Regulatory Decision Summary for Methofill Self-Dose Injector

The purpose of this New Drug Submission (NDS) was to obtain market authorization for Methofill Self-Dose Injector (methotrexate injection), filed by Accord Healthcare Inc., via the Drug Submissions Relying on Third-Party Data (SRTD) pathway. Methofill Self-Dose Injector is a drug-device combination product consisting of an injectable methotrexate (as methotrexate sodium) formulation in a single-use prefilled auto-injector for subcutaneous administration.

The sponsor submitted the application in support of a 50 mg/mL fixed concentration of methotrexate available in eight different volumes corresponding to 7.5 mg to 25 mg of methotrexate in 2.5 mg increments.

The proposed indication was:

Methofill Self-Dose Injector (methotrexate injection) is indicated as a disease-modifying antirheumatic drug (DMARD) for:

• Severe disabling psoriasis/psoriatic arthritis in adult patients

• Severe disabling rheumatoid arthritis (RA) in adult patients

Upon review, the indication was revised to the following approved indication:

Methofill Self-Dose Injector (methotrexate injection) is indicated as a disease-modifying antirheumatic drug (DMARD) in the following diseases where standard therapeutic interventions fail:

• Severe disabling psoriasis/psoriatic arthritis in adult patients

• Severe disabling rheumatoid arthritis (RA) in adult patients

Methofill Self-Dose Injector is a drug-device combination product containing methotrexate sodium in an auto-injector. The active pharmaceutical ingredient in a prefilled syringe was previously approved by Health Canada in 2019. Methotrexate is a synthetic drug listed on the Prescription Drug List and has been approved internationally for over 70 years.

The submission was filed in accordance with Health Canada’s Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). As such, the safety and efficacy of Methofill Self-Dose Injector were supported by published literature on low-dose methotrexate products and comparable product labelling.

Scientific literature demonstrated that self-administration of methotrexate, including via auto-injector, can reduce the burden of weekly clinic visits for patients. This approach is supported by the Canadian Arthritis Association. A Human Factors Study and a Simulated Clinical Use Study were submitted to support the usability of the injection procedure and the effectiveness of the device’s sharps injury prevention features.

The submission met the quality requirements outlined in Health Canada’s Pharmaceutical Quality of Aqueous Solutions guidance. The lot formulation and manufacturing process used in the comparative physico-chemical study were representative of those proposed for commercial production.

Clinical pharmacology data were derived from scientific literature and demonstrated that the pharmacokinetics and pharmacodynamics of Methofill Self-Dose Injector are comparable to other approved methotrexate products.

The sponsor provided literature supporting the established efficacy of methotrexate in the treatment of rheumatic disorders. Evidence was presented for doses ranging from 5 mg to 25 mg per week in the treatment of severe psoriasis, psoriatic arthritis, and rheumatoid arthritis. Efficacy was demonstrated both as monotherapy and in combination with standard treatments for severe psoriasis and rheumatoid arthritis, with relevant clinical outcomes observed within 24 weeks and maintenance of efficacy up to 84 weeks in rheumatoid arthritis patients. When used according to the approved labelling, the efficacy of Methofill Self-Dose Injector is expected to be consistent with other approved subcutaneous methotrexate products.

The safety profile of methotrexate is well established through extensive clinical use. Methotrexate is associated with serious and potentially life-threatening toxicities, including gastrointestinal, hepatic, hematologic, pulmonary, renal, neurologic, reproductive, and dermatologic adverse effects. Methotrexate is contraindicated in patients who are pregnant or breastfeeding, have severe renal impairment, chronic liver disease, immunodeficiency syndromes, or pre-existing blood dyscrasias.

The Product Monograph for Methofill Self-Dose Injector includes detailed information on serious and common adverse reactions, as well as guidance on preventive and corrective measures. Known drug interactions, including the contraindicated use with nitrous oxide anesthesia, are included. To mitigate the risk of dosing errors—particularly inadvertent daily instead of weekly administration—the Product Monograph, internal and external labelling, and Patient Card include bold warnings. The Human Factors Study demonstrated that trained patients and caregivers can accurately use the device when deemed competent by a healthcare provider. The device includes a passive sharps injury protection system, which was successfully deployed in 560 tests by a relevant population.

An updated Risk Management Plan for Methofill Self-Dose Injector was reviewed by Health Canada and considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Methofill Self-Dose Injector for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Methofill Self-Dose Injector, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.