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Canagliflozin

Medically reviewed by Drugs.com. Last updated on Jul 2, 2020.

Pronunciation

(kan a gli FLOE zin)

Dosage Forms

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

Tablet, Oral:

Invokana: 100 mg, 300 mg

Brand Names: U.S.

  • Invokana

Pharmacologic Category

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

Pharmacology

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 (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

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

Vdss: 83.5 L (intravenous administration)

Metabolism

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

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)

Onset of Action

Within 24 hours (dose-dependent)

Time to Peak

Plasma: 1 to 2 hours

Duration of Action

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

Half-Life Elimination

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

Protein Binding

99% mainly to albumin

Use: Labeled Indications

Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; 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.

Contraindications

Serious hypersensitivity (eg, anaphylaxis, angioedema) to canagliflozin or any component of the formulation; patients on dialysis.

Dosing: Adult

Note: Hypovolemia, if present, should be corrected prior to initiation. May require a gradual dose reduction of insulin and/or insulin secretagogues to avoid hypoglycemia.

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for patients who fail initial therapy with lifestyle intervention and metformin or who cannot take metformin. May be preferred in patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease given demonstrated cardiovascular and renal benefits (ADA 2020; DeSantis 2020; Neal 2017; Perkovic 2019).

Management of hyperglycemia: Oral: Initial: 100 mg once daily prior to first meal of the day; may increase to 300 mg once daily after 4 to 12 weeks if needed to achieve glycemic goals (DeSantis 2020; manufacturer's labeling).

Use in patients with or at risk for atherosclerotic cardiovascular disease: Oral: 100 or 300 mg once daily. Note: Risk reduction for major adverse cardiovascular events has been demonstrated in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease or multiple cardiovascular risk factors (Neal 2017).

Use in patients with diabetic kidney disease: Oral: 100 mg once daily prior to the first meal of the day in patients with urinary albumin excretion >300 mg/day; no further dose titration is necessary for renal benefit. Note: Some experts also use this regimen off label in patients without severely increased albuminuria (eg, urinary albumin excretion ≤300 mg/day); benefits and harms may be more closely balanced due to smaller absolute benefit (Neal 2017; Perkovic 2018; Perkovic 2020). Because sodium-glucose cotransporter 2 inhibitors have less glycemic benefit as eGFR declines, another agent may be needed to achieve glycemic goals (Wexler 2020).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Administration

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

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

Drug Interactions

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

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

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

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. 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. Consider therapy modification

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

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

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. 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. Consider therapy modification

Loop Diuretics: Canagliflozin may enhance the hypotensive effect of Loop Diuretics. Monitor therapy

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

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

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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. 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. 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. Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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. 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. Consider therapy modification

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. 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. Consider therapy modification

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

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. 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.

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

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.

• 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). Risk may be increased with higher doses. 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: 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.

• Volume depletion: Intravascular volume depletion manifesting as acute transient changes in creatinine or symptomatic creatinine may occur; risk may be increased in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), the elderly, or patients on loop diuretics. Acute kidney injury requiring dialysis and hospitalization has also been reported. 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.

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 not recommended in patients with eGFR <30 mL/minute/1.73 m2 (if primary intent is glycemic control) and is contraindicated in patients on dialysis.

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. HbA1c 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.

• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2020).

• 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.

Monitoring Parameters

Blood glucose, HbA1c (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 2020); renal function (baseline and as clinically needed); volume status (eg, BP, 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]).

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 HbA1c 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).

Patient Education

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.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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