News from the FDA: Canagliflozin Approval

FDA Approval of INVOKANA™ (Canagliflozin) for the Treatment of Type 2 Diabetes Mellitus

On March 29, 2013, the FDA approved INVOKANA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2DM). INVOKANA is available in two strengths – 100 mg and 300 mg tablets. The recommended starting dose is 100 mg once daily (QD) before the first meal of the day. The dose of INVOKANA can be increased to 300 mg QD in patients tolerating INVOKANA 100 mg QD who have an eGFR of ≥ 60 mL/min/1.73 m² and require additional glycemic control. INVOKANA is limited to 100 mg QD in patients who have eGFR between 45 and less than 60 mL/min/1.73m². INVOKANA should not be initiated in patients with renal impairment who have an eGFR < 45 mL/min/1.73m². Assessment of renal function is recommended prior to initiation of INVOKANA therapy and periodically thereafter.

Canagliflozin is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2). SGLT2 is expressed in the proximal renal tubules and is responsible for the reabsorption of glucose from the tubular lumen. Canagliflozin lowers plasma glucose concentrations in T2DM patients by reducing the reabsorption of filtered glucose which also lowers the threshold for renal glucose excretion.

The efficacy and safety of canagliflozin was studied in nine double-blind, placebo/active controlled trials where it was evaluated as monotherapy or in combination with other approved antihyperglycemic agents. Both doses of canagliflozin demonstrated glucose lowering efficacy. HbA1c reductions with canagliflozin 100 mg and 300 mg as a single agent relative to placebo were -0.91% and -1.16%, respectively. In combination therapies, when INVOKANA and placebo were given on background of other approved antihyperglycemic agents, the HbA1c reductions relative to placebo were in the range of -0.62% to -0.74% for the 100 mg dose and -0.73% to -0.92% for the 300 mg dose, respectively. In a trial in moderate renal impairment (eGFR 30 to 50 mL/min/1.73m²), modest placebo-subtracted HbA1c reductions of -0.30% and -0.40% were observed with 100 mg and 300 mg dose, respectively.

Adverse events related to intravascular volume depletion (e.g., hypotension and postural dizziness) were observed. Renal function changes (i.e., decrease in eGFR), electrolyte changes, and renal-related events such as renal failure were observed. The incidence of volume depletion and renal-related events were dose-dependent and notably increased in subjects with moderate renal impairment. In addition, there was a dose-dependent increase in LDL-C. Adverse events of genital mycotic infection and urinary tract infection were also increased in patient treated with INVOKANA.

The absolute bioavailability of canagliflozin is approximately 65%. O-glucuronidation is the major metabolic pathway for canagliflozin which is mediated by UGT1A9 and UGT2B4, resulting in two inactive metabolites. Approximately 60% of the dose is excreted in feces, mainly as unchanged drug. About 33% of the radioactive dose is excreted in urine, mainly as metabolites, with less than 1% of the dose excreted in the urine as unchanged drug. Canagliflozin is a substrate of P-glycoprotein and MRP2 transporters. There was no change in the drug exposure in mild to moderate hepatic impairment and no dose adjustment is needed. The effect of severe hepatic impairment on canagliflozin exposure was not studied and it is not recommended to use canagliflozin in this population.

There was an increase in the AUC and Cmax of digoxin (20% and 36%, respectively) when co-administered with canagliflozin. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.

Rifampin, a UGT enzyme inducer, decreased canagliflozin AUC by approximately 50% which may diminish its therapeutic effectiveness. If an UGT inducer (e.g., rifampin, phenytoin, phenobarbitol, ritonavir) is co administered with INVOKANA, consider increasing the dosage to 300 mg QD in patients currently tolerating INVOKANA 100 mg QD who have an eGFR of ≥ 60 mL/min/1.73m² and require additional glycemic control. Consider another antihyperglycemic agent in patients with eGFR of 45 to 60 mL/min/1.73m² receiving concurrent therapy with a UGT inducer.

Full prescribing information is available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf

By Jaya Bharathi Vaidyanathan, Ph.D., Division of Clinical Pharmacology II, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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