Product: Invokamet

Company: Janssen Pharmaceuticals 

Pharmacologic class: Sodium-glucose cotransporter 2 inhibitor + biguanide

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Active ingredients: Canagliflozin, metformin HCl 50 mg/500 mg, 50 mg/ 1000 mg, 150 mg/500 mg, 150 mg/1000 mg; tablets

Indication: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) who are not adequately controlled on a regimen containing metformin or canagliflozin or who are already being treated with both canagliflozin and metformin. Limitations of use: not for treating type 1 diabetes or diabetic ketoacidosis.

Pharmacology: Canagliflozin acts by reducing reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin decreases hepatic glucose production and intestinal absorption of glucose and increases peripheral glucose uptake and use. 

Clinical trials: Canagliflozin was studied as add-on combination therapy with metformin alone, metformin + sulfonylurea, metformin + pioglitazone, and metformin + insulin (with or without other antihyperglycemics). In patients with T2DM, therapy with canagliflozin + metformin produced statistically significant improvements in HbA1c vs. placebo.

Adults: See full labeling. Individualize. Take twice daily with meals; increase dose gradually. Max daily dose: 300 mg/2000 mg. Moderate renal impairment (eGFR 45-<60 mL/min/1.73m2): max canagliflozin 50 mg twice daily. Concomitant UGT inducers in patients with eGFR ≥60 mL/min/1.73m2: consider increase to canagliflozin 150 mg twice daily; if eGFR 45-<60 mL/min/1.73m2: consider other antihyperglycemics.

Children: <18 years: not established.

Contraindications: Renal impairment (SCr ≥1.5 mg/dL [men], ≥1.4 mg/dL [women], or eGFR <45 mL/min/1.73 m2), ESRD, or on dialysis. Metabolic acidosis, diabetic ketoacidosis. 

Warnings/precautions: Confirm normal renal function before starting and monitor thereafter (esp. in elderly). Discontinue if lactic acidosis, renal impairment, shock, acute MI or congestive heart failure, dehydration, sepsis, hypoxemia, pancreatitis, or hypersensitivity reactions occur. Avoid in hepatic disease. Discontinue prior to any intravascular radiocontrast study or surgery; withhold for 48 hours after procedure. Correct volume depletion before initiating.

Monitor for symptomatic hypotension after starting therapy (esp. elderly, renal impairment, low systolic BP, on diuretics or drugs that interfere with the RAAS system). Monitor serum K+ levels in patients predisposed to hyperkalemia.

Elderly, debilitated, uncompensated strenuous exercise, malnourished or deficient caloric intake, adrenal or pituitary insufficiency, or ­alcohol intoxication: increased risk of hypoglycemia. Monitor for genital mycotic infections, hematology (esp. serum vitamin B12), increases in LDL-C; treat if occur. Pregnancy (Category C). Nursing mothers.