INVOKANA® mechanism of action


Glucose reabsorption

  • The kidneys reabsorb glucose via sodium-glucose co-transporters (SGLTs), primarily SGLT21-3

Reduced with INVOKANA®

  • INVOKANA® (canagliflozin) provides SGLT2 inhibition, reducing renal glucose reabsorption and increasing urinary glucose excretion2
  • INVOKANA® results in the excretion of approximately 80 grams to 120 grams of glucose per day4
  • INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

  • INVOKANA® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

  • INVOKAMET™ is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing metformin or canagliflozin, or in patients who are already treated with both canagliflozin and metformin.

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

  • Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

  • The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

  • Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

  • If lactic acidosis is suspected, INVOKAMET™ should be discontinued and the patient hospitalized immediately.

  • Renal impairment (ie, serum creatinine levels 1.5 mg/dL for males or 1.4 mg/dL for females, or eGFR is less than 45 mL/min/1.73m2), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; end stage renal disease (ESRD) or patients on dialysis

  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis

  • History of a serious hypersensitivity reaction to canagliflozin or metformin

  • Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with INVOKAMET™. When lactic acidosis occurs, it is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years (with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.


    Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. INVOKAMET™ treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, INVOKAMET™ should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.


    Because impaired hepatic function has been associated with some cases of lactic acidosis, INVOKAMET™ should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism.


    In addition, INVOKAMET™ should be temporarily discontinued prior to any intravascular radiocontrast study, withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been confirmed to be normal. For any surgical procedure necessitating restricted intake of food or fluids, INVOKAMET™ should be temporarily discontinued and not be initiated until the patient’s oral intake has resumed and renal function has been evaluated as normal.


    Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria or ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking INVOKAMET™, the drug should be discontinued immediately and general supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions), and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery.

  • Hypotension: Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET™, particularly in patients with an eGFR <60 mL/min/1.73 m2, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure. Before initiating INVOKAMET™ in patients with 1 of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.

  • Impairment in Renal Function: Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKAMET™.


    Before initiation of INVOKAMET™ therapy and at least annually thereafter, assess and verify normal renal function. In patients in whom development of renal impairment is anticipated (eg, elderly patients), assess renal function more frequently and discontinue INVOKAMET™ if evidence of renal impairment is present (ie, serum creatinine levels 1.5 mg/dL for males or 1.4 mg/dL for females, or eGFR is <45 mL/min/1.73m2).


    Use of Concomitant Medications That May Affect Renal Function or Metformin Disposition

    Monitor and adjust dose of INVOKAMET™ or concomitant drug in patients taking medication(s) that may affect renal function, result in a significant hemodynamic change, or interfere with the disposition of metformin.

  • Hyperkalemia: Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia.


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

  • Impaired Hepatic Function: Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis. Therefore, INVOKAMET™ is not recommended in patients with clinical or laboratory evidence of hepatic impairment.

  • Use With Medications Known to Cause Hypoglycemia


    Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET™.


    Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or when used concomitantly with other glucose-lowering agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Monitor for a need to lower the dose of INVOKAMET™ to minimize the risk of hypoglycemia in these patients.

  • Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections. Patients with a history of these infections and uncircumcised males were more likely to develop these infections. Monitor and treat appropriately.

  • Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET™; treat per standard of care and monitor until signs and symptoms resolve.

  • Vitamin B12 Levels: In clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measure hematologic parameters on an annual basis in patients on INVOKAMET™ and investigate and treat if abnormalities occur. Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to develop subnormal vitamin B12 levels.

  • Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET™.

  • Hypoxic States: Cardiovascular collapse (shock) from whatever cause (eg, acute congestive heart failure, acute myocardial infarction, or other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, promptly discontinue INVOKAMET™.

  • Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with canagliflozin. Monitor LDL-C and treat per standard of care after initiating INVOKAMET™.

  • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with canagliflozin or metformin or any other antidiabetic drug.

  • Drug Interactions With Metformin

    Cationic Drugs

    Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except with cimetidine), careful patient monitoring and dose adjustment of INVOKAMET™ and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.


    Carbonic Anhydrase Inhibitors

    Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.


    Drugs Affecting Glycemic Control

    Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET™, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET™, the patient should be observed closely for hypoglycemia.

  • Drug Interactions With Canagliflozin

    UGT Enzyme Inducers

    Rifampin: Rifampin lowered canagliflozin exposure, which may reduce the efficacy of INVOKAMET™. If an inducer of UGT enzymes must be coadministered with INVOKAMET™, consider increasing the dose to canagliflozin 150 mg twice daily if patients are currently tolerating INVOKAMET™ with 50 mg canagliflozin twice daily, have an eGFR 60 mL/min/1.73 m2, and require additional glycemic control.


    Canagliflozin increased digoxin exposure. Digoxin, as a cationic drug, also has the potential to compete with metformin for common renal tubular transport systems. Monitor patients taking INVOKAMET™ with concomitant digoxin for a need to adjust dose of either drug.

  • Drug/Laboratory Test Interference

    Positive Urine Glucose Test

    Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose test results. Use alternative methods to monitor glycemic control.

    Interference With 1,5-Anhydroglucitol (1,5-AG) Assay

    Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

  • Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women with INVOKAMET™ or its individual components. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters.

  • Nursing Mothers: No studies in lactating animals have been conducted with the combined components of INVOKAMET™. Because of the potential for serious adverse reactions in nursing infants, discontinue INVOKAMET™.

  • Pediatric Use: Safety and effectiveness of INVOKAMET™ in patients <18 years of age have not been established.

  • Geriatric Use: 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, frequently monitor renal function after initiating INVOKAMET™ in elderly patients and adjust dose based on renal function.


    2034 patients 65 years and 345 patients 75 years were exposed to canagliflozin in 9 clinical studies. Patients 65 years had a higher incidence of adverse reactions related to reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years. Smaller reductions in HbA1c relative to placebo were seen in patients 65 years (-0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg).


    Controlled clinical studies of metformin 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 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.

  • Renal Impairment: No dose adjustment of INVOKAMET™ is needed in patients with mild renal impairment or normal renal function (eGFR 60 mL/min/1.73 m2). INVOKAMET™ should not be used in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis.

  • In the event of an overdose with INVOKAMET™, contact the Poison Control Center. Employ the usual supportive measures (eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as needed.


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


    Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.

  • The most common (5%) adverse reactions with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.

  • The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.


Please see full Prescribing Information, including Boxed WARNING, and Medication Guide for INVOKAMET™.

Please see full Prescribing Information and Medication Guide for INVOKANA®.