
  
  8.3 Females and Males of Reproductive Potential

  Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
  )
  
• Geriatrics
  : Higher incidence of adverse reactions related to reduced intravascular volume. Assess renal function more frequently (
  
  
  8.5 Geriatric Use

  INVOKAMET and INVOKAMET XR

  Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET or INVOKAMET XR in the elderly and then adjust dose based on renal function

  [see Dosage and Administration (2.4)and Warnings and Precautions (5.1, 5.4)]

  .

  Canagliflozin

  In 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin HCl

  [see Clinical Studies (14.1)]

  . Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older

  [see Dosage and Administration (2.1)and Adverse Reactions (6.1)].

  Smaller reductions in HbA_1Cwith canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo).

  Metformin HCl

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

  [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)]

  .
  )
  
• Renal Impairment
  : Higher incidence of adverse reactions related to hypotension and renal function (
  
  
  8.6 Renal Impairment

  Canagliflozin

  The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m²). These patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using canagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury

  [see Warnings and Precautions (5.4)]

  .

  Efficacy and safety trials with canagliflozin did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m²

  [see Clinical Pharmacology (12.3)]

  .

  Metformin HCl

  Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET or INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or in patients on dialysis

  [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
  )
  
• Hepatic Impairment
  : Avoid use in patients with hepatic impairment (
  
  
  8.7 Hepatic Impairment

  Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET or INVOKAMET XR is not recommended in patients with hepatic impairment

  [see Warnings and Precautions (5.1)].
  )