Regulatory Decision Summary for Esamuze

The purpose of this New Drug Submission (NDS) was to obtain market authorization for Esamuze (bendamustine hydrochloride for injection) for the treatment of patients with relapsed indolent B-cell non-Hodgkin lymphoma who did not respond to or progressed during or shortly following treatment with a rituximab regimen, and for the treatment of patients with symptomatic chronic lymphocytic leukemia who have received no prior treatment.

This submission was filed for the same medicinal ingredient and intended for the same indications, dose, and route of administration as the Canadian Reference Product for bendamustine hydrochloride. However, Esamuze was filed as a New Drug Submission because it is a ready-to-dilute solution that contains a higher concentration of bendamustine hydrochloride than the Reference Product.

As the active medicinal ingredient and proposed indications for Esamuze (bendamustine hydrochloride for injection) are identical to those of the Canadian Reference Product, Treanda, the sponsor submitted summaries of clinical efficacy, safety, pharmacology, and non-clinical data primarily derived from published literature and the Treanda Product Monograph.

Key clinical pharmacology and non-clinical findings were consistent with other bendamustine products authorized in Canada. The excipients used in Esamuze-polyethylene glycol 300 and butylated hydroxytoluene - are not expected to impact the clinical activity or pharmacokinetics of bendamustine.

Efficacy data supporting Esamuze for the proposed indications were based on two pivotal trials conducted with Treanda. The first was a multicentre, open-label, single-arm trial involving 100 patients with indolent B-cell non-Hodgkin lymphoma who were non-responsive to or had progressed following a rituximab regimen. The second was a randomized, open-label trial comparing bendamustine to chlorambucil in 319 previously untreated patients with Binet stage B or C chronic lymphocytic leukemia. These studies provided evidence supporting the efficacy of bendamustine for the proposed indications.

The safety profile of Esamuze was informed by the pivotal trials and post-market experience described in the Treanda Product Monograph. All significant safety risks identified for other bendamustine products in Canada are considered applicable to Esamuze and are reflected in the Warnings and Precautions section of the Esamuze Product Monograph.

Esamuze is supplied as a ready-to-dilute solution with a concentration of 45 mg/mL, which is higher than the concentrations of other bendamustine products currently available in Canada (5 mg/mL after reconstitution or 25 mg/mL in solution). This difference introduces a potential risk for medication errors due to confusion between multiple formulations and concentrations.

A Risk Management Plan (RMP) for Esamuze (version 2.0, dated December 22, 2021) was submitted and reviewed by Health Canada. The RMP was considered acceptable. The sponsor was requested to submit quarterly reports of Canadian cases of medication errors to the Marketed Health Products Directorate for two years following approval. Submission of Periodic Safety Update Reports (PSURs) was not required, as the safety profile of bendamustine has been sufficiently characterized through long-term post-market experience with Treanda.

The submission was found to comply with the quality data requirements outlined in Section C.08.002 of the Food and Drug Regulations. The labelling documents were reviewed and considered acceptable, conforming to applicable regulatory requirements and guidance documents.

Esamuze contains the same active medicinal ingredient, is indicated for the same conditions, and is intended to be administered at the same concentrations as other bendamustine products authorized in Canada. However, it is supplied as a 45 mg/mL concentrated solution rather than a lyophilized powder. Safety concerns related to medication errors are considered manageable under the proposed conditions of use. Therefore, Esamuze is considered to have a favourable benefit-risk profile.

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