AHFS Class:

• Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors 68:20.18

Generic Name(s):

• Canagliflozin

• Canagliflozin and Metformin Hydrochloride

Chemical Name:

• (1 S )-1,5-Anhydro-1- C -[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol hydrate (2:1)

Molecular Formula:

• C₂₄H₂₅FO^₅S•½H₂O

Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an antidiabetic agent.1,15

Type 2 Diabetes Mellitus

Canagliflozin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,2,11 In addition, canagliflozin is used to reduce the risk of major cardiovascular events (e.g., cardiovascular death, nonfatal myocardial infarction [MI], nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease.1 In addition, canagliflozin is used to reduce the risk of end-stage renal disease (ESRD), doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria (exceeding 300 mg/day).1,86,87

Canagliflozin is commercially available in fixed combination with immediate- or extended-release metformin hydrochloride (Invokamet^® or Invokamet^® XR); the fixed combination is used when treatment with both drugs is appropriate.63 Canagliflozin also is used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [thiazolidinedione]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.1,3,4,5,6,7,10

Glycemic Control

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients,698 some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, SGLT2 inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another agent) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic classes with complementary mechanisms of action.698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,704,705,706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure should receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.704,705 (See Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Liraglutide 68:20.06 and also see Reduction in Risk of Heart Failure-Related Hospitalization under Uses: Type 2 Diabetes Mellitus, in Dapagliflozin 68:20.18.) Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' HbA_1c.704 GLP-1 receptor agonists and SGLT2 inhibitors appear to have effects on the kidneys independent of their glycemic effects, and some experts suggest that an agent from one of these classes of drugs be considered in patients with type 2 diabetes mellitus and chronic kidney disease (CKD). 698,704,706 (See Beneficial Effects on Renal Function and Cardiovascular Morbidity and Mortality in Diabetic Nephropathy under Uses: Type 2 Diabetes Mellitus.) In patients without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, sulfonylurea, basal insulin) to metformin therapy should be based on avoidance of adverse effects, cost, and individual patient factors.704

The manufacturer states that canagliflozin should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1,63

Canagliflozin Monotherapy

When given as monotherapy for the management of type 2 diabetes mellitus, canagliflozin improves glycemic control compared with placebo as evidenced by reductions in glycosylated hemoglobin HbA_1c and in fasting and 2-hour postprandial plasma glucose concentrations.1,2,11 Efficacy of canagliflozin as monotherapy for the management of type 2 diabetes mellitus has been established in a double-blind, placebo-controlled study of 26 weeks' duration.1,2 Canagliflozin (100 or 300 mg once daily) improved glycemic control as evidenced by reductions in HbA_1c and fasting and 2-hour postprandial plasma glucose concentrations.1,2 HbA_1c was reduced by 0.77 or 1% in patients receiving canagliflozin 100 or 300 mg once daily, respectively, compared with an increase of 0.1% in those receiving placebo.1,2 Patients receiving canagliflozin 100 or 300 mg once daily also lost substantially more body weight (2.8 or 3.9%, respectively) than those receiving placebo (0.6%).1,2

Combination Therapy

When given in combination with one or more oral antidiabetic agents or insulin, canagliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight.1,3,4,5,6,7,10 Canagliflozin generally is well tolerated, although genital mycotic infections appear to be more common with canagliflozin than with other antidiabetic agents.1,2,3,6,7,8,9 (See Genital Mycotic Infections under Cautions: Warnings/Precautions.)

Efficacy of canagliflozin in combination with metformin, a sulfonylurea, and/or a thiazolidinedione for the management of type 2 diabetes mellitus (in patients inadequately controlled with metformin, a sulfonylurea, and/or a thiazolidinedione monotherapy) is supported by results from several long-term, randomized, active- or placebo-controlled trials.1,3,4,5,6,7,16 In these trials, the addition of canagliflozin (100 or 300 mg once daily) to existing therapy improved glycemic control as evidenced by reductions in HbA_1c, fasting plasma glucose, 2-hour postprandial plasma glucose concentrations, and/or body weight compared with placebo.1,3,4,5,6,7 In a 26-week study in patients receiving metformin hydrochloride therapy (dosage of at least 1.5 g daily), the addition of canagliflozin resulted in a reduction of 0.8-0.9% in HbA_1c, while HbA_1c was increased by 0.1% with add-on placebo.1 In a 52-week study in patients receiving metformin hydrochloride therapy (dosage of at least 1.5 g daily), canagliflozin 100 mg once daily was noninferior to glimepiride (titrated to 6 or 8 mg once daily), and canagliflozin 300 mg once daily was superior to glimepiride, in reducing HbA_1c; patients achieved reductions of 0.8, 0.9, or 0.8% in HbA_1c with canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride, respectively.1,3 In an 18-week trial in patients receiving a sulfonylurea (generally glimepiride, glyburide [glibenclamide], or gliclazide [not commercially available in the US]), add-on therapy with canagliflozin 100 or 300 mg once daily resulted in a reduction in HbA_1c of 0.74 or 0.83%, respectively, compared with placebo.1,4

Efficacy and safety of the combination of canagliflozin and metformin as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise is supported by results of a 26-week, randomized, double-blind trial.1,44 In this trial, concurrent therapy with canagliflozin (100 or 300 mg once daily) and metformin hydrochloride extended-release (dosage of at least 1.5 g daily; 90% of patients achieved a dosage of 2 g daily) substantially improved glycemic control (as evidenced by reductions in HbA_1c) compared with canagliflozin or metformin hydrochloride monotherapy.1,44 Reductions in HbA_1c were 1.77 or 1.78% with canagliflozin 100 or 300 mg once daily, respectively, plus metformin hydrochloride; 1.37 or 1.42% with canagliflozin 100 or 300 mg once daily, respectively; and 1.3% with metformin hydrochloride monotherapy.1,44 Additionally, a greater percentage of patients achieved an HbA_1c of less than 7% with canagliflozin and metformin combination therapy compared with canagliflozin or metformin hydrochloride monotherapy.1,44

In a 26-week trial in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily) and a sulfonylurea (sulfonylurea not specified), addition of canagliflozin 100 or 300 mg once daily resulted in a reduction in HbA_1c of 0.85 or 1.06%, respectively, compared with a 0.13% reduction in HbA_1c with placebo.1,5 In a 52-week study in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily) and a sulfonylurea (generally glipizide, glyburide [glibenclamide], or gliclazide [not commercially available in the US]), addition of canagliflozin 300 mg or sitagliptin 100 mg resulted in a reduction in HbA_1c of 1 or 0.6%, respectively.1,6 Canagliflozin was noninferior to sitagliptin and demonstrated superiority to sitagliptin in reducing HbA_1c in subsequent analyses.6 In a 26-week trial in patients inadequately controlled on metformin hydrochloride (dosage of at least 1.5 g daily) and sitagliptin (100 mg daily),54 the addition of canagliflozin (100 mg daily titrated to 300 mg daily) resulted in a substantial reduction in HbA_1c from baseline at 26 weeks compared with the addition of placebo (reduction of 0.83 versus 0.03%, respectively).1

In a 26-week trial in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily) and pioglitazone (30 or 45 mg daily), addition of canagliflozin 100 or 300 mg once daily or placebo resulted in a reduction in HbA_1c of approximately 0.9, 1, or 0.3%, respectively.1,7

Efficacy of canagliflozin in combination with insulin in the management of type 2 diabetes mellitus in patients who have inadequate glycemic control with insulin is supported by results of an 18-week, randomized, placebo-controlled trial.1 In this trial, addition of canagliflozin (100 or 300 mg daily) to existing insulin therapy resulted in improvements in HbA_1c, fasting plasma glucose, and body weight.1 In patients who received canagliflozin 100 or 300 mg as add-on therapy to insulin, 20 or 25%, respectively, had HbA_1c reductions to less than 7%, compared with 8% of patients receiving add-on placebo.1

Reduction in Risk of Major Adverse Cardiovascular Events

Canagliflozin is used to reduce the risk of major cardiovascular events (e.g., cardiovascular death, nonfatal myocardial infarction [MI], nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease.1,704,705 In addition to lowering blood glucose, SGLT2 inhibitors appear to modify several nonglycemic cardiovascular risk factors such as blood pressure, body weight, adiposity, and arterial stiffness.84,85 While canagliflozin reduces the risk of adverse cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and increased cardiovascular risk, such therapy is associated with an increased risk of lower extremity amputations.1,82,83 The Canagliflozin Cardiovascular Assessment Studies (CANVAS and CANVAS-R) were designed to assess the cardiovascular safety and efficacy of canagliflozin in patients with type 2 diabetes mellitus.1,82,83 In CANVAS and CANVAS-R, adults (mean age: 63.3 years) with type 2 diabetes mellitus and established cardiovascular disease (i.e., secondary prevention treatment group) or at high risk for cardiovascular disease (i.e., primary prevention treatment group [at least 50 years of age with at least 2 risk factors for cardiovascular disease]) received canagliflozin (100 or 300 mg) once daily or placebo for a mean of 149 weeks.1,82,83 During the studies, antidiabetic and cardiovascular therapies were modified to achieve standard-of-care treatment targets with respect to blood glucose, lipids, and blood pressure.1 Concomitant use of other standard-of-care treatments for diabetes mellitus and atherosclerotic cardiovascular disease (renin-angiotensin system inhibitors [80%], β-blockers [53%], loop diuretics [36%], statins [75%], antiplatelet agents [74%]) was permitted.1 The primary outcome was the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.1,82,83 In these studies, patients who received treatment with canagliflozin had substantially lower rates of the primary cardiovascular outcome compared with those who received placebo (event rate 9.2 versus 10.4%).1 However, canagliflozin therapy was associated with a twofold increase in the risk of lower limb amputations in these studies.1,82,83

Beneficial Effects on Renal Function and Cardiovascular Morbidity and Mortality in Diabetic Nephropathy

Canagliflozin is used to reduce the risk of ESRD, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria exceeding 300 mg/day.1,82,84,86,87,706 SGLT2 inhibitors such as canagliflozin reduce renal tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, and albuminuria and slow glomerular filtration rate (GFR) loss through mechanisms that appear to be independent of glucose-lowering effects.706 Some experts state that use of an SGLT2 inhibitor should be considered to reduce the risk of CKD progression, cardiovascular events, or both in patients with type 2 diabetes mellitus and diabetic kidney disease with albuminuria (an eGFR of at least 30 mL/minute per 1.73 m² and urinary albumin exceeding 30 mg/g creatinine, particularly urinary albumin exceeding 300 mg/g creatinine).706

The effects of canagliflozin on renal outcomes have been evaluated in a randomized, double-blind, placebo-controlled study (CREDENCE) in approximately 4400 patients with type 2 diabetes mellitus, CKD (eGFR 30-89 mL/minute per 1.73 m²; mean: 56.2 mL/minute per 1.73 m²), and albuminuria (urine albumin:creatinine ratio exceeding 300 but less than 5000 mg/g) .1,86,87 In this study, patients received canagliflozin 100 mg orally or placebo once daily in conjunction with the standard of care for glycemic control.1,86,87 Patients also had to have been receiving a stable dosage of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor antagonist for at least 4 weeks prior to randomization.86 The primary outcome was the composite of ESRD, doubling of serum creatinine concentrations from baseline, or death from renal or cardiovascular disease.1,86 The study was stopped early after a planned interim analysis (median follow-up: 2.6 years) at which the relative risk of the primary outcomes was found to be 30% lower in the canagliflozin group than in the placebo group.1,86 Additionally, treatment with canagliflozin reduced the relative risk of hospitalization for heart failure by 39%.1 These outcomes were observed despite very small differences in blood glucose control, weight, and blood pressure between the canagliflozin and placebo groups.86 These findings suggest that the beneficial renal effects of SGLT2 inhibitors may be independent of glucose homeostasis and may be related to other mechanisms, such as a reduction in intraglomerular pressure.86,88

In several cardiovascular outcomes trials involving the use of SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus at high risk for cardiovascular disease or with existing cardiovascular disease, beneficial effects on renal function have been observed as a secondary outcome.84,706 In the CANVAS trials (see Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus), canagliflozin therapy was associated with a 27% reduction in the risk of progression of albuminuria; in addition, regression of albuminuria occurred more frequently among those receiving canagliflozin versus placebo.82 The composite outcome of a sustained 40% reduction in eGFR, the need for renal replacement therapy, or death from renal causes also occurred less frequently among those receiving canagliflozin compared with placebo.82

Administration

Canagliflozin should be administered orally once daily, before the first meal of the day.1 The fixed combination of canagliflozin and immediate-release metformin hydrochloride should be administered twice daily with meals.63 The fixed combination of canagliflozin and extended-release metformin hydrochloride should be administered once daily with the morning meal; the tablet should be swallowed whole and should not be crushed, chewed, or cut.63

If a dose is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.1,63 If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.1,63

Dosage

Dosage of canagliflozin is expressed in terms of anhydrous canagliflozin.1

Type 2 Diabetes Mellitus

Patients with volume depletion should have this condition corrected before initiation of canagliflozin therapy.1

Canagliflozin Monotherapy

The recommended initial dosage of canagliflozin in patients with type 2 diabetes mellitus and an estimated glomerular filtration rate (eGFR) of at least 60 mL/minute per 1.73 m² is 100 mg once daily, taken before the first meal of the day.1 If this initial dosage is well tolerated and additional glycemic control is needed in such patients, the dosage may be increased to 300 mg once daily.1

In patients with an eGFR of at least 60 mL/minute per 1.73 m² who are receiving concurrent therapy with a uridine diphosphate-glucuronosyltransferase (UGT) enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir), the dosage of canagliflozin should be increased to 200 mg once daily in patients who are tolerating a dosage of 100 mg once daily.1 The dosage of canagliflozin may be increased to 300 mg once daily in patients who require additional glycemic control and who are tolerating a dosage of 200 mg once daily.1 (See Drug Interactions: Uridine Diphosphate-glucuronosyltransferase Enzyme Inducers.)

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Dosage of canagliflozin in fixed combination with metformin hydrochloride should be individualized based on the patient's current antidiabetic regimen.63 In patients with an eGFR of at least 60 mL/minute per 1.73 m², the dosage of the fixed-combination preparation may be increased gradually based on effectiveness and tolerability up to a maximum of 300 mg of canagliflozin and 2 g of metformin hydrochloride daily.63

In patients not currently receiving treatment with either canagliflozin or metformin hydrochloride, the recommended initial dosage of the fixed combination of canagliflozin and immediate-release metformin hydrochloride (Invokamet^®) is 50 mg of canagliflozin and 500 mg of metformin hydrochloride twice daily; the recommended initial dosage of the fixed combination of canagliflozin and extended-release metformin hydrochloride (Invokamet^® XR) is 100 mg of canagliflozin and 1 g of metformin hydrochloride once daily.63

In patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is 100 mg of canagliflozin and a metformin hydrochloride dosage similar to the patient's existing total daily dosage, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).63 Patients who are currently receiving an evening dose of extended-release metformin hydrochloride should skip their last dose prior to initiating therapy with the fixed combination of canagliflozin and metformin hydrochloride the following morning.63

In patients currently receiving canagliflozin, the recommended initial total daily dosage of the fixed combination is the same daily dosage of canagliflozin and 1 g of metformin hydrochloride, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).63

In patients currently receiving both canagliflozin and metformin hydrochloride as separate components, the recommended initial total daily dosage of the fixed combination is the same daily dosage of canagliflozin and a metformin hydrochloride dosage similar to the patient's existing total daily dosage, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).63

In patients currently receiving both canagliflozin and metformin hydrochloride who have an eGFR of at least 60 mL/minute per 1.73 m² and who are receiving concurrent therapy with a UGT enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir), the total daily dosage of canagliflozin should be increased to 200 mg in patients who are tolerating a canagliflozin dosage of 100 mg daily.63 The total daily dosage of canagliflozin may be increased to a maximum of 300 mg in patients who are tolerating a daily canagliflozin dosage of 200 mg and require additional glycemic control.63 (See Drug Interactions: Uridine Diphosphate-glucuronosyltransferase Enzyme Inducers.)

Special Populations

Hepatic Impairment

Canagliflozin Monotherapy

No dosage adjustment is necessary in patients with mild or moderate hepatic impairment.1 Data are lacking on use of canagliflozin in patients with severe hepatic impairment, and the manufacturer states that use in such patients is not recommended.1

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Use of the fixed-combination preparations of canagliflozin and metformin hydrochloride is not recommended in patients with hepatic impairment.63

Renal Impairment

Canagliflozin Monotherapy

No dosage adjustment is necessary in patients with mild renal impairment (eGFR of at least 60 mL/minute per 1.73 m²).1 In patients with moderate renal impairment (eGFR of 45 to less than 60 mL/minute per 1.73 m²), the dosage of canagliflozin should not exceed 100 mg daily.1 The manufacturer states there are insufficient data to support dosage recommendations for the initiation of canagliflozin therapy in patients who have (1) an eGFR of less than 30 mL/minute per 1.73 m² with albuminuria exceeding 300 mg/day or (2) an eGFR of 30 to less than 45 mL/minute per 1.73 m² with albuminuria of 300 mg/day or less.1 In patients already receiving canagliflozin therapy who have a reduction in eGFR to less than 30 mL/minute per 1.73 m² and who have albuminuria exceeding 300 mg/day, canagliflozin therapy can be continued at a dosage of 100 mg once daily.1 Canagliflozin use is contraindicated in patients with severe renal impairment (an eGFR less than 30 mL/minute per 1.73 m²) when used for glycemic control.1 Canagliflozin also is contraindicated in patients with end-stage renal disease (ESRD) on dialysis.1

In patients with an eGFR of less than 60 mL/minute per 1.73 m² who are receiving concomitant therapy with a UGT enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir), the total daily dosage of canagliflozin may be increased to 200 mg in patients who are tolerating a dosage of 100 mg daily.1 In patients who require additional glycemic control, addition of another antihyperglycemic agent should be considered.1 (See Drug Interactions: Uridine Diphosphate-glucuronosyltransferase Enzyme Inducers.)

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

In patients with moderate renal impairment (eGFR 45 to less than 60 mL/minute per 1.73 m²), the dosage of the canagliflozin component should not exceed 100 mg daily.63 In patients with an eGFR of 30 to less than 45 mL/minute per 1.73 m² and albuminuria exceeding 300 mg/day, the benefits and risks of continuing canagliflozin and metformin hydrochloride should be considered;, additionally, the dosage of canagliflozin in these patients should be limited to 100 mg daily.63 Use of the fixed-combination preparation of canagliflozin and metformin hydrochloride is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m² and in patients on dialysis.63

In patients with an eGFR of less than 60 mL/minute per 1.73 m² who are receiving concurrent therapy with a UGT enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir), the total daily dosage of canagliflozin should be increased to a maximum of 200 mg in patients who are tolerating a dosage of 100 mg daily.63 (See Drug Interactions: Uridine Diphosphate-glucuronosyltransferase Enzyme Inducers.)

Geriatric Patients

Canagliflozin Monotherapy

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Renal function should be monitored frequently after initiating the fixed-combination preparation; the dosage should be adjusted according to the patient's renal function.63 (See Renal Impairment under Dosage and Administration: Special Populations.)

Contraindications

History of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) to canagliflozin.1,63

Severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute per 1.73 m²) in patients who are being treated for glycemic control or on dialysis.1,63

Warnings/Precautions

Warnings

Lower Limb Amputation

In 2 randomized, placebo-controlled studies (Canagliflozin Cardiovascular Assessment Study [CANVAS] and CANVAS-R) evaluating the effects of canagliflozin on the risk of cardiovascular disease and the overall safety and tolerability of the drug, canagliflozin-treated patients had a twofold increased risk of lower limb (leg and foot) amputations (mostly affecting the toes and midfoot) compared with placebo.1,52,53,55,56 In the CANVAS study, canagliflozin- or placebo-treated patients had 5.9 or 2.8 amputations per 1000 patients per year, respectively; the amputation rate in the CANVAS-R trial was 7.5 or 4.2 per 1000 patients per year with canagliflozin or placebo, respectively.1,55 Amputations below and above the knee also occurred, and some patients had more than one amputation (some involving both lower limbs).1,55 The increased risk of lower limb amputation was observed with both the 100- and 300-mg daily dosage regimens.1,55 Patients with a baseline history of prior amputation, peripheral vascular disease, or neuropathy were at greatest risk for amputation.1,55,56 The most common precipitating medical events leading to an amputation were lower limb infections, gangrene, diabetic foot ulcers, and ischemia.1,55

Prior to initiating therapy with canagliflozin, clinicians should consider patient factors that may predispose them to the need for amputation, such as a history of amputation, peripheral vascular disease, neuropathy, or diabetic foot ulcers.1,55 Clinicians should monitor patients receiving canagliflozin for the presence of infection (including osteomyelitis), new pain or tenderness, and sores or ulcers involving the lower limbs; canagliflozin should be discontinued if such complications occur.1,55 Patients should also be counseled on the importance of routine preventative foot care.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., generalized urticaria), some serious, have been reported with canagliflozin treatment.1 These reactions generally occurred within hours to days of canagliflozin initiation.1 If a hypersensitivity reaction occurs, the drug should be discontinued, appropriate treatment instituted, and the patient monitored until signs and symptoms resolve.1

Other Warnings/Precautions

Use of Fixed Combinations

When canagliflozin is used in fixed combination with other drugs (e.g., metformin), the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) must be considered in addition to those associated with canagliflozin.1,63

Ketoacidosis

Use of sodium glucose cotransporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus may lead to ketoacidosis requiring hospitalization.1,39,40,41,42,50 Ketoacidosis associated with use of SGLT2 inhibitors may be present without markedly elevated blood glucose concentrations (e.g., less than 250 mg/dL).1,39,40,41,42,50

FDA identified 73 cases of acidosis (reported as diabetic ketoacidosis [DKA], ketoacidosis, or ketosis) associated with SGLT2 inhibitor use in the FDA Adverse Event Reporting System (FAERS) between March 2013 and May 2015. 41,50 DKA had an atypical presentation in most of the reported cases in that type 2 diabetes mellitus was noted as the indication for the drug, and glucose concentrations were only slightly elevated (median: 211 mg/dL); type 1 diabetes mellitus was named as the indication in a few cases, and in some reports the indication was not specified.39,40,50 The median time to onset of symptoms of acidosis following initiation or increase in dosage of the SGLT2 inhibitor was 43 days (range: 1-365 days).50 No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified.50 In all reported episodes, a diagnosis of DKA or ketoacidosis was made by the clinician and hospitalization or treatment in an emergency department was warranted.39,50 In most cases, at least 1 diagnostic laboratory criterion suggestive of ketoacidosis (e.g., high anion gap metabolic acidosis, ketonemia, reduced serum bicarbonate) was reported.50 Most cases of ketoacidosis were associated with a concurrent event, most commonly dehydration, infection, or change in insulin dosage.50 Potential factors for development of ketoacidosis with SGLT2 inhibitor therapy identified in the 73 cases included infection, low carbohydrate diet or reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes mellitus, history of pancreatitis, pancreatic surgery), reduced dosage or discontinuance of insulin, discontinuance of an oral insulin secretagogue, and alcohol use.1,50

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to ketoacidosis, such as pancreatic insulin deficiency from any cause, reduced caloric intake, and alcohol abuse.1,50

Clinicians should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis while receiving SGLT2 inhibitors, regardless of the patient's blood glucose concentration.39,40,50 For patients who are to undergo scheduled surgery, discontinuation of canagliflozin at least 3 days prior to surgery should be considered.1 Clinicians should consider monitoring for ketoacidosis and temporarily discontinuing therapy with an SGLT2 inhibitor in other clinical situations known to predispose individuals to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery).1,50 If acidosis is confirmed, the SGLT2 inhibitor should be discontinued and appropriate treatment initiated to correct the acidosis; glucose concentrations should be monitored appropriately.39,40 In addition, supportive medical treatment should be instituted to treat and correct factors that may have precipitated or contributed to the metabolic acidosis.39 Risk factors for ketoacidosis should be resolved prior to restarting canagliflozin.1

Euglycemic DKA associated with SGLT2 inhibitors may be detected and potentially prevented by having patients monitor urine and/or plasma ketone levels if they feel unwell, regardless of ambient glucose concentrations.1,40,42,50 Clinicians should inform patients and caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and instruct patients to discontinue the SGLT2 inhibitor and immediately seek medical attention should they experience such signs or symptoms.1,39,42,50

Hypotension

Canagliflozin may cause intravascular volume contraction.1 Following initiation of canagliflozin, symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR less than 60 mL/minute per 1.73 m²), geriatric patients, patients receiving diuretics or drugs that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists), or patients with low systolic blood pressure.1 (See Drug Interactions: Drugs Affecting the Renin-Angiotensin System, and also see Drug Interactions: Diuretics.) Prior to initiating canagliflozin in such patients, intravascular volume should be assessed and corrected.1 Patients should be monitored for signs and symptoms of hypotension after initiating canagliflozin therapy.1

Renal Effects

Canagliflozin causes intravascular volume contraction and can cause acute kidney injury.1,51 Initiation of canagliflozin may cause an increase in serum creatinine and decrease in eGFR.1 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.1 Increases in serum creatinine that do not fit this pattern should be evaluated to exclude the possibility of acute kidney injury.1 Renal function should be evaluated prior to initiation of canagliflozin and monitored periodically thereafter.1 If acute kidney injury occurs during canagliflozin therapy, the drug should be discontinued and appropriate treatment initiated.1,51

FDA identified 101 cases of acute kidney injury associated with canagliflozin or dapagliflozin therapy in FAERS between March 2013 and October 2015.51 Hospitalization for evaluation and management of kidney injury was warranted in most cases, and some cases required admission to an intensive care unit and initiation of dialysis.1,51 In approximately half of the cases, onset of acute kidney injury occurred within 1 month or less of initiating canagliflozin or dapagliflozin therapy, and most patients' kidney function improved after stopping the drug.51 However, kidney injury may not be fully reversible in some situations and has led to death in some patients.51

Prior to initiating canagliflozin therapy, clinicians should consider patient factors that may predispose the patient to acute kidney injury, including hypovolemia, chronic renal insufficiency, heart failure, and concomitant drug therapy (e.g., diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]).1,51 Clinicians should consider temporarily discontinuing canagliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure).1,51

Concomitant Therapy with Hypoglycemic Agents

When canagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the risk of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1 Therefore, patients receiving canagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1 (See Drug Interactions: Antidiabetic Agents.)

Fournier Gangrene

Fournier gangrene (necrotizing fasciitis of the perineum), a rare but serious or life-threatening bacterial infection requiring urgent surgical intervention, has been reported during postmarketing surveillance in men and women with type 2 diabetes mellitus receiving an SGLT2 inhibitor, including canagliflozin.1,60 Permanent disfigurement, prolonged hospitalization, disability, and complications from sepsis all may be associated with Fournier gangrene.59 Although diabetes mellitus is a risk factor for developing Fournier gangrene, this condition is still rare among patients with diabetes mellitus.60

FDA identified 12 cases of Fournier gangrene in patients taking an SGLT2 inhibitor reported in FAERS and the medical literature between March 2013 and May 2018.60,61,62 Since FDA's review, additional cases of Fournier gangrene have been reported.59 In the initial cases reviewed by FDA, the average time to onset of infection was 9.2 months (range 7 days to 25 months) after initiation of therapy with an SGLT2 inhibitor.60 Some experts speculate that the variation in time to diagnosis of Fournier gangrene might be due to fluctuating glycemic control, microvascular complications, or an inciting event associated with SGLT2 inhibitors (e.g., urinary tract infection, mycotic infection, skin or mucosal breakdown due to pruritus).59 In all reported cases, hospitalization and surgery were required.60 Among these cases, some patients required multiple disfiguring surgeries, some developed complications (e.g., diabetic ketoacidosis, acute kidney injury, septic shock), and 1 patient died.60 In a review of other antidiabetic drugs (e.g., insulin, biguanides, sulfonylureas, dipeptidyl peptidase-4 inhibitors) over a period of more than 30 years, only 6 cases of Fournier gangrene were identified; all of theses cases occurred in men.60

Patients receiving canagliflozin who develop pain or tenderness, erythema, or swelling in the genital or perineal area, in addition to fever or malaise, should be assessed for necrotizing fasciitis.1,60 If Fournier gangrene is suspected, canagliflozin should be discontinued and treatment should be initiated with broad-spectrum antibiotics; surgical debridement should be performed if necessary.1,60 Blood glucose concentrations should be closely monitored; alternative antidiabetic agents should be initiated to maintain glycemic control.1,60

Genital Mycotic Infections

Canagliflozin may increase the risk of genital mycotic infections in males (e.g., balanoposthitis, candidal balanitis) and females (e.g., vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis).1 In clinical trials, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop such infections.1 Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.1

Urosepsis and Pyelonephritis

Treatment with an SGLT2 inhibitor (e.g., canagliflozin) increases the risk for serious urinary tract infections.1

Cases of serious urinary tract infections, including urosepsis and pyelonephritis, have been reported in patients receiving an SGLT2 inhibitor.1,50 FDA identified 19 cases of urosepsis and pyelonephritis, which began as urinary tract infections associated with SGLT2 inhibitor use, in FAERS between March 2013 and October 2014.50 In all cases reported, hospitalization was warranted and some patients required admission to an intensive care unit or dialysis for treatment.50 The median time to onset of infection following initiation of the SGLT2 inhibitor was 45 days (range: 2-270 days).50

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose them to serious urinary tract infections, such as a history of difficulty urinating or infections of the bladder, kidneys, or urinary tract.50 Patients should be monitored for urinary tract infections and treatment instituted if indicated.1,50

Risk of Bone Fracture

In the CANVAS study, an increased risk of bone fracture was observed in patients receiving canagliflozin 100 or 300 mg once daily.1 Fractures were observed as early as 12 weeks after initiation of treatment and were more likely to affect the distal portion of upper and lower extremities and be associated with minor trauma (e.g., falls from no greater than standing height).1 Dose-related decreases in bone mineral density (e.g., hip and lumbar spine) also have been observed in older adults (mean age: 64 years) receiving canagliflozin therapy over a period of 2 years.1,43 Clinicians should consider factors that contribute to fracture risk and counsel patients about such factors prior to initiating canagliflozin therapy.1,43 (See Advice to Patients.)

Laboratory Test Interferences

SGLT2 inhibitors such as canagliflozin increase urinary glucose excretion and will result in false-positive urine glucose tests.1 Data from healthy individuals receiving a single 300-mg dose of canagliflozin indicate that the elevation in urinary glucose excretion approaches baseline after approximately 3 days.1 In addition, the manufacturer states that the 1,5-anhydroglucitol assay is unreliable for monitoring glycemic control in patients taking SGLT2 inhibitors.1 Alternative methods of monitoring glycemic control should be used in patients receiving SGLT2 inhibitors.1

Specific Populations

Pregnancy

Based on the results of reproductive and developmental toxicity studies in animals, canagliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy.1 Limited data with canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage, and poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus; however, canagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.1

Lactation

Canagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions in nursing infants from canagliflozin, use of the drug is not recommended while breastfeeding.1

Pediatric Use

Safety and efficacy of canagliflozin have not been established in pediatric patients younger than 18 years of age.1

Geriatric Use

Among patients in 13 clinical trials, 2294 were 65 years of age or older and 351 were 75 years of age or older, including one trial in patients 55 to 80 years of age.1,8 Geriatric patients experienced reduced efficacy of canagliflozin compared with younger patients, which may be related to decreased renal function in geriatric patients.1,8 Geriatric patients also were more likely to experience certain adverse effects related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration) with canagliflozin, particularly those receiving 300 mg daily.1,8

Hepatic Impairment

Compared with values in individuals with normal hepatic function, canagliflozin area under the concentration-time curve (AUC) and peak plasma concentrations were increased by 10 and 7%, respectively (based on geometric mean ratios), in patients with mild hepatic impairment (Child-Pugh class A) following a single 300-mg dose of the drug; canagliflozin AUC was increased by 11% and peak plasma concentration was decreased by 4% in patients with moderate hepatic impairment (Child-Pugh class B).1 These differences were not considered clinically important.1

Data are lacking on the use of canagliflozin in patients with severe hepatic impairment (Child-Pugh class C), and such use is not recommended.1

Renal Impairment

Safety and efficacy of canagliflozin for glycemic control were evaluated in a study that included 269 patients with moderate renal impairment (eGFR 30 to less than 50 mL/minute per 1.73 m²) and type 2 diabetes mellitus.1,9 These patients experienced less overall improvement in glycemic control and had higher rates of adverse effects related to reduced intravascular volume, renal-related adverse effects, and decreases in eGFR compared with those who had mild renal impairment or normal renal function.1,9 Patients receiving canagliflozin 300 mg were more likely to experience increases in serum potassium concentrations.1

Renal impairment did not affect peak plasma concentrations of canagliflozin.1 In patients with mild (eGFR 60 to less than 90 mL/minute per 1.73 m²), moderate (eGFR 30 to less than 60 mL/minute per 1.73 m²), or severe renal impairment (eGFR less than 30 mL/minute per 1.73 m²), canagliflozin AUC was increased by 15, 29, or 53%, respectively, compared with that in healthy individuals following a single 200-mg dose of the drug.1

Renal function should be assessed prior to initiation of therapy and periodically thereafter.1 Reduction of canagliflozin dosage is required for patients with an eGFR less than 60 mL/minute per 1.73 m².1 (See Renal Impairment under Dosage and Administration: Special Populations.)

The fixed combination of canagliflozin and metformin is contraindicated in patients with eGFR less than 30 mL/minute per 1.73 ².63

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving canagliflozin in clinical trials and more frequently than with placebo include female genital mycotic infections,1 urinary tract infection,1 increased urination,1 male genital mycotic infections,1 vulvovaginal pruritus,1 thirst,1 constipation,1 and nausea.1

The major metabolic elimination pathway for canagliflozin is O -glucuronidation; the drug is mainly glucuronidated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes UGT1A9 and UGT2B4.1

Canagliflozin is a P-glycoprotein substrate and weakly inhibits P-glycoprotein.1 Canagliflozin also is a substrate of MRP2.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Canagliflozin did not induce cytochrome P-450 (CYP) isoenzymes 3A4, 2C9, 2C19, 2B6, or 1A2 in cultured human hepatocytes.1 Canagliflozin also does not inhibit CYP isoenzymes 1A2, 2A6, 2C19, 2D6, or 2E1 but weakly inhibits CYP2B6, 2C8, 2C9, and 3A4 in human hepatic microsomes.1

Drugs Affecting the Renin-Angiotensin System

Concomitant use of canagliflozin with drugs that interfere with the renin-angiotensin-aldosterone system, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, may increase the incidence of symptomatic hypotension.1 Prior to initiating canagliflozin in such patients, intravascular volume should be assessed and corrected; patients should be monitored for signs and symptoms of hypotension after initiating therapy.1 (See Hypotension under Cautions: Warnings/Precautions.) These drugs also may cause hyperkalemia in patients with moderate renal impairment.1 Serum potassium concentrations should be monitored periodically following initiation of canagliflozin in patients predisposed to hyperkalemia due to drug therapy.1 (See Hyperkalemia under Cautions: Warnings/Precautions.)

Uridine Diphosphate-glucuronosyltransferase Enzyme Inducers

Concomitant use of canagliflozin with an inducer of UGT enzymes may decrease the efficacy of canagliflozin.1 When a single dose of canagliflozin (300 mg) was administered to patients receiving rifampin (600 mg once daily for 8 days), a nonselective inducer of UGT isoenzymes 1A9 and 2B4, canagliflozin area under the concentration-time curve (AUC) was decreased by 51% and peak plasma concentration was reduced by 28% (based on geometric mean ratios).1 If a UGT enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir) is used concomitantly with canagliflozin in patients who are currently tolerating canagliflozin 100 mg once daily, the dosage of canagliflozin should be increased to 200 mg once daily in patients with an estimated glomerular filtration rate (eGFR) of at least 60 mL/minute per 1.73 m².1 The dosage may be increased to 300 mg once daily in patients currently tolerating canagliflozin 200 mg daily who require additional glycemic control.1 In patients with an eGFR less than 60 mL/minute per 1.73 m² who are receiving concomitant therapy with a UGT enzyme inducer and currently tolerating canagliflozin 100 mg once daily, the dosage of canagliflozin should be increased to 200 mg once daily.1 The addition of another antidiabetic agent should be considered in such patients who require additional glycemic control.1

Acetaminophen

Administration of a single dose of acetaminophen (1 g) to individuals receiving canagliflozin (300 mg twice daily for 25 days) had no effect on peak plasma acetaminophen concentration; acetaminophen AUC increased by 6% (based on geometric mean ratios).1 No adjustment of concomitant acetaminophen dosage is necessary.1

Antidiabetic Agents

When canagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1 Patients receiving canagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Administration of a single dose of glyburide (1.25 mg) to individuals receiving canagliflozin (200 mg once daily for 6 days) increased glyburide AUC by 2% (based on geometric mean ratios) and decreased peak plasma concentrations by 7% (based on geometric mean ratios).1 No adjustment of glyburide dosage is necessary with concomitant canagliflozin.1

Cyclosporine

Administration of a single dose of cyclosporine (400 mg) to individuals receiving canagliflozin (300 mg once daily for 8 days) increased canagliflozin AUC and peak plasma concentrations by 23 and 1%, respectively (based on geometric mean ratios).1 No adjustment of canagliflozin dosage is necessary with concomitant cyclosporine.1

Digoxin

Concomitant use of canagliflozin (300 mg once daily for 7 days) and digoxin (0.5 mg once daily for one day, then 0.25 mg once daily for 6 days) increased AUC and mean peak plasma concentration of digoxin by 20 and 36%, respectively (based on geometric mean ratios).1 Patients should be monitored appropriately when receiving canagliflozin and digoxin concomitantly.1

Diuretics

Concomitant use of canagliflozin with diuretics may increase the incidence of symptomatic hypotension.1 Prior to initiation of canagliflozin, volume status should be assessed and corrected in patients receiving diuretics.1 Patients should be monitored for signs and symptoms of symptomatic hypotension following initiation of canagliflozin therapy.1

Patients with moderate renal impairment receiving potassium-sparing diuretics are more likely to develop hyperkalemia.1 Serum potassium concentrations should be monitored periodically following initiation of canagliflozin in patients predisposed to hyperkalemia due to drug therapy.1

Hormonal Contraceptives

Administration of a single dose of ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg) to individuals receiving canagliflozin (200 mg once daily for 6 days) increased ethinyl estradiol and levonorgestrel AUC (7 and 6%, respectively, based on geometric mean ratios) and peak plasma concentration (22% for both drugs, based on geometric mean ratios) and decreased canagliflozin AUC and peak plasma concentration (9 and 8%, respectively, based on geometric mean ratios).1 No dosage adjustment is necessary for any of the drugs.1

Hydrochlorothiazide

Concurrent use of hydrochlorothiazide (25 mg once daily for 35 days) and canagliflozin (300 mg once daily for 7 days) increased canagliflozin AUC and peak plasma concentrations (12 and 15%, respectively, based on geometric mean ratios) and decreased hydrochlorothiazide AUC and peak plasma concentrations (1 and 6%, respectively, based on geometric mean ratios).1 No dosage adjustment is necessary for either drug.1 (See also Drug Interactions: Diuretics.)

Metformin

In individuals receiving canagliflozin (300 mg once daily for 8 days), a single dose of metformin hydrochloride (2 g) increased canagliflozin and metformin AUCs (10 and 20%, respectively, based on geometric mean ratios) and peak plasma concentrations (5 and 6%, respectively, based on geometric mean ratios).1 No dosage adjustment is necessary for either drug.1

Probenecid

Concomitant use of probenecid (500 mg twice daily for 3 days) and canagliflozin (300 mg once daily for 17 days) increased canagliflozin AUC and peak plasma concentration by 21 and 13%, respectively (based on geometric mean ratios).1 No adjustment of canagliflozin dosage is necessary.1

Simvastatin

Administration of a single dose of simvastatin (40 mg) in individuals receiving canagliflozin (300 mg once daily for 7 days) increased simvastatin AUC and peak plasma concentration by 12 and 9%, respectively (based on geometric mean ratios).1 No simvastatin dosage adjustment is necessary.1

Warfarin

Administration of a single dose of warfarin (30 mg) in individuals receiving canagliflozin (300 mg once daily for 12 days) slightly increased R - and S -warfarin AUC (1 and 6%, respectively, based on geometric mean ratios) and peak plasma concentrations (3 and 1%, respectively, based on geometric mean ratios).1 No warfarin dosage adjustment is necessary.1

Description

Canagliflozin inhibits sodium-glucose cotransporter 2 (SGLT2), a transporter that is expressed in the proximal renal tubules and is responsible for most of the reabsorption of filtered glucose from the tubular lumen.1,14 Through inhibition of SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion;1,12,13 increased glucose excretion is independent of insulin secretion.14 Canagliflozin also may delay oral glucose absorption through transient inhibition of SGLT1 in the intestinal lumen.13,14

Canagliflozin also increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption.1 This effect may increase tubuloglomerular feedback and reduce intraglomerular pressure.1

Following oral administration of a single dose of canagliflozin, the median time to peak plasma concentration was 1-2 hours; mean absolute oral bioavailability of the drug is 65%.1,12 Administration of canagliflozin with a high-fat meal had no effect on the pharmacokinetics of the drug; canagliflozin may be administered with or without food.1 However, based on the potential of the drug to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, the manufacturer recommends that canagliflozin be taken with the first meal of the day.1 Following administration of a radiolabeled dose of canagliflozin, the dose was recovered in feces as unchanged drug (41.5%), a hydroxylated metabolite (7%), and an O -glucuronide metabolite (3.2%) and in urine as the O -glucuronide metabolites (30.5%) and unchanged drug (less than 1%).1 Terminal elimination half-life of canagliflozin was 10.6 and 13.1 hours for single doses of 100 and 300 mg, respectively.1

The fixed combination of canagliflozin and extended-release metformin hydrochloride (Invokamet^® XR) contains immediate-release canagliflozin and extended-release metformin hydrochloride.63 Results of a bioequivalence study indicate that the fixed-combination tablets containing canagliflozin and immediate-release metformin hydrochloride (Invokamet^®) are bioequivalent to individual tablets of canagliflozin and metformin hydrochloride administered concomitantly in equivalent doses under fed conditions.63

Advice to Patients

When canagliflozin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).1,63

Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1,17

Importance of informing patients of the potential risks and benefits of canagliflozin and of alternative therapies.1 Importance of not using canagliflozin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1,17

Importance of informing patients that if a dose of canagliflozin or the fixed combination of canagliflozin and metformin hydrochloride is missed, it should be taken as soon as it is remembered; if it is almost time for the next dose, the patient should skip the missed dose and take the drug at the next regularly scheduled time.1,63 Advise patients not to take 2 doses of the drug at the same time.1,63

Importance of informing patients that ketoacidosis, which can be a life-threatening condition and is sometimes associated with illness or surgery among other risk factors, has been reported with canagliflozin therapy.1,17 Importance of informing patients receiving canagliflozin and their caregivers about the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and of instructing patients to discontinue canagliflozin and seek medical attention immediately should they experience any such signs or symptoms.1,17,39,42,50 Advise patients to use a ketone dipstick to check for ketones in their urine (when possible) if symptoms of ketoacidosis occur, even if blood glucose is not elevated (i.e., less than 250 mg/dL).1,17,50

Importance of informing patients that canagliflozin therapy is associated with an increased risk of requiring lower limb amputations; risk may be higher in some patients, including those with peripheral vascular disease, neuropathy, diabetic foot ulcers, or a history of amputation.1,55 Importance of counseling patients on the importance of routine preventative foot care.1 Advise patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical attention immediately should they experience such signs or symptoms.1,52,55

Importance of informing patients that symptomatic hypotension may occur with canagliflozin and to report such symptoms to their clinicians.1 Inform patients that canagliflozin-induced dehydration may increase the risk of hypotension and that patients should maintain adequate fluid intake.1,17

Importance of informing patients that acute kidney injury has been reported with canagliflozin therapy.1,17,51 Advise patients to seek medical attention immediately if they experience decreased urine output, or swelling of the legs or feet.51 Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue canagliflozin in those settings.1,51

Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis).1,17 Importance of informing female patients of the signs and symptoms of vaginal yeast infections (e.g., vaginal discharge, odor, itching) and male patients of the signs and symptoms of balanitis or balanoposthitis (e.g., rash or redness of the glans or foreskin of the penis).1,17 Advise patients of treatment options and when to seek medical advice.1,17

Importance of informing patients of the potential for urinary tract infections, which may be serious, with canagliflozin therapy.1,17,50 Advise patients of the signs and symptoms of urinary tract infection and the need to contact a clinician promptly if such signs and symptoms occur.1,50

Importance of informing patients that necrotizing infections of the perineum (Fournier gangrene) have occurred with canagliflozin therapy.1,60 Advise patients to seek prompt medical attention if they experience any symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, occurring with a fever above 38°C or malaise.1,60

Importance of informing patients that due to the mechanism of action of canagliflozin, patients taking the drug will test positive for glucose in urine.1 Importance of not using urine glucose tests to monitor glycemic status while taking canagliflozin.1 (See Laboratory Test Interferences under Cautions: Warnings/Precautions.)

Risk of serious hypersensitivity reactions, such as rash, urticaria, and swelling of the face, lips, tongue, and throat that may result in difficulty breathing or swallowing.1,17 If signs or symptoms of such a reaction or anaphylaxis or angioedema occur, importance of discontinuing canagliflozin and informing clinician promptly.1,17

Importance of informing patients about the potential for bone fractures (e.g., hip, lumbar spine) with canagliflozin therapy and of providing them with information about factors contributing to fracture risk.1,17,43

Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.1,17

Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as drug dosage requirements may change.1,17

Importance of taking canagliflozin exactly as directed by clinician.1,17 Importance of advising patients not to discontinue canagliflozin without first discussing it with the prescribing clinician.1,17,43

Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1,17 Advise pregnant women and women of childbearing potential of the possible risk to the fetus with canagliflozin therapy.1 Advise women that breastfeeding is not recommended during canagliflozin therapy.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., diuretics, rifampin, phenytoin, phenobarbital, ritonavir, digoxin) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,17

Importance of informing patients of other important precautionary information.1,17 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Janssen Pharmaceuticals, Inc. Invokana^® (canagliflozin) tablets prescribing information. Titusville, NJ; 2020 Jan.

2. Stenlöf K, Cefalu WT, Kim KA et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab . 2013; 15:372-82. [PubMedCentral][PubMed 23279307]

3. Cefalu WT, Leiter LA, Yoon KH et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet . 2013; :. [PubMed 23850055]

4. Fulcher G, Matthews DR, Perkovic V et al. Canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea (SU) monotherapy: a CANVAS study. Abstract presented at 73rd annual American Diabetes Association scientific sessions. Chicago, IL, 2013 June 21-5. Abstract No. 1124-P.

5. Wilding JP, Mathieu C, Vercruysse F et al. Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, improves glycemic control and reduced body weight in subjects with type 2 diabetes (T2D) inadequately controlled with metformin (MET) and sulfonylurea (SU). Abstract presented at 72rd annual American Diabetes Association scientific sessions. Philadelphia, PA, 2012 June 8-12. Abstract No. 1022-P.

6. Schernthaner G, Gross JL, Rosenstock J et al. Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial. Diabetes Care . 2013; :.

7. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes on metformin and pioglitazone. Abstract presented at 4th World Congress on controversies to consensus in diabetes, obesity, and hypertension (CODHy). Barcelona, Spain, 2012 Nov 8-11.

8. Bode B, Stenlöf K, Sullivan D et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995) . 2013; 41:72-84. [PubMed 23680739]

9. Yale JF, Bakris G, Cariou B et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab . 2013; 15:463-73. [PubMedCentral][PubMed 23464594]

10. Devineni D, Morrow L, Hompesch M et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab . 2012; 14:539-45. [PubMed 22226086]

11. Inagaki N, Kondo K, Yoshinari T et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab . 2013; :. [PubMedCentral][PubMed 23782594]

12. Devineni D, Curtin CR, Polidori D et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol . 2013; 53:601-10. [PubMed 23670707]

13. Polidori D, Sha S, Mudaliar S et al. Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion: Results of a randomized, placebo-controlled study. Diabetes Care . 2013; 36:2154-61. [PubMedCentral][PubMed 23412078]

14. Riser Taylor S, Harris KB. The Clinical Efficacy and Safety of Sodium Glucose Cotransporter-2 Inhibitors in Adults with Type 2 Diabetes Mellitus. Pharmacotherapy . 2013; :. [PubMed 23744749]

15. Nomura S, Sakamaki S, Hongu M et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem . 2010; 53:6355-60. [PubMed 20690635]

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