Canagliflozin

Pharmacologic Category

Antidiabetic Agent, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor; Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Dosing: Adult

Note: Hypovolemia, if present, should be corrected prior to initiation.

Diabetes mellitus, type 2: Note: May be used as an adjunctive agent or alternative monotherapy for patients who fail initial therapy with lifestyle intervention and metformin or cannot take metformin. Canagliflozin may be preferred as an additional antidiabetic agent or alternative first-line agent in patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease given canagliflozin's demonstrated cardiovascular and renal benefits (ACC [Das 2018]; ADA 2019; DeSantis 2019; Neal 2017; Neuen 2019; Perkovic 2019; Zelniker 2019). Because sodium-glucose cotransporter 2 inhibitors have less glycemic benefit as eGFR declines, another agent may be needed to achieve glycemic goals in patients with chronic kidney disease (Neuen 2018).

Oral: Initial: 100 mg once daily prior to first meal of the day; may increase to 300 mg once daily if needed to achieve glycemic goals.

Dosing adjustment for concomitant therapy with UDP-glucuronosyl transferase inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Initial: 100 mg once daily; if tolerated, may increase to 200 mg once daily. If additional glycemic control is required, may further increase to 300 mg once daily (if eGFR ≥60 mL/minute/1.73 m²) or consider adding an alternative agent (if eGFR <60 mL/minute/1.73 m²).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

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

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

eGFR 30 to <45 mL/minute/1.73 m² with:

Urinary albumin excretion ≤300 mg/day: The manufacturer's labeling states there are insufficient data to support dosing recommendations for initiation of therapy.

Urinary albumin excretion >300 mg/day: 100 mg once daily.

eGFR <30 mL/minute/1.73 m² with:

Urinary albumin excretion ≤300 mg/day: Use is contraindicated when used for glycemic control.

Urinary albumin excretion >300 mg/day: The manufacturer's labeling states there are insufficient data to support dosing recommendations for initiation of therapy; however, patients previously established on canagliflozin may continue 100 mg once daily.

Hemodialysis: Use is contraindicated.

Dosing: Hepatic Impairment: Adult

Mild-to-moderate impairment (Child-Pugh class A, B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): Use not recommended (has not been studied).

Calculations

Use: Labeled Indications

Diabetes mellitus, type 2: Treatment of type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control; risk reduction of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease; risk reduction of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with urinary albumin excretion >300 mg/day.

* See Uses in AHFS Essentials for additional information.

Comparative Efficacy

CANAGLIFLOZIN

Clinical Practice Guidelines

American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE), “Consensus Statement on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 Executive Summary,” January 2019

American Diabetes Association, “Standards of Medical Care in Diabetes - 2019,” January 2019

Diabetes Canada, “Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada,” 2018

Administration: Oral

May be administered with or without food. It is recommended to take before the first meal of the day (may reduce postprandial hyperglycemia via delayed intestinal glucose absorption).

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage/Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

• It is used to lower the chance of heart attack, stroke, new or worse kidney problems, having to go to the hospital for heart failure, and death in some people.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in the amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.

• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy.

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.

• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating.

• Vaginal yeast infection

• Penile yeast infection

• Pain, sores, or ulcers in legs or feet

• Infection in the legs, feet, genitals, or rectum

• Bone pain

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204042s036lbl.pdf#page=49, must be dispensed with this medication.

Contraindications

Serious hypersensitivity (eg, anaphylaxis, angioedema) to canagliflozin or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m²) when used for glycemic control; patients on dialysis.

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: An increased incidence of bone fracture has been reported in the CANVAS clinical trial program (comprised of the CANVAS and CANVAS-R trials); fractures were observed as early as 12 weeks after treatment initiation in the CANVAS trial (Neal 2017; Watts 2016; manufacturer's labeling). The similarly designed CANVAS-R trial (n = 5,812) did not show an increased fracture risk when analyzed separately from the CANVAS trial (n = 4,330); reasons for these conflicting data within the CANVAS program are not clear (Zhou 2019). Meta-analyses and pooled analyses (excluding CANVAS trial) have not demonstrated a risk of increased fractures (Ruanpeng 2017; Tang 2016; Watts 2016), and fracture risk was not increased in the CREDENCE trial (Perkovic 2019). Consider patient's risk of fracture prior to initiation.

• Genital mycotic infections: May increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.

• Hypersensitivity reactions: Hypersensitivity reactions (eg, angioedema, anaphylaxis) may occur; generally occurs within hours to days after therapy initiation. Discontinue therapy if hypersensitivity occurs and treat as appropriate.

• Hypotension: May cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m²), elderly, patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, or angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.

• Hyperkalemia: May cause hyperkalemia. Predisposing factors for hyperkalemia include renal impairment, higher doses (eg, 300 mg daily), and concomitant use of potassium-sparing diuretics, ACE inhibitors, and ARBs (Weir 2014). In the CREDENCE trial, use of canagliflozin 100 mg daily in patients with a mean eGFR ~56 +/- 18 mL/minute/1.73 m² did not increase the risk of hyperkalemia compared to placebo (Perkovic 2019). Monitor serum potassium after initiation in those who are predisposed.

• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy at least 3 days prior surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.

• Lower limb amputation: [US Boxed Warning]:An increased risk of lower limb amputations associated with canagliflozin use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease or were at risk for cardiovascular disease. Amputations involved the toe, midfoot, or less frequently the leg (above or below the knee). Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating factors. Prior to initiation consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care. Discontinue therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs.

• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving canagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.

• Renal effects: Acute kidney injury has been reported. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. Assess renal function prior to initiation and periodically during treatment; correct volume depletion prior to initiation. In the CREDENCE trial, patients with type 2 diabetes and chronic kidney disease (ie, eGFR 30 to 90 mL/minute/1.73 m²) and receiving canagliflozin had a greater decline in eGFR at 3 weeks compared to placebo; however, further decline in eGFR tended to be slower with canagliflozin over a median follow-up of 2.6 years (Perkovic 2019).

• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with SGLT2 inhibitors increase the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Melissas 2013).

– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.

• Renal impairment: Glycemic efficacy may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. Dosage adjustment is recommended if eGFR <60 mL/minute/1.73 m². In the CREDENCE trial, use of canagliflozin in patients with diabetes and renal impairment (including ~30% of patients with eGFR 30 to <45 mL/minute/1.73 m²) led to a significant reduction in the primary composite outcome of end-stage kidney disease, doubling of serum creatinine or death from renal or cardiovascular disease; median follow-up was 2.6 years (Perkovic 2019). Use is contraindicated in patients with eGFR <30 mL/minute/1.73 m² (if primary intent is glycemic control) and in patients on dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Elderly patients (≥65 years of age) may have an increased risk of symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, dizziness, syncope, and dehydration) during therapy, especially with the 300 mg dose; elderly patients ≥75 years of age may experience a more pronounced risk. HbA_1c reductions may be less in patients >65 years of age compared to younger patients.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.

• Surgical procedures: Consider temporary discontinuation of therapy at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.

* See Cautions in AHFS Essentials for additional information.

Pregnancy Considerations

Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use of canagliflozin during the second and third trimesters of pregnancy.

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than canagliflozin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

Breast-Feeding Considerations

It is not known if canagliflozin is present in breast milk.

Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.

Lexicomp Pregnancy & Lactation, In-Depth

Canagliflozin

Briggs' Drugs in Pregnancy & Lactation

Canagliflozin

Adverse Reactions

>10%: Infection: Genitourinary fungal infection (females: 11% to 12%; males: 4%; patients who developed infections were more likely to experience recurrence)

1% to 10%:

Cardiovascular: Hypotension (3%)

Central nervous system: Falling (2%), fatigue (2%)

Endocrine & metabolic: Hypoglycemia (4%), hypovolemia (2% to 3%), increased thirst (2% to 3%), increased serum potassium (eGFR 45 to 60 mL/minute: >5.4 mEq/mL: 9%; ≥6.5% mEQ/mL: 1%)

Gastrointestinal: Abdominal pain (2%), constipation (2%), nausea (2%)

Genitourinary: Urinary tract infection (6%), increased urine output (5%), vulvovaginal pruritus (2% to 3%)

Hematologic & oncologic: Increased hemoglobin (3% to 4%)

Hypersensitivity: Hypersensitivity reaction (4%)

Neuromuscular & skeletal: Asthenia (≤1%)

Miscellaneous: Limb injury (toe, foot, lower limb amputations: 2% to 4%)

Frequency not defined:

Endocrine & metabolic: Increased LDL cholesterol, increased serum cholesterol (non-HDL)

Neuromuscular & skeletal: Bone fracture, decreased bone mineral density

Renal: Decreased estimated GFR (eGFR), increased serum creatinine

<1%, postmarketing, and/or case reports: Acute renal failure, anaphylaxis, angioedema, ketoacidosis, necrotizing fasciitis (perineum), pancreatitis, phimosis, pyelonephritis, skin photosensitivity, urinary tract infection with sepsis

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

Substrate of CYP3A4 (minor), MRP2, P-glycoprotein/ABCB1, UGT1A9, UGT2B4; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Exceptions: Danazol. Risk C: Monitor therapy

Digoxin: Canagliflozin may increase the serum concentration of Digoxin. Risk C: Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Fosphenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Loop Diuretics: Canagliflozin may enhance the hypotensive effect of Loop Diuretics. Management: If canagliflozin is combined with a loop diuretic, monitor for symptoms of intravascular volume depletion and hypotension. Canadian product labeling recommends avoiding the combination of canagliflozin and loop diuretics. Risk D: Consider therapy modification

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

PHENobarbital: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Phenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Primidone: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy

RifAMPin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Ritonavir: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Test Interactions

Positive test for glucosuria; may interfere with 1,5-anhydroglucitol (1,5-AG) assay; use alternative methods to monitor glycemic control.

Monitoring Parameters

Blood glucose, HbA_1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change (ADA 2019); renal function (baseline and periodically during treatment); volume status (eg, blood pressure, hematocrit, electrolytes); serum potassium (periodically after initiation in renal impairment and those predisposed to hyperkalemia); genital mycotic infections and urinary tract infection; hypersensitivity reactions; BP; lower limb and feet (sores, ulcers, infection); if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults with diabetes (ADA 2019):

HbA_1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA_1c goal may be targeted based on patient-specific characteristics)

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Peak postprandial capillary blood glucose: <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Older adults (≥65 years) with diabetes (ADA 2019):

HbA_1c: <7.5% (healthy); <8% (complex/intermediate health); <8.5% (very complex/poor health) (individualization may be appropriate based on patient and caregiver preferences)

Preprandial capillary blood glucose: 90 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health)

Bedtime capillary blood glucose: 90 to 150 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health)

Advanced Practitioners Physical Assessment/Monitoring

Assess renal function; dosage adjustments may be needed. Obtain urine glucose, urine ketones, fasting blood glucose, HbA1c (at least twice yearly in stable patients and quarterly in patients not meeting treatment goals), serum glucose, electrolytes, CBC, serum potassium, serum magnesium, serum phosphate, and LDL-C. Monitor blood pressure. Observe for signs of UTI or genital infection. Assess for signs and symptoms of vitamin B12 and/or folic acid deficiency during therapy; supplementation may be required. Assess for signs and symptoms of metabolic acidosis. Refer patient to diabetes educator for instruction if needed.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor blood pressure. Watch for signs of hypoglycemia. Refer patient to diabetes educator for instruction if needed. Educate patient about increased risk of urinary tract or genital infection and to report any signs or symptoms.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Invokana: 100 mg, 300 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Invokana: 100 mg, 300 mg

Anatomic Therapeutic Chemical (ATC) Classification

A10BK02

Generic Available (US)

Pricing: US

Tablets (Invokana Oral)

100 mg (per each): $20.74

300 mg (per each): $20.74

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, canagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RT_G). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RT_G result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

Pharmacodynamics/Kinetics

Onset of action: Within 24 hours (dose-dependent)

Duration of action: Suppression of the renal threshold for glucose (RT_G) occurs throughout the 24-hour dosing interval; maximal RT_G suppression occurred with the 300 mg dose (RT_G decreased from baseline of ~240 mg/dL to a mean of 70 to 90 mg/dL over 24 hours).

Absorption: Not affected by food; however, administration prior to the first meal of the day may delay intestinal glucose absorption, thereby reducing postprandial hyperglycemia.

Distribution: V_dss: 83.5 L (intravenous administration)

Protein binding: 99% mainly to albumin

Metabolism: Major metabolism through O-glucuronidation by UGT1A9 and UGT2B4 to two inactive metabolites; minor oxidative metabolism (~7%) through CYP3A4.

Bioavailability: ~65%

Half-life elimination: Apparent terminal half-life: 100 mg dose: 10.6 hours; 300 mg dose: 13.1 hours

Time to peak, plasma: 1 to 2 hours

Excretion: Feces (41.5% as unchanged drug, 7% as hydroxylated metabolite, 3.2% as O-glucuronide metabolite); urine ~33% (30.5% as O-glucuronide metabolites, <1% as unchanged drug)

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Hypoglycemia reported; patients should be appointed for dental treatment in the morning in order to minimize chance of stress-induced hypoglycemia. Dizziness and syncope have been reported; patients may experience orthostatic hypotension as they stand up after treatment; especially if lying in dental chair for extended periods of time. Use caution with sudden changes in position during and after dental treatment.

Canagliflozin-dependent patients with diabetes (noninsulin dependent, type 2) should be questioned by the dental professional at each dental visit to assess their risk for stress-induced hypoglycemia. The dental professional should inquire about the patient’s routine (ie, work, sleep schedule, eating patterns), history of hypoglycemia, time of last medication dose, last meal, and most recent blood sugar assessment. Keep a supply of glucose tablets and other carbohydrates in the office to prepare for a hypoglycemic event. Seek medical attention when necessary (American Diabetes Association 2016).

Effects on Bleeding

No information available to require special precautions

Related Information

FDA Approval Date

March 29, 2013

References

American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 201: Pregestational diabetes mellitus. Obstet Gynecol. 2018;132(6):e228-e248. doi: 10.1097/AOG.0000000000002960.[PubMed 30461693]

American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet Gynecol. 2018;131(2):e49-e64.[PubMed 29370047]

American Diabetes Association (ADA). Diabetes Care. 2019;42(suppl 1):S1-S193. http://care.diabetesjournals.org/content/42/Supplement_1. Accessed October 24, 2019.

American Diabetes Association (ADA). Standards of medical care in diabetes–2020. Diabetes Care. 2020;43(suppl 1):S1-S212. https://care.diabetesjournals.org/content/43/Supplement_1. Accessed January 22, 2020.

Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249.[PubMed 24194617 ]

Bobart SA, Gleason B, Martinez N, Norris K, Williams SF. Euglycemic ketoacidosis caused by sodium-glucose cotransporter 2 inhibitors: a case report. Ann Intern Med. 2016;165(7):530-532.[PubMed 27699391]

Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on expert consensus decision pathways. J Am Coll Cardiol. 2018;72(24):3200-3223. doi: 10.1016/j.jacc.2018.09.020.[PubMed 30497881]

DeSantis A. Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 22, 2019.

Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis. Endocr Pract. 2016;22(6):753-762.[PubMed 27082665]

Invokana (canagliflozin) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals; January 2020.

Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013;9(2):159-191. doi: 10.1016/j.soard.2012.12.010.[PubMed 23537696]

Melissas J, Leventi A, Klinaki I, et al. Alterations of global gastrointestinal motility after sleeve gastrectomy: a prospective study. Ann Surg. 2013;258(6):976-982. doi: 10.1097/SLA.0b013e3182774522.[PubMed 23160151]

Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(21):2099. doi: 10.1056/NEJMc1712572.[PubMed 29166232]

Neuen BL, Ohkuma T, Neal B, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018;138(15):1537-1550. doi: 10.1161/CIRCULATIONAHA.118.035901.[PubMed 29941478]

Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019;7(11):845-854. doi: 10.1016/S2213-8587(19)30256-6.[PubMed 31495651]

Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi: 10.1056/NEJMoa1811744.[PubMed 30990260]

Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes Metab Res Rev. 2017;33(6). doi: 10.1002/dmrr.2903.[PubMed 28440590]

Schaefer-Graf UM, Hartmann R, Pawliczak J, et al. Association of breast-feeding and early childhood overweight in children from mothers with gestational diabetes mellitus. Diabetes Care. 2006;29(5):1105-1107.[PubMed 16644645]

Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016;18(12):1199-1206. doi: 10.1111/dom.12742.[PubMed 27407013]

van Niekerk C, Wallace J, Takata M, Yu R. Euglycaemic diabetic ketoacidosis in bariatric surgery patients with type 2 diabetes taking canagliflozin [published online August 20, 2018]. BMJ Case Rep. doi: 10.1136/bcr-2017-221527.[PubMed 30131409]

Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101(1):157-166. doi: 10.1210/jc.2015-3167.[PubMed 26580237]

Weir MR, Kline I, Xie J, Edwards R, Usiskin K. Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR). Curr Med Res Opin. 2014;30(9):1759-1768. doi: 10.1185/03007995.2014.919907.[PubMed 24786834]

Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31-39. doi: 10.1016/S0140-6736(18)32590-X.[PubMed 30424892]

Zhou Z, Jardine M, Perkovic V, et al. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia. 2019;62(10):1854-1867. doi: 10.1007/s00125-019-4955-5.[PubMed 31399845]

Brand Names: International

Canaflo (BD); Canaglif (BD); Canaglu (JP); Invocana (BD); Invokana (AE, AT, BB, BE, BH, CH, CR, CY, CZ, DE, DK, DO, EE, EG, ES, FI, GB, GR, GT, HK, HN, HR, HU, IE, IL, IN, KR, KW, LB, LT, LU, MT, MY, NI, NL, NZ, PA, PH, PL, PT, RO, SE, SG, SI, SK, SV, TH, TR, UA); Ivoglita (EG); Parkflozin (EG); Sulicent (IN)

Last Updated 2/20/20

Google Sites

Report abuse