Regulatory Decision Summary for Argatroban

The purpose of this Supplement to New Drug Submission (SNDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Argatroban ready-to-use solution (1 milligram per millilitre [mg/mL]) filed by Sandoz Canada Incorporated. Argatroban is currently available in Canada as a concentrated solution (100 mg/mL) that has to be diluted prior to use. Argatroban ready-to-use solution (1 mg/mL) has a different formulation and does not require dilution prior to use. Additionally, the SNDS was submitted to update the Product Monograph to the 2020 Master Template and to request authorization for the addition of:

• a manufacturing site involving: production and testing of the drug substance.

• drug product manufacturing site involving production, primary packaging and testing.

• a primary container closure system, for a sterile product.

This Supplement to a New Drug Submission (SNDS) was a refile of a submission seeking market authorization for a new strength (1 mg/mL; ready-to-use) of argatroban solution and received a Notice of Non-Compliance Withdrawal (NON-W) on April 18, 2023. In the current SNDS, the sponsor submitted updated quality data to address the major objections issued by Health Canada.

Since the sponsor refiled the submission within five years of receiving the NON-W, as per The Management of Drug Submissions and Applications guidance document, the sponsor was only required to resubmit the information to address the issues identified in the NON-W letter.

A comprehensive assessment of potential nitrosamine impurities was requested in the NON-W letter. Control of a potential impurity within the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Guideline on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk (ICH M7) “cohort of concern” required specific toxicological justification. Sufficient data was provided demonstrating that this impurity would be below a suitably qualified limit in the drug substance. In addition, the toxicology data in support of the control strategy for potentially genotoxic impurities was found acceptable. All the outstanding quality concerns were adequately addressed in the current submission.

The clinical issues were adequately addressed in the previous submission therefore no clinical deficiencies were included in the NON-W letter. The sponsor had previously addressed clinical concerns by conducting a new in vitro coagulation study comparing the clotting times of the proposed ready-to-use solution to the approved concentrated argatroban solution (100 mg/mL), which was the Canadian Reference Product. The results of this in vitro study showed that the proposed ready-to-use argatroban solution (1 mg/mL) was equivalent, from a pharmacodynamics perspective, to the approved concentrated argatroban solution (100 mg/mL) when diluted to the intended concentration for use.

Following review and requested revisions, the proposed Product Monograph was considered to be acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Argatroban ready-to-use solution (1 mg/mL) by Sandoz Canada Incorporated for the approved indication when used under the conditions of use recommended in the approved Product Monograph.

A Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

For further details about Argatroban, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database .