Invokana - Drug Monograph

Introduction

Invokana (canagliflozin) is an oral antidiabetic medication belonging to the sodium-glucose cotransporter 2 (SGLT2) inhibitor class. Approved by the FDA in 2013, it represents a novel approach to type 2 diabetes management by targeting renal glucose reabsorption. This monograph provides comprehensive clinical information for healthcare professionals regarding the appropriate use, monitoring, and safety considerations of canagliflozin therapy.

Mechanism of Action

Canagliflozin inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules. SGLT2 is responsible for approximately 90% of renal glucose reabsorption. By blocking this transporter, canagliflozin reduces renal glucose reabsorption and increases urinary glucose excretion, resulting in lowered plasma glucose concentrations. This insulin-independent mechanism provides a unique approach to diabetes management that complements existing therapies.

Indications

• Primary Indication: Improvement of glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise
• Secondary Indications:

- Reduction of major adverse cardiovascular events 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 albuminuria

Dosage and Administration

• Initial dose: 100 mg orally once daily, taken before the first meal of the day
• May increase to 300 mg once daily in patients tolerating 100 mg daily who require additional glycemic control

• Renal Impairment:

- eGFR ≥60 mL/min/1.73 m²: No dosage adjustment necessary - eGFR 45 to <60 mL/min/1.73 m²: Limit to 100 mg daily - eGFR <45 mL/min/1.73 m²: Not recommended - ESRD: Contraindicated

• Hepatic Impairment: No dosage adjustment necessary for mild to moderate impairment; use with caution in severe impairment
• Elderly: Consider potential for reduced renal function; dose selection should be cautious
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Rapidly absorbed with Tmax of 1-2 hours; bioavailability ~65%
• Distribution: Protein binding ~99%, primarily to albumin; steady state reached in 4-5 days
• Metabolism: Primarily via UGT1A9 and UGT2B4 glucuronidation; minor oxidation via CYP3A4
• Elimination: Half-life ~10.6-13.1 hours; primarily excreted in feces (41.5%) and urine (30.5%)
• Special Considerations: No clinically significant effect of food on absorption

Contraindications

• History of serious hypersensitivity reaction to canagliflozin
• Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis
• Concomitant use with other SGLT2 inhibitors

Warnings and Precautions

• Lower Limb Amputation: Increased risk of amputations, primarily of the toe and midfoot

• Ketoacidosis: Reports of ketoacidosis in patients with type 1 and type 2 diabetes
• Acute Kidney Injury: Postmarketing reports of acute kidney injury requiring hospitalization
• Urosepsis and Pyelonephritis: Serious urinary tract infections
• Hypotension: Volume depletion-related adverse reactions
• Hypoglycemia: Risk increased with concomitant insulin or insulin secretagogues
• Genital Mycotic Infections: Higher incidence in patients with history of infections
• Hyperkalemia: Monitor potassium levels in patients with renal impairment
• LDL-C Increases: Dose-related increases in LDL cholesterol observed

Drug Interactions

• Diuretics: Increased risk of volume depletion
• Digoxin: Monitor digoxin levels (canagliflozin may increase digoxin exposure)
• UGT Inducers: Rifampin may decrease canagliflozin exposure
• Insulin/Insulin Secretagogues: Increased risk of hypoglycemia (dose reduction may be needed)
• Lithium: Canagliflozin may decrease lithium concentrations

Adverse Effects

• Female genital mycotic infections (10.4% with 100 mg, 11.4% with 300 mg)
• Urinary tract infections (5.9% with 100 mg, 4.3% with 300 mg)
• Increased urination
• Thirst
• Constipation

• Ketoacidosis
• Acute kidney injury
• Urosepsis and pyelonephritis
• Hypersensitivity reactions
• Bone fracture risk
• Lower limb amputations

Monitoring Parameters

• Glycemic Control: HbA1c, fasting plasma glucose
• Renal Function: Serum creatinine, eGFR at baseline and periodically
• Volume Status: Blood pressure, signs/symptoms of volume depletion
• Foot Examination: Regular foot exams for signs of infection, ulceration, or necrosis
• Electrolytes: Serum potassium, magnesium, phosphate
• Lipid Profile: LDL cholesterol
• Genitourinary Symptoms: Signs of infection
• Ketones: In patients presenting with symptoms consistent with ketoacidosis

Patient Education

• Administration: Take once daily before the first meal
• Hydration: Maintain adequate fluid intake to prevent volume depletion
• Hypoglycemia: Recognize signs and symptoms, especially when used with other diabetes medications
• Foot Care: Daily foot inspection and prompt reporting of any sores, ulcers, or infections
• Genital Hygiene: Maintain good hygiene to prevent fungal infections
• Sick Days: Contact healthcare provider during illness; may need to temporarily discontinue
• Symptoms to Report: Nausea, vomiting, abdominal pain, fatigue, difficulty breathing (possible ketoacidosis)
• Pregnancy: Not recommended during second and third trimesters

References

1. FDA Prescribing Information: Invokana (canagliflozin). Revised 2020. 2. Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657. 3. Perkovic V, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. 4. American Diabetes Association. Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022;45(Suppl 1):S1-S264. 5. Inzucchi SE, et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach. Diabetes Care. 2015;38(1):140-149. 6. Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. 7. ClinicalTrials.gov: CANVAS Program (Canagliflozin Cardiovascular Assessment Study).