Regulatory Decision Summary for INVOKAMET

No clinical efficacy studies were conducted with Invokamet; however, bioequivalence of Invokamet to canagliflozin and metformin co-administered as individual tablets was demonstrated in healthy subjects. The bioequivalence of Invokamet to canagliflozin and metformin co-administered as individual tablets was demonstrated for the six proposed strengths (50 mg or 150 mg canagliflozin each with 500 mg, 850 mg, or 1,000 mg metformin). The twice-daily regimen of canagliflozin was comparable to the once-daily regimen for the same total daily doses of 100 mg and 300 mg as demonstrated in a Pharmacokinetic/pharmacodynamic study (DIA1032) and confirmed by a Phase II efficacy and safety study (DIA2003). Bridging efficacy and safety data from the Phase III clinical program with the once daily regimen of 100 mg or 300 mg of canagliflozin to support the use of Invokamet for the proposed indications was therefore considered acceptable.

The efficacy results from six Phase III studies (add-on to metformin alone or in combination with a sulfonylurea, pioglitazone or insulin) demonstrated that canagliflozin 100 mg and 300 mg provided clinically meaningful and statistically significant improvements in glycemic control, lowering heamoglobin A_1c, fasting plasma glucose (FPG), and increases in the percentage of patients achieving the target HbA_1c <0.7%. The reductions in HbA_1c and FPG observed with canagliflozin were sustained over 52 weeks of treatment.

The safety of Invokamet is supported by safety data derived from the Phase III clinical program for canagliflozin. The two pooled Phase III datasets, DS1-M for short‑term safety and DS3M-LT2 for long‑term safety, including subjects on a background of metformin, provided primary evidence for the safety of Invokamet.

The overall safety profile of the canagliflozin/metformin combination was comparable to the safety profile of canagliflozin and no new safety concerns were identified. More common adverse events included genital mycotic infections, urinary tract infections, osmotic diuresis and reduced intravascular volume-related adverse events, infrequently leading to discontinuation.

As canagliflozin treatment may lead to reduced renal function and metformin is mainly excreted by kidney, reduced renal function would increase the risk of metformin accumulation and lactic acidosis, which is fatal in approximately 50% of the cases. Invokamet is therefore contraindicated in patients with serum creatinine levels above the upper limit of normal range, renal disease, renal dysfunction, or abnormal creatinine clearance (<60 mL/min). Monitoring of renal function before initiating Invokamet and periodically thereafter is recommended. Invokamet is also contraindicated in patients with hepatic impairment, which also increases the risk of lactic acidosis.

The proposed indications were revised to eliminate the use of Invokamet in patients who have not been treated with metformin, since canagliflozin is not approved as a first-line treatment.

The benefit/risk profile of Invokamet is considered positive for improving glycemic control as an adjunct to diet and exercise in adult patients with type 2 diabetes mellitus inadequately controlled with metformin (alone or in combination with a sulfonylurea, pioglitazone, or insulin), or in patients who are already treated with these combinations as separate tablets and achieved glycemic control.