Regulatory Decision Summary for Bortezomib Injection

The purpose of this New Drug Submission (NDS) by Dr. Reddy’s Laboratories Ltd. was to gain market authorization for a new liquid formulation of bortezomib (bortezomib injection). This liquid formulation of bortezomib differs from the formulation of the innovator product Velcade, which is a sterile lyophilized powder for injection. Although there are many generic versions of Velcade, this is the first liquid formulation of bortezomib that has been submitted to Health Canada for review and is not a generic of Velcade.

To support the market authorization of Bortezomib Injection, the sponsor conducted a comprehensive review of the literature on the effectiveness of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib is a proteasome inhibitor that directly targets myeloma cells, and acts in the bone marrow micro-environment by inhibiting the binding of myeloma cells to bone marrow stromal cells. Bortezomib, as part of a combination therapy, has been effective in patients with previously untreated multiple myeloma and relapsed/refractory multiple myeloma. Bortezomib is also effective and well tolerated when used as part of a first-line regimen in previously untreated multiple myeloma, patients with untreated multiple myeloma not eligible for transplantation, and patients who were previously untreated prior to transplantation. In addition, bortezomib in combination with thalidomide and dexamethasone has been shown to improve clinical outcomes in patients with newly diagnosed multiple myeloma when used before and after double autologous transplantation. Finally, bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone has been effective in the treatment of previously untreated mantle cell lymphoma unsuitable for stem-cell transplantation.

The sponsor has provided an overview of the clinical safety of the bortezomib drug product that stemmed from the published literature. The most commonly reported adverse reactions during treatment with Bortezomib are nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnea, rash, herpes zoster and myalgia.

Serious adverse reactions reported during treatment with Bortezomib include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy.

The literature review also provided insights to the non-clinical and clinical studies that support the use of the proposed drug product for the treatment of multiple myeloma or mantle cell lymphoma.

The physicochemical properties (pH, osmolarity and surface tension) of Bortezomib Injection did not conform with Health Canada’s Pharmaceutical Quality of Aqueous Solutions guidance. Therefore, the sponsor was requested to provide scientific justification in support of the observed deviations. Upon review, the sponsor’s justification in support of differences in the physicochemical properties (pH, osmolarity and surface tension) of the proposed drug formulation was considered acceptable. The differences observed are not expected to impact the overall clinical pharmacology, safety and efficacy of bortezomib.

A Risk Management Plan (RMP) for Bortezomib Injection was submitted by Dr. Reddy’s Laboratories Ltd. to Health Canada. In a consultation with the Patient Safety Section (PSS), the risk of medication error was not recommended for inclusion in the RMP based on the fewer preparation steps required prior to use as compared to the lyophilized powder products, the sufficiency of the proposed labelling to address the risk, and the absence of a need for additional risk minimization measures. Routine pharmacovigilance activities are in place to monitor the safety profile of Bortezomib Injection. No additional pharmacovigilance activities are proposed. Overall, the RMP is acceptable. No follow-up is required.

Although the sponsor did not conduct clinical or non-clinical studies, the overall benefit-harm-uncertainty profile of the proposed drug product is considered favorable. Since the proposed drug product has the same active pharmaceutical ingredient, indications, dosage regimens, conditions of use and route of administration as the reference product currently approved for the Canadian market (Velcade), the benefit-risk-uncertainty profile is expected to be consistent with that of the reference product.

Based on the review of data regarding safety and efficacy, the benefit-risk-uncertainty assessment of the proposed bortezomib drug product for the treatment of patients with multiple myeloma or mantle cell lymphoma is favorable. A Notice of Compliance (NOC) is recommended.

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