canagliflozin (Rx)

Brand and Other Names:Invokana
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 100mg
  • 300mg

Type 2 Diabetes Mellitus

Initial: 100 mg PO qDay taken before the first meal of the day

May increase dose to 300 mg qDay if 100 mg/day tolerated in patients who have eGFR ≥60 mL/min/1.73 m² and require additional glycemic control

Indications

  • Indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM)
  • Also indicated to reduce risk of major adverse cardiovascular events (cardiovascular death, nonfatal MI and stroke) in adults with T2DM and established cardiovascular disease
  • Indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria ˃300 mg/day

Dosage Modifications

Renal impairment

  • eGFR ≥60 mL/min/1.73 m2: No dosage adjustment required
  • eGFR 45 to <60 mL/min/1.73 m2: Do not exceed 100 mg/day
  • eGFR < 45 mL/min/1.73 m2 with albuminuria ≤300 mg/day: Insufficient data to support dosing recommendations
  • eGFR 30 to <45 mL/min/1.73 m2 with albuminuria >300 mg/day: Do not exceed 100 mg/day
  • eGFR <30 mL/min/1.73 m2 with albuminuria >300 mg/day: Insufficient data to support dosing recommendations
  • Not recommended with eGFR that declines persistently below 45 mL/min/1.73 m2
  • eGFR <30 mL/min/1.73 m2: Contraindicated
  • Patients already on therapy who have an eGFR <30 mL/min/1.73 m2 with albuminuria >300 mg/day, continue at 100 mg qDay
  • eGFR <30 mL/min/1.73 m2 being treated for glycemic control or patients on dialysis: Contraindicated

UGT enzyme inducers

  • eGFR ≥60 mL/min/1.73 m2
    • May increase canagliflozin dose to 200 mg qDay if currently tolerating 100 mg/day
    • May increase canagliflozin dose to 300 mg qDay if currently tolerating 200 mg/day
  • eGFR <60 mL/min/1.73 m2
    • May increase canagliflozin dose to 200 mg qDay if currently tolerating 100 mg/day
    • Consider adding another antihyperglycemic agent in patients who require additional glycemic control

Hepatic impairment

  • Mild-to-moderate: No dosage adjustment is necessary
  • Severe: Not studied and is therefore not recommended

Dosing Considerations

Not recommended for treating type 1 diabetes mellitus or diabetic ketoacidosis

Before initiating treatment

  • Correct volume depletion
  • Assess renal function and periodically thereafter

Safety and efficacy not established

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Interactions

Interaction Checker

and canagliflozin

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Female genital mycotic infections (10.4-11.4%)

            1-10%

            Urinary tract infections (4.4-5.9%)

            Increased urination (4.6-5.1%)

            Male genital mycotic infections (3.8-4.2%)

            Thirst (2.4-2.8%)

            Constipation (1.8-2.4%)

            Nausea (2.1-2.3%)

            Volume depletion

            • Overall population (2.3-3.4%)
            • Age >75 yr (4.9-8.7%)
            • eGFR <60/mL/min/1.73 m³ (4.7-8.1%)
            • Use of loop diuretic (3.2-8.8%)

            Postmarketing reports

            Ketoacidosis

            Acute kidney injury

            Anaphylaxis

            Angioedema

            Urosepsis

            Pyelonephritis

            Necrotizing fasciitis of the perineum (Fournier’s gangrene)

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            Warnings

            Black Box Warnings

            Lower limb amputation

            • Increased risk of lower limb amputations associated with canagliflozin use was observed in 2 large, randomized, placebo-controlled trials (CANVAS AND CANVAS-R) in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD
            • Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed; some patients had multiple amputations, some involving both limbs
            • Before initiating, consider factors that may increase the risk of amputation (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)
            • Monitor for infection, new pain or tenderness, and sores or ulcers involving the lower limbs; discontinue if these complications occur

            Contraindications

            Serious hypersensitivity reaction (eg, anaphylaxis, angioedema)

            Severe renal impairment (eGFR <30 mL/min/1.73 m2) who are being treated for glycemic control

            Patients on dialysis

            Cautions

            An increased risk of lower limb amputations was observed in clinical trials (see Black Box Warnings)

            Causes intravascular volume contraction and symptomatic hypotension and/or acute kidney injury can occur, particularly if eGFR <60 mL/min/1.73 m2, advance age, existing low systolic BP, or taking either diuretics or drugs that interfere with renin-angiotensin-aldosterone system (RAS) (eg, ACE inhibitors, ARBs); before initiating therapy, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACE inhibitors, or ARB; monitor for signs and symptoms during therapy

            Ketoacidosis associated with SGLT2 inhibitors reported; monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness); assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level; consider risk factors for ketoacidosis prior to initiating therapy; patients may require temporary discontinuation of therapy in clinical situation that may predispose to ketoacidosis

            Causes intravascular volume contraction and can cause renal impairment; acute kidney injury, some requiring hospitalization and dialysis reported

            Increases in serum creatinine and decreases in estimated GFR also observed with initiation

            Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated

            Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever >100.4 F or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

            Genital mycotic infections may occur, patients with history of genital mycotic infections and uncircumcised males are more susceptible

            Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, reported; consider factors that contribute to fracture risk before initiating therapy

            Hypersensitivity reactions, including angioedema and anaphylaxis reported; these reactions generally occurred within hours to days after initiation; if hypersensitivity reactions occur, discontinue therapy; treat and monitor until signs and symptoms resolve

            Drug interaction overview

            • Major substrate of UGT1A9 and UGT2B4; weak inhibitor of P-gp
            • Coadministration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin AUC by 51%
            • Hypoglycemia risk increased with insulin and insulin secretagogues, consider a lower dose of insulin or the insulin secretagogue
            • An increase in AUC and mean peak drug concentration of digoxin (a P-gp substrate) was observed when coadministered with canagliflozin 300 mg; monitor
            • Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests; use alternative methods to monitor glycemic control
            • Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5- AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
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            Pregnancy & Lactation

            Pregnancy

            Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy

            Data are limited in pregnant women and are not sufficient to determine a drug associated risk for major birth defects or miscarriage

            Clinical considerations

            • Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications
            • Poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia related morbidity

            Lactation

            No information regarding distribution in human milk or effects on the breastfed infant or milk production

            Present in milk of lactating rats

            Since human kidney maturation occurs in utero and during the first 2 yr of life when lactational exposure may occur, there may be risk to the developing human kidney

            Inform women not to breastfeed while taking canagliflozin

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Selective sodium-glucose transporter-2 (SGLT2) inhibitor

            SGLT-2 inhibition lowers the renal glucose threshold (ie, the plasma glucose concentration which exceed the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion

            Absorption

            Bioavailability: 65%

            Peak plasma time: 1-2 hr

            Distribution

            Protein bound: 99% (predominantly to albumin)

            Vd: 119 L

            Metabolism

            O-glucuronidation is the major metabolic elimination pathway, mainly by UGT1A9 and UGT2B4 to 2 inactive O-glucuronide metabolites

            CYP3A4-mediated (oxidative) metabolism is minimal (~7%)

            Elimination

            Half-life: 10.6 hr (100 mg dose); 13.1 hr (300 mg dose)

            Total body clearance: 192 mL/min

            Excretion

            • Feces: 41.5% (canagliflozin), 7% (hydroxylated metabolite), 3.2% (O-glucuronide metabolite)
            • Urine: 33% excreted in urine, mainly as O-glucuronide metabolites (30.5%); <1% excreted unchanged
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.