Regulatory Decision Summary for Nordimet

This New Drug Submission (NDS) was filed by Nordic Group B.V. via the Drug Submissions Relying on Third Party Data (SRTD) pathway for the drug/device combination product Nordimet. This product consisted of an injectable methotrexate (MTX) formulation in a single-use pre-filled pen (autoinjector) for subcutaneous administration. The Sponsor proposed a 25 mg/mL fixed concentration of MTX available in 8 different volumes that corresponded to 7.5 to 25 mg of MTX in 2.5 mg increments.

In the original submission the proposed indications were:

“Nordimet (methotrexate injection) is indicated for as a Disease Modifying Antirheumatic Drug (DMARD) in the following diseases where standard therapeutic interventions fail:

• Treatment of severe disabling active rheumatoid arthritis (RA)

• Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy.

In the treatment of psoriasis, Nordimet should be restricted to severe recalcitrant, disabling psoriasis, which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established after dermatologic consultation.”

Upon review of the Response to Notice of Non-compliance (R-NON) the recommended indications are:

“Nordimet (methotrexate injection) is indicated for as a Disease Modifying Antirheumatic Drug (DMARD) in the following diseases where standard therapeutic interventions fail:

• severe disabling active rheumatoid arthritis (RA) in adult patients

• severe, disabling psoriasis/psoriatic arthritis in adult patients

In the treatment of psoriasis, Nordimet should be restricted to severe recalcitrant, disabling psoriasis, which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established after dermatologic consultation.”

A New Drug Submission was filed, in accordance with the Health Canada Guidance “Drug Submissions Relying on Third-Party Data (Literature and Market Experience)”, to support the approval of Nordimet (Nordic Group Ltd.). Nordimet is a drug/device combination product with the active ingredient methotrexate (MTX) as an aqueous solution (25 mg/mL) contained in an auto-injector for subcutaneous (SC) administration; it has been marketed in the Netherlands and Europe since 2014 and 2016, respectively. Methotrexate is a synthetic drug on the Prescription Drug List that was approved in Canada as a tablet in 1955 and as a solution for injection in 1976. At low doses, MTX acts as a disease-modifying antirheumatic drug that is established to be efficacious for the treatment of inflammatory arthritis and psoriasis.

The current review assessed data that was submitted as part of a Response to a Notice of Non-compliance (R-NON). The NON was issued in April 2023.

The quality data for Nordimet was based originally on a physiochemical comparison with two Health Canada-approved MTX that are authorized for SC and intramuscular (IM) administration. Major and minor issues were identified that warranted the NON. These included missing quality information (rubber stopper composition, results of extractable and leachable study and elemental impurity risk assessment), a difference in the surface tension between the proposed and products used to support the SRTD, and insufficient data to compare the free acid:salt ratio of MTX:methotrexate-sodium in Nordimet and the products used to support the SRTD. In the R-NON, a different and an appropriate physiochemical comparator without benzyl alcohol was used that showed comparable surface tension. All other quality issues were adequately resolved.

Since one of the cited products in the literature differed from Nordimet in route of administration, data demonstrated a lack of significant difference in bioavailability of MTX (7.5 to 15 mg) when equivalent doses were administered by IM vs SC. In the R-NON, literature was provided to support bioequivalence of MTX when administered IM and SC. The totality of evidence was considered sufficient to support the bioavailability and bioequivalence of MTX that is administration SC (i.e., by Nordimet) with MTX that is administered IM.

Primary and review articles provided in the original and the R-NON filing were reflective of the established efficacy of MTX; evidence was supportive of parenteral MTX at doses of 7.5 to 25 mg/week as monotherapy or as part of combination therapy in the treatment of psoriasis (PsO) and rheumatoid arthritis (RA). Data from studies were provided to demonstrate that a change in route of administration from oral to SC MTX can be beneficial. Efficacy for PsO and RA were assessed by relevant disease-specific clinical outcomes. Data to demonstrate the efficacy of MTX treatment of psoriatic arthritis (PsA) was limited, but included a meta-analysis that showed improvement in a single study in a relevant disease-specific clinical outcome. The totality of evidence including long standing history of use in the PsA population and extrapolation from RA and PsO data, was considered supportive. The efficacy of Nordimet is not expected to differ from approved MTX products.

The safety profile of MTX was established with decades of use; high and low doses of MTX have the potential for serious and life-threatening toxicities. Risk mitigation for MTX products, and proposed for Nordimet, include appropriate patient selection and monitoring, labelling, and ongoing pharmacovigilance. Dosing errors with MTX, including inappropriate frequency or device handling, can result in serious adverse reactions; these risks may be elevated when MTX is administered with reduced healthcare professional (HCP) oversite. In the R-NON, the Sponsor provided a Human Factor Study (HFS) that assessed patient/caregiver acceptability and usability of Nordimet. The HFS showed that the Instructions for Use (IFU) combined with Nordimet training was sufficient to support the completion of necessary steps for appropriate use of the auto-injector. The accepted Nordimet Product Monograph (PM) included the same IFU, with minor changes to layout and text for clarity, and a statement that training should be provided prior to delegation of administration.

Interactions between MTX and concomitant drugs were established in the literature; interaction between nitrous oxide anesthesia and MTX is reported to cause nephritis, and so is contraindicated. Additional interactions proposed for inclusion in the Nordimet PM were generally supported by literature or labeling of other MTX products with the exception of the Sponsor proposed inclusion of interaction between MTX with corticosteroids; due to a lack of data, additional support was requested through the NON.

A Risk Management Plan (RMP) for Nordimet submitted by Nordic Group B.V. to Health Canada was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Overall, there is a favourable benefit-harm-uncertainty for the use of Nordimet for the proposed indication when used in accordance with accepted labeling.

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