Regulatory Decision Summary for Labetalol Hydrochloride Injection in 5% Dextrose Labetalol Hydrochloride Injection in 0.72% Sodium Chloride

This New Drug Submission was filed by Hikma Canada Limited to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Labetalol Hydrochloride Injection in 5% Dextrose (labetalol hydrochloride), 1 milligram per millilitre (mg/mL) (ready-to-use, 200 mL bag), intravenous and Labetalol Hydrochloride Injection in 0.72% Sodium Chloride (labetalol hydrochloride), 1 mg/mL (ready-to-use, 100 mL, 200 mL, and 300 mL bag), intravenous, for the emergency treatment of severe hypertension when prompt and urgent reduction of blood pressure is essential.

Upon review of the submitted data package, Health Canada authorized Labetalol Hydrochloride Injection in 5% Dextrose and Labetalol Hydrochloride Injection in 0.72% Sodium Chloride for the following indication: for the emergency treatment of severe hypertension when prompt and urgent reduction of blood pressure is essential.

No clinical or non-clinical data was submitted to support this New Drug Submission.

The sponsor submitted a request for waiver to perform comparative in vivo bioequivalence studies. The properties of the proposed drug products (Labetalol Hydrochloride Injection in 5% Dextrose and Labetalol Hydrochloride Injection in 0.72% Sodium chloride [1 mg/mL] ready-to-use solutions) were compared to the Labetalol Hydrochloride Injection USP by Sandoz Canada Inc. (5 mg/mL) diluted in 5% dextrose or 0.9% sodium chloride with the labetalol hydrochloride concentration of 1 mg/mL post dilution.

In the first review cycle, a Notice of Non-Compliance (NON) was issued by Health Canada due to the following issues:

• the nitrosamine risk was considered to be high for the proposed drug products, and following communication with the sponsor detailing the significant nitrosamine risk factors, the sponsor’s response was not considered acceptable;

• the assessment for the leachables for the proposed container closure system was not considered to be acceptable;

• the analytical method used for qualifying the impurity 5-hydroxymethylfurfural (5-HMF) was found to underestimate this impurity in the drug product.

Additionally, the sponsor did not perform the comparison between the proposed drug products and the diluted reference product in all testing parameters as described in Health Canada’s, Notice: Guidance for Industry: Pharmaceutical Quality of Aqueous Solutions document.

In response to the NON, the sponsor addressed the identified major objections. With respect to nitrosamine risk, the sponsor provided an updated control strategy for nitrosamine risk, by including the nitrosamine testing in the drug product specifications for release and stability. The control strategy was considered acceptable. The sponsor provided the justification and toxicology study reports necessary to assess the leachables from the proposed container closure system. Following the assessment of these reports, the extractables and leachables levels in the container closure system were considered acceptable. With respect to the analytical method used for qualifying the impurity 5-HMF, the sponsor clarified the dilutions used in the analytical procedure, and the method was considered acceptable. The Quality requirements of Health Canada’s Notice: Guidance for Industry: Pharmaceutical Quality of Aqueous Solutions document were met.

A Risk Management Plan was not required for this submission and it was not submitted by the sponsor. The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Labetalol Hydrochloride Injection in 5% Dextrose 1 mg/mL (ready-to-use, 200 mL bag), and Labetalol Hydrochloride Injection in 0.72% Sodium Chloride 1 mg/mL (ready-to-use, 100 mL, 200 mL and 300 mL bag), for the authorized indication when used under the conditions of use recommended in the authorized Product Monograph. Therefore, a Notice of Compliance was recommended.

For further details about Labetalol Hydrochloride Injection in 5% Dextrose and Labetalol Hydrochloride Injection in 0.72% Sodium Chloride, please refer to the Product Monograph, authorized by Health Canada and available through the Drug Product Database.