Regulatory Decision Summary for Meropenem for Injection USP and Sodium Chloride Injection USP

This Supplement to a New Drug Submission (SNDS) was filed to obtain market authorization for Meropenem for Injection USP (United States Pharmacopeia) and Sodium Chloride Injection USP in the Duplex container for the intravenous treatment in adult and pediatric patients (3 months of age and older) of the following infections when caused by susceptible strains of designated microorganisms: lower respiratory tract infections (namely, community-acquired pneumonia (CAP) and nosocomial pneumonia); complicated urinary tract infections (cUTIs); complicated intra-abdominal infections (cIAIs), gynecologic infections, including pelvic inflammatory disease (PID); uncomplicated skin and skin structure infections (uSSSIs); complicated skin and skin structure infections (cSSSIs), except infected skin burns; bacterial meningitis; and bacterial septicemia.

Meropenem for Injection USP and Sodium Chloride Injection USP was proposed based on comparison to Meropenem for Injection USP as a reference product. Meropenem for Injection USP is marketed in Canada for the intravenous treatment of the indications proposed in this submission. The main difference between the proposed product and the Meropenem for Injection reference product is the proposed container closure system. Meropenem for Injection USP is commercially available in a glass vial, while a Duplex container, which contains the drug powder in one chamber and the diluent, 0.9% sodium chloride, in another chamber, has been proposed for Meropenem for Injection USP and Sodium Chloride Injection USP. Since the Duplex container is new to the Canadian market, the conditions of use of the proposed product were considered to be sufficiently different to warrant submission as a SNDS rather than an Abbreviated New Drug Submission (ANDS).

A comparative study to compare physicochemical properties between the proposed product and the Meropenem for Injection USP reference product was provided. As the proposed product in the Duplex container and Meropenem for Injection reference product are designated as USP (United States Pharmacopeia) and the drug product intermediate (DPI) for both come from the same supplier, both products are tested in the same manner and must meet the same USP requirements prior to release for the manufacturing of the final drug products. The comparative study was, therefore, focused on the testing of the drug products after they are reconstituted in 0.9% Sodium Chloride Injection USP diluent. This approach allowed the study to gather data from both drug products after they are reconstituted for use according to the respective product insert or Product Monograph. Testing was done on samples reconstituted for use over the entire in-use shelf life of the products. The study provided evidence demonstrating that the proposed product in the Duplex container is qualitatively and quantitatively the same as the Meropenem for Injection USP reference product in the glass vial. A request for waiver to perform comparative in vivo bioequivalence studies against Meropenem for Injection USP was submitted. As the final form of both the proposed and reference product are injectable aqueous solutions and the relevant parameters in Health Canada’s Pharmaceutical Quality of Aqueous Solutions guidance were met, the requested waiver was acceptable.

Clinical studies on the proposed product in the Duplex container were not submitted. As the proposed product was established to be qualitatively and quantitatively the same as the Meropenem for Injection USP reference product, clinical studies on the proposed product were not required. The clinical data package included literature-based clinical and non-clinical overviews to support efficacy and safety of the proposed drug product, as well post-marketing safety data related to the use of the proposed drug product in the Duplex container.

The bacteriological and clinical efficacy of intravenous meropenem in the eight proposed indications was shown in several third-party randomized controlled studies that were provided as supportive publications. In most of these studies, meropenem was non-inferior to the active comparator standard-of-care treatments. Clinical practice guidelines supported the use of meropenem for the proposed indications. Intravenous meropenem was well tolerated. Gastrointestinal disorders, rash, and injection site inflammation were the most common adverse drug reactions in a meta-analysis of more than 6,000 patients. Few laboratory adverse events (hematological, renal and hepatic function parameters) were reported during meropenem treatment, but meropenem did not induce organ damage. However, serious adverse reactions associated with intravenous meropenem included fatal hypersensitivity reactions and severe cutaneous adverse reactions. Pharmacokinetic drug interactions were observed between intravenous meropenem and probenecid as well as valproic acid. The sponsor adequately addressed these safety issues with appropriate labelling. Subgroup analyses did not show any influence of demographic factors such as age, sex, race, ethnicity on the treatment effect relative to the outcome of interest.

The sponsor submitted customer complaints reports covering the period from January 2015 to December 2021 in order to support the use of the Duplex container. These reports provided a list of complaints by issue category, a summary of the investigation results, a determination of the risk severity and rate of occurrence, and any relevant corrective and preventive action (CAPA) initiated and/or other actions taken for the specified issue category. No major safety concerns were noted with the use of this product in the proposed Duplex container. Wherever applicable, the sponsor implemented CAPA proportional to the relevant risks in order to ensure that the overall benefit-risk ratio was maintained.

A Risk Management Plan was not required because the proposed drug product did not contain a new active substance. However, the sponsor provided foreign post-marketing safety reports (Periodic Benefit Risk Evaluation Reports) covering the period from April 2015 (when the drug was approved in the United States) to December 2021. These were literature-based reports of adverse drug reactions. No new safety issues were identified for the product. The safety profile of the drug had not changed since its launch in September 2015 in the United States and remains favorable.

Following the review of the data submitted by the sponsor, Health Canada has determined that the overall benefit-harm-uncertainty profile of Meropenem for Injection USP and Sodium Chloride Injection USP in the Duplex container is favorable when used under the conditions of use recommended in the approved Product Monograph. Therefore, A Notice of Compliance was recommended.

For further details about Meropenem for Injection USP and Sodium Chloride Injection USP, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.