Regulatory Decision Summary for Prz-Metformin

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

Metformin hydrochloride

Therapeutic area:

Drugs used in diabetes

Type of submission:

New Drug Submission

Control number:

263913
What was the purpose of this submission?

This New Drug Submission (NDS) was filed to seek approval of Prz-Metformin (metformin hydrochloride) 1,000 mg immediate-release tablets. Given that there are no metformin hydrochloride 1,000 mg tablet products currently marketed in Canada, the submission for this strength was submitted as an NDS. The 500 mg and 850 mg Prz-Metformin (metformin hydrochloride) tablets have been previously approved through an Abbreviated New Drug Submission (ANDS).

A new Product Monograph (PM) was developed for Prz-Metformin 1,000 mg tablets in the 2020 format. The final recommended indication is: for use to improve glycemic control in adult patients with responsive, stable, mild, non-ketosis prone, type 2 diabetes mellitus (T2DM) as an adjunct to proper dietary management, exercise, and weight reduction, or when insulin therapy is not appropriate. Prz-Metformin can be used as monotherapy or in combination with other antidiabetic agents.

Why was the decision issued?

The innovator product in Canada for metformin hydrochloride immediate-release tablets is Glucophage (Sanofi-aventis Canada Inc.). Glucophage is not currently marketed in Canada as a 1,000 mg immediate-release tablet. Glucophage 1,000 mg tablets previously received a DIN from Health Canada (DIN 02446065); however, this strength was cancelled by the DIN holder prior to marketing for reasons unrelated to safety or efficacy. There are no metformin hydrochloride 1,000 mg tablet products currently marketed in Canada. Consequently, an Abbreviated New Drug Submission (ANDS) was not a filing option for Prz-Metformin 1,000 mg tablets. There are, however, several fixed dose combination products approved in Canada that include a 1,000 mg metformin hydrochloride strength in combination with another antihyperglycemic agent, and when taken twice daily the 1,000 mg metformin hydrochloride dose falls within the recommended maximum daily dose of 2.55 g per day as stated in the Glucophage labelling. Consequently, metformin hydrochloride has a market history in Canada of dosing at the proposed 1,000 mg strength. Additionally, metformin has been used widely worldwide in the treatment of T2DM for over 50 years.

To support approval, the sponsor has submitted a comparative bioavailability study comparing Prz-Metformin 1,000 mg tablets to Glucophage 500 mg tablets, administered as a 1,000 mg dose. The results of the biopharmaceutical study demonstrated the comparable bioavailability of Prz-Metformin 1,000 mg tablets, administered as single 1 x 1,000 mg doses, and Glucophage 500 mg tablets, administered as single 2 x 500 mg doses to healthy adult male subjects in the fasted state. Data from this study have shown that the Prz-Metformin 1,000 mg tablets provide similar exposure (AUC) and Cmax as compared with Glucophage tablets (2 x 500 mg) under fasting conditions. These data concluded that 1,000 mg metformin hydrochloride tablets are bioequivalent to two 500 mg Glucophage tablets when administered to healthy, adult males, under fasting conditions. The Prz-Metformin tablets incorporate approved excipients, all of which are recognized to be safe. The study successfully bridges the proposed product to Glucophage.

In addition, published data has been cited in support of the safety and efficacy of metformin at this strength. A brief summary of the studies supporting the efficacy and safety of 1,000 mg metformin have been included in the overview of efficacy and safety sections. These studies include a comparison of various doses of metformin (500, 1,000, 1,500, 2,000, and 2500 mg), a comparison of extended release formulation of metformin with immediate release metformin, study of metformin with sitagliptin, vildagliptin, pioglitazone, glicliazide and a comparison of combination therapy of metformin with troglitazone, linagliptin, empagliflozin, saxagliptin, sitagliptin, glyburide and their monotherapy.

In these studies, the metformin dose is gradually uptitrated from 500 mg/day increments to 2,000 mg/day (1,000 mg twice a day) in the metformin treatment groups. Overall the study durations range from 14-104 weeks. From the results of these studies, it appears that metformin 1,000 mg has a well-established safety profile, is well-tolerated and is found to be efficacious both as monotherapy and in combination with other oral antidiabetic agents.

Prz-Metformin 1,000 mg is not recommended as initial therapy, but can replace two 500mg metformin tablets. The Prz-Metformin PM was updated to reflect information from the Canadian Reference Product (Glucophage). The PM was also updated with the recent safety information regarding the use of metformin in patients with renal impairment and elderly populations.

Based on the totality of the available data, Prz-Metformin 1,000 mg has a positive benefit-risk profile and a Notice of Compliance (NOC), pursuant to section C.08.004 of the Food and Drug Regulations, was issued.

Decision issued

Authorized; issued a Notice of Compliance (NOC) in accordance with the Food and Drug Regulations.