Regulatory Decision Summary for METOJECT SUBCUTANEOUS

Bioavailability was compared between the 10 mg/mL methotrexate solution given by intramuscular (IM) and subcutaneous (SC) administration, as well as between the 50 mg/mL and the 10 mg/mL methotrexate formulation by SC administration. Analysis of comparative pharmacokinetic data concluded that rate and extent of absorption are similar when methotrexate is administered intramuscularly or subcutaneously. Further, since methotrexate sodium is considered to be a simple aqueous solution that is completely absorbed when administered parenterally, the extent of exposure between the IM and SC routes of administration will have similar area under the plasma drug concentration-time curve (AUC) profiles.

The sponsor provided the requested chemistry and manufacturing data to support the new strengths (12.5 mg, 17.5 mg, and 22.5 mg) allowing for gradual dosing titration improving safe use of the product, as per the dosing recommendations. It is considered that the methotrexate efficacy profile of the currently approved IM route of administration is similar to the proposed SC route of administration.

Support for efficacy, safety and tolerability of subcutaneous methotrexate was provided through literature references, as well as clinical study MC-MTX.6/RH, which demonstrated efficacy and safety of 10 mg/mL subcutaneously administered methotrexate, compared to oral methotrexate, in rheumatoid arthritis patients. Additionally, clinical and non-clinical data showed acceptable local tolerance and improved tolerability of the subcutaneous 50 mg/ml compared to the 10 mg/mL formulation. The proposed concentration allows for a reduced volume of the same dose to be administered compared to the currently approved product with improved tolerability. These data, along with the clinical pharmacology data, and the long established market history of methotrexate in the proposed indications support approval.

The availability of a SC route of administration for methotrexate allows for alignment with current treatment guidelines and clinical practice. The benefit risk assessment of the proposed 50 mg/mL concentration is favorable.