Brand name: Invokana
Drug class: Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors
Chemical name: (1S)-Hydrate (2:1), 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol
Molecular formula: C₂₄H₂₅FO₅S•½H₂O
CAS number: 928672-86-0

Medically reviewed by Drugs.com on Jun 12, 2023. Written by ASHP.

Introduction

Antidiabetic agents; sodium-glucose cotransporter 2 (SGLT2) inhibitor.

Uses for Canagliflozin

Type 2 Diabetes Mellitus

Glycemic Control

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Commercially available in fixed combination with immediate- or extended-release metformin hydrochloride (Invokamet or Invokamet XR); use the fixed combination when treatment with both drugs is appropriate.

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.

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).

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, 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.

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target). In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other drug classes with complementary mechanisms of action.

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.

For patients with inadequate glycemic control on metformin monotherapy, consider 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 preferences when selecting additional antidiabetic agents for combination therapy.

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of at least 300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.

Experts recommend that patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit. In patients with these comorbidities, consider GLP-1 receptor agonist or SGLT2 inhibitor therapy independently of patient's HbA_1c.

In patients with type 2 diabetes mellitus and CKD, consider a GLP-1 receptor agonist or SGLT2 inhibitor shown to reduce the risk of CKD progression, cardiovascular events, or both, in addition to metformin therapy or in those in whom metformin cannot be used.

In patients on metformin monotherapy without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, base decision regarding addition of other antidiabetic agents on avoidance of adverse effects, cost, and individual patient factors.

Not indicated for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Reduction in Risk of Major Adverse Cardiovascular Events

Used to reduce the risk of major cardiovascular events (e.g., cardiovascular death, nonfatal MI, nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease. Cardiovascular benefits of SGLT2 inhibitors may be accompanied by increased risk of amputations. (See Lower Limb Amputations under Cautions.)

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

Used to reduce the risk of end-stage renal disease (ESRD), doubling of S_cr, cardiovascular death, and hospitalization for heart failure in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria exceeding 300 mg/day.

Related/similar drugs

losartan, metformin, Ozempic, Jardiance, simvastatin, Trulicity, enalapril

Canagliflozin Dosage and Administration

General

• Correct volume depletion prior to initiating canagliflozin; assess renal function prior to treatment and periodically thereafter.

Administration

Oral Administration

Administer canagliflozin once daily, before the first meal of the day.

Administer the fixed combination of canagliflozin and immediate-release metformin hydrochloride twice daily with meals.

Administer the fixed combination of canagliflozin and extended-release metformin hydrochloride once daily with the morning meal; swallow the tablet whole and do not crush, chew, or cut.

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule. If missed dose is not remembered until the time of the next dose, skip missed dose and resume regular schedule; do not double dose to replace a missed dose.

Dosage

Dosage of canagliflozin expressed in terms of anhydrous canagliflozin.

If necessary, correct volume depletion before initiation of canagliflozin therapy.

Adults

Type 2 Diabetes Mellitus

Canagliflozin Monotherapy

Oral

Initially, 100 mg once daily, taken before first meal of the day.

If initial dosage well tolerated and additional glycemic control required, increase dosage to 300 mg once daily in patients with an eGFR ≥60 mL/minute per 1.73 m².

Patients with an eGFR ≥60 mL/minute per 1.73 m² receiving concurrent therapy with a uridine diphosphate-glucuronosyltransferase (UGT) enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir): Increase canagliflozin dosage to 200 mg once daily in patients tolerating 100 mg once daily. May increase dosage to 300 mg once daily in patients who require additional glycemic control and are currently tolerating 200 mg once daily. (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

Canagliflozin/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Individualize dosage based on the patient's current antidiabetic regimen. May increase dosage gradually based on effectiveness and tolerability.

Patients not currently receiving treatment with either canagliflozin or metformin hydrochloride: Initially, 50 mg of canagliflozin and 500 mg of immediate-release metformin hydrochloride (Invokamet) twice daily.

Patients currently receiving metformin hydrochloride: Initially, 100 mg of canagliflozin and a total daily metformin hydrochloride dosage similar to the patient's existing dosage, administered in 2 divided doses. In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose prior to initiating therapy with the fixed combination of canagliflozin and metformin hydrochloride the following morning.

Patients currently receiving canagliflozin: Initially, same daily dosage of canagliflozin and metformin hydrochloride 1 g daily, administered in 2 divided doses.

Patients currently receiving canagliflozin and metformin hydrochloride: Initially, same daily dosage of canagliflozin and a total daily metformin hydrochloride dosage similar to patient's existing dosage, administered in 2 divided doses.

Patients currently receiving both canagliflozin and metformin hydrochloride with an eGFR ≥60 mL/minute per 1.73 m² and concurrent therapy with a UGT enzyme inducer: Increase total daily dosage of canagliflozin to 200 mg in patients currently tolerating 100 mg daily. May increase total daily dosage of canagliflozin to 300 mg in patients who require additional glycemic control and are currently tolerating 200 mg daily. (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

Canagliflozin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Individualize dosage based on the patient's current antidiabetic regimen. May increase dosage gradually based on effectiveness and tolerability.

Patients not currently receiving treatment with either canagliflozin or metformin hydrochloride: Initially, 100 mg of canagliflozin and 1 g of extended-release metformin hydrochloride (Invokamet XR) once daily.

Patients currently receiving metformin hydrochloride: Initially, 100 mg of canagliflozin and a total daily metformin hydrochloride dosage similar to the patient's existing dosage once daily. In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose prior to initiating therapy with the fixed combination of canagliflozin and metformin hydrochloride the following morning.

Patients currently receiving canagliflozin: Initially, same daily dosage of canagliflozin and 1 g metformin hydrochloride once daily.

Patients currently receiving canagliflozin and metformin hydrochloride: Initially, same daily dosage of canagliflozin and a total daily metformin hydrochloride dosage similar to patient's existing dosage once daily.

Patients with an eGFR ≥60 mL/minute per 1.73 m² receiving concurrent therapy with a UGT enzyme inducer: Increase total daily dosage of canagliflozin to 200 mg in patients who are tolerating 100 mg daily. May increase total daily dosage of canagliflozin to 300 mg in patients who require additional glycemic control and are currently tolerating 200 mg daily. (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

Special Populations

Hepatic Impairment

Canagliflozin Monotherapy

Mild or moderate hepatic impairment: No dosage adjustment necessary.

Severe hepatic impairment: Data lacking; not recommended.

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Use of the fixed-combination preparation of canagliflozin and metformin hydrochloride not recommended.

Renal Impairment

Canagliflozin Monotherapy

eGFR ≥60 mL/minute per 1.73 m²: No dosage adjustment necessary.

Patients with an eGFR <60 mL/minute per 1.73 m² receiving concurrent therapy with a UGT enzyme inducer: Increase canagliflozin dosage to 200 mg once daily in patients currently tolerating 100 mg daily. Consider adding another antihyperglycemic agent in such patients who require additional glycemic control. (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

eGFR 45 to <60 mL/minute per 1.73 m²: 100 mg once daily.

eGFR 30 to <45 mL/minute per 1.73 m²: In patients with albuminuria >300 mg/day, recommended dosage is 100 mg once daily. Insufficient data to support dosage recommendations for initiation of therapy in patients with albuminuria ≤300 mg/day.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): Contraindicated in patients who are being treated for glycemic control. Insufficient data to support dosage recommendations for initiation of therapy in patients with albuminuria >300 mg/day. In patients already receiving therapy whose eGFR decreases to <30 mL/minute per 1.73 m² and who have albuminuria >300 mg/day, may continue therapy at 100 mg once daily.

Dialysis: Contraindicated.

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Moderate renal impairment (eGFR 45 to <60 mL/minute per 1.73 m²): Do not exceed 100 mg of canagliflozin component daily.

Patients with an eGFR of <60 mL/minute per 1.73 m² receiving concurrent therapy with a UGT enzyme inducer: May increase total daily dosage of canagliflozin to a maximum of 200 mg in patients who are tolerating 100 mg daily. (See UGT Enzyme Inducers and see Specific Drugs and Laboratory Tests under Interactions.)

eGFR 30 to <45 mL/minute per 1.73 m² with albuminuria >300 mg/day: Assess the benefits and risks of continuing canagliflozin and metformin hydrochloride; limit the total daily dosage of canagliflozin to 100 mg daily.

eGFR <30 mL/minute per 1.73 m²: Contraindicated; discontinue use.

Dialysis: Contraindicated.

Geriatric Patients

Canagliflozin Monotherapy

No specific dosage recommendations.

Canagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Monitor renal function frequently after initiating the fixed-combination preparation; adjust dosage according to the patient's renal function. (See Renal Impairment under Dosage and Administration.)

Cautions for Canagliflozin

Contraindications

• History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema) to canagliflozin.

• Severe renal impairment (eGFR <30 mL/minute per 1.73 m²) in patients who are being treated for glycemic control.

Warnings/Precautions

Warnings

Lower Limb Amputation

Analysis of data from clinical studies evaluating canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS] and CANVAS-R) revealed a twofold increase in leg and foot amputations, mostly affecting the toes and midfoot, in patients receiving the drug. (See Boxed Warning.)

Prior to initiating canagliflozin therapy, consider factors that may predispose patients to the need for amputation (e.g., history of amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers).

Monitor patients for the presence of infection (including osteomyelitis), new pain or tenderness, or sores or ulcers involving the lower limbs; discontinue canagliflozin if such complications occur.

Other Warnings/Precautions

Use of Fixed Combinations

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

Ketoacidosis

Ketoacidosis (e.g., diabetic ketoacidosis, ketoacidosis, ketosis) requiring hospitalization reported with SGLT2 inhibitors; may occur without markedly elevated blood glucose concentrations (e.g., <250 mg/dL).

Evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis regardless of the patient's blood glucose concentration; discontinue SGLT2 inhibitor and initiate appropriate treatment to correct acidosis if confirmed. (See Advice to Patients.)

Prior to initiating canagliflozin therapy, consider factors that may predispose patients to ketoacidosis (e.g., pancreatic insulin deficiency, reduced caloric intake, alcohol abuse).

Consider discontinuing canagliflozin for ≥3 days prior to surgery for patients with scheduled surgery.

Consider temporarily discontinuing SGLT2 inhibitor in patients with clinical situations known to predispose patients to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Risk factors for ketoacidosis should be resolved prior to restarting canagliflozin.

Advise patients to monitor urine and/or plasma ketone levels if patients feel unwell (see Advice to Patients).

Hypotension

May cause intravascular volume contraction. Symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR <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 BP. Assess and correct intravascular volume prior to initiating canagliflozin in such patients.

Monitor patients for sign and symptoms of hypotension after initiating therapy.

Renal Effects

Causes intravascular volume contraction and can cause renal impairment.

May increase S_cr concentration and decrease eGFR. In patients with moderate renal impairment, the increase in S_cr generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases in S_cr that do not fit this pattern should be evaluated to exclude the possibility of acute kidney injury.

Consider factors that may predispose patients to acute kidney injury, such as hypovolemia, chronic renal insufficiency, heart failure, concomitant medications (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIAs), prior to initiating canagliflozin therapy.

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).

Evaluate renal function prior to initiation of canagliflozin and periodically thereafter. Discontinue canagliflozin and initiate appropriate treatment if such injury occurs.

Concomitant Therapy with Hypoglycemic Agents

When adding canagliflozin to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider reducing dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia. (See Specific Drugs and Laboratory Tests under Interactions.)

Fournier Gangrene

Fournier gangrene (necrotizing fasciitis of the perineum), a rare but serious or life-threatening bacterial infection requiring urgent surgical intervention, reported during postmarketing surveillance in men and women with type 2 diabetes mellitus receiving an SGLT2 inhibitor.

Assess for necrotizing fasciitis in patients receiving canagliflozin who develop pain or tenderness, erythema, or swelling in the genital or perineal area, in addition to fever or malaise. Discontinue canagliflozin if Fournier gangrene suspected; initiate treatment with broad-spectrum antibiotics and perform surgical debridement if necessary. Monitor blood glucose concentrations closely; initiate alternative antidiabetic agents to maintain glycemic control.

Genital Mycotic Infections

Possible increased risk of genital mycotic infections in males (e.g., balanoposthitis, candidal balanitis) and females (e.g., vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis). Patients with a history of genital mycotic infections and uncircumcised males more likely to develop such infections.

Monitor patients for genital mycotic infections and institute appropriate treatment if these infections occur.

Urosepsis and Pyelonephritis

May increase the risk of serious urinary tract infections (e.g., urosepsis, pyelonephritis requiring hospitalization).

Prior to initiating canagliflozin therapy, consider patient factors that may predispose to serious urinary tract infections (e.g., history of difficulty urinating; infection of the bladder, kidneys, or urinary tract).

Monitor patients for urinary tract infections and initiate treatment if indicated.

Risk of Bone Fracture

Increased risk of bone fracture. Fractures observed as early as 12 weeks after initiation of canagliflozin treatment; 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).

Dose-related decreases in bone mineral density also observed in older adults (mean age: 64 years) receiving canagliflozin.

Consider factors that contribute to fracture risk and counsel patients about such factors prior to initiating canagliflozin therapy.

Sensitivity Reactions

Hypersensitivity reactions (e.g., generalized urticaria), some serious, reported. Discontinue the drug if hypersensitivity reaction occurs, institute appropriate treatment, and monitor patients until signs and symptoms resolve.

Specific Populations

Pregnancy

Studies in animals indicate that canagliflozin use during pregnancy may affect renal development and maturation.

Not recommended for use in the second or third trimesters of pregnancy.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

Reduced efficacy compared with younger patients, which may be related to decreased renal function in geriatric patients. Such patients more likely to experience certain adverse effects related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration), particularly with canagliflozin 300 mg daily.

Hepatic Impairment

Canagliflozin: Not studied in severe hepatic impairment (Child-Pugh class C); use not recommended. (See Hepatic Impairment under Dosage and Administration.)

Fixed combination of canagliflozin and metformin hydrochloride: Use not recommended.

Renal Impairment

Canagliflozin: Dosage reduction required for patients with an eGFR <60 mL/minute per 1.73 m². (See Renal Impairment under Dosage and Administration.) Contraindicated in patients with severe renal impairment when used for glycemic control and in patients on dialysis. (See Contraindications.) Assess renal function prior to initiation of therapy and periodically thereafter.

Fixed combination of canagliflozin and metformin hydrochloride: Use contraindicated in patients with eGFR <30 mL/minute per 1.73 m². (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Female genital mycotic infections, urinary tract infection, increased urination, male genital mycotic infections, vulvovaginal pruritus, thirst, constipation, nausea.

Drug Interactions

Major metabolic elimination pathway is O-glucuronidation; mainly glucuronidated by uridine disphosphoglucuronosyltransferase (UGT) isoenzymes UGT1A9 and UGT2B4.

P-glycoprotein substrate and weak P-glycoprotein inhibitor. Also a substrate of MRP2.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Did not induce CYP-450 isoenzymes 3A4, 2C9, 2C19, 2B6, or 1A2 in cultured human hepatocytes; did not inhibit CYP1A2, 2A6, 2C19, 2D6, or 2E1 but weakly inhibits CYP2B6, 2C8, 2C9, and 3A4 in human hepatic microsomes.

UGT Enzyme Inducers

Concomitant use of canagliflozin with an inducer of UGT enzymes may decrease the efficacy of canagliflozin.

If a UGT enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir) is used concomitantly with canagliflozin in patients with an eGFR ≥60 mL/minute per 1.73 m², increase and titrate canagliflozin dosage according to tolerance in patients who require additional glycemic control. (See Specific Drugs and Laboratory Tests under Interactions.)

If a UGT enzyme inducer (e.g., phenobarbital, phenytoin, rifampin, ritonavir) is used concomitantly with canagliflozin in patients with an eGFR <60 mL/minute per 1.73 m², increase dosage of canagliflozin according to tolerance and consider adding another antidiabetic agent in patients who require additional glycemic control. (See Specific Drugs and Laboratory Tests under Interactions.)

Specific Drugs and Laboratory Tests

Canagliflozin Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1–2 hours after oral dosing. Mean absolute oral bioavailability approximately 65%.

Bioequivalence study: Fixed-combination tablets of 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.

Fixed combination of canagliflozin and extended-release metformin hydrochloride (Invokamet XR) contains immediate-release canagliflozin and extended-release metformin hydrochloride.

Food

Administration with a high-fat meal had no effect on canagliflozin pharmacokinetics. However, based on the drug's potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, take canagliflozin with the first meal of the day.

Specific Populations

Mild hepatic impairment (Child-Pugh class A): AUC and peak plasma concentration increased by 10 and 7%, respectively, compared with individuals with normal hepatic function.

Moderate hepatic impairment (Child-Pugh class B): AUC increased by 11% and peak plasma concentration decreased by 4% compared with individuals with normal hepatic function.

Mild renal impairment (eGFR 60 to <90 mL/minute per 1.73 m²): AUC increased by 15%, compared with healthy individuals following a single 200-mg dose of the drug.

Moderate renal impairment (eGFR 30 to <60 mL/minute per 1.73 m²): AUC increased by 29% compared with healthy individuals following a single 200-mg dose of the drug.

Severe renal impairment (eGFR <30 mL/minute per 1.73 m²): AUC was increased by 53% compared with healthy individuals following a single 200-mg dose of the drug.

Distribution

Extent

Extensively distributes into tissues.

Plasma Protein Binding

99% (mainly to albumin).

Specific Populations

Renal or hepatic impairment does not meaningfully alter plasma protein binding.

Elimination

Metabolism

Metabolized principally via O-glucuronidation by UGT1A9 and UGT2B4 to inactive metabolites.

Elimination Route

41.5, 7, and 3% recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively.

33% excreted in urine; 30.5% as O-glucuronide metabolite and <1% as unchanged drug.

Half-life

Terminal elimination half-life was 10.6 and 13.1 hours for single doses of 100 and 300 mg, respectively.

Stability

Storage

Oral

Tablets

Canagliflozin: 25°C (may be exposed to 15–30°C).

Fixed combination of canagliflozin and metformin hydrochloride: 20–25°C (may be exposed to 15–30°C). Store and dispense in original container. May store in pill box for ≤30 days.

Actions

• Inhibits SGLT2, a transporter expressed in proximal renal tubules and responsible for majority of reabsorption of filtered glucose from tubular lumen.

• Reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion.

• Increases glucose excretion independent of insulin secretion.

• May delay oral glucose absorption through transient inhibition of SGLT1 in the intestinal lumen.

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

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).

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

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

• 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. Advise patients not to take 2 doses of the drug at the same time.

• 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. Importance of informing patients and their caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status change) and of instructing patients to discontinue canagliflozin and seek medical attention immediately should they experience any such signs or symptoms. 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., <250 mg/dL).

• Importance of informing patients that canagliflozin therapy is associated with an increased risk of the need for lower limb amputation, which may be higher in some patients, including those with peripheral vascular disease, neuropathy, diabetic foot ulcers, or a history of amputation. Importance of counseling patients on the importance of routine preventative foot care. 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.

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

• Importance of informing patients that acute kidney injury has been reported with canagliflozin therapy. Advise patients to seek medical attention immediately if they experience decreased urine output, or swelling of the legs or feet. 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.

• Importance of informing patients that yeast infection may occur (e.g., vulvovaginitis, balanitis, balanoposthitis). 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). Advise patients of treatment options and when to seek medical advice.

• Importance of informing patients of the potential for urinary tract infections, which may be serious. 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.

• Importance of informing patients that necrotizing infections of the perineum (Fournier gangrene) have occurred with canagliflozin therapy. 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.

• Importance of informing patients that due to the mechanism of action of canagliflozin, patients taking the drug will test positive for glucose in their urine. Importance of not using urine glucose tests to monitor glycemic status.

• 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. If signs or symptoms of such a reaction or anaphylaxis or angioedema occur , importance of discontinuing canagliflozin and informing clinician promptly.

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

• 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.

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

• Importance of taking canagliflozin exactly as directed by clinician. Importance of patients not discontinuing canagliflozin without discussion with prescribing clinician.

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

• 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• How effective Is Invokana?
• Is Invokana the same as metformin?

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