In accordance with paragraph 8 of Section IV of the Procedure for Expert Evaluation, the applicant must amend the instructions for medical use of the medicinal product upon receipt of new data, including bringing the instructions for medical use into line with the approved instructions for medical use of the original (reference) medicinal product, and ensure that the information on the medicinal product corresponds to current scientific knowledge.
The Pharmacovigilance Risk Assessment Committee (PRAC), based on the analysis of Periodic Safety Update Reports (PSURs) for medicinal products containing methotrexate, PSUSA/00002014/202510, reached the following conclusions.
In view of the data available in the literature and in spontaneous reports on epidermal necrosis, including in some cases a close temporal relationship and a positive de-challenge, and given the plausible mechanism of action, the PRAC considers that a causal relationship between the use of methotrexate and epidermal necrosis is at least reasonably possible. The PRAC concluded that the instructions for medical use of medicinal products containing methotrexate should be amended accordingly.
Having considered the PRAC recommendations, the Committee for Medicinal Products for Human Use (CHMP) agrees with the overall conclusions of the PRAC and the grounds for the recommendations.
Based on the scientific conclusions on methotrexate, the CHMP considers that the benefit / risk balance of medicinal products containing methotrexate remains unchanged, provided that the proposed changes are made to the instructions for medical use.
Changes to be made to the relevant sections of the instruction for medical use (new text underlined and in bold).
All medicinal products containing methotrexate:
“Special precautions for use” section
The following warning should be added:
Toxic effects on the skin
[If another heading with a similar meaning is already used in the section, the additional wording should be added under the corresponding heading.]
During methotrexate use, cases of epidermal necrosis have been reported, mostly accompanied by leukopenia, thrombocytopenia, and mucosal lesions (see the section “Adverse Reactions”). This skin reaction may clinically resemble Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Patients should be informed of the signs and symptoms of severe cutaneous adverse reactions and should seek immediate medical attention from their doctor if they notice any signs or symptoms suggestive of such reactions. If signs and symptoms suggestive of these reactions occur, methotrexate should be discontinued immediately and appropriate treatment should be started. The use of folinic acid has been described for the treatment of epidermal necrosis. Methotrexate should not be restarted until SJS and TEN have been ruled out.
“Adverse reactions” section
The following adverse reaction should be added to the System Organ Class (SOC) “Skin and subcutaneous tissue disorders” with a frequency of “not known”:
epidermal necrosis
[If skin necrosis is already listed, updating the section “Adverse reactions” to add epidermal necrosis is not required.]
Changes to the safety information of medicinal products containing methotrexate following the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 08 – 11 June 2026
The European Medicines Agency (EMA) has published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) held on 08 – 11 June 2026. Following the meeting, it was decided that safety-related changes need to be made to the registration materials/instructions for medical use of medicinal products containing methotrexate.
Methotrexate (methotrexate) – YLAMVO; NORDIMET – PSUSA/00002014/202510
Methotrexate – an analog of folic acid belonging to the therapeutic classes of antimetabolites and immunosuppressants. It is used as a chemotherapeutic agent and, in low doses, to treat certain autoimmune diseases.
Based on the evaluation of periodic safety update reports (PSURs), the PRAC reviewed the benefit/risk balance of the medicinal products YLAMVO (methotrexate), NORDIMET (methotrexate), and other medicinal products containing methotrexate, and provided relevant recommendations.
Summary of recommendations and conclusions
- Based on the analysis of safety and efficacy data, the benefit/risk balance of medicinal products containing methotrexate (methotrexate) for the approved indications remains unchanged.
- At the same time, the instructions for medical use should be updated to include epidermal necrosis as an adverse reaction with a frequency of “unknown”. Accordingly, appropriate changes should be made to the current instructions for medical use1.
- In the next PSUR, registration certificate holders (RCHs) must apply generally accepted guidelines for the assessment of causality [e.g., those of the WHO Uppsala Monitoring Centre (UMC)], report cases of overdose and errors associated with the use of the medicinal product separately by dosage form and region within the European Economic Area (EEA) and outside it, and continue to evaluate the effectiveness of risk minimization measures in accordance with Article 31 regarding the use of the medicinal product once a week in inflammatory diseases. In addition, RCHs must ensure appropriate reporting of reproductive toxicity, include the geographical distribution of skin cancer cases, provide updated information or statements regarding identified risks where relevant (only for the RCHs Easymed, Laboratorios Gebro Pharma and Oresund Pharma), and submit a cumulative review of electrolyte imbalance with a proposed term and distribution by system organ class (SOC). Finally, RCHs must provide comments on limiting the list of safety concerns in the PSUR to the core list, which includes important identified risks for all indications, and for non-oncology indications one important potential risk of skin cancer, including malignant melanoma, without including missing information.
- The registration certificate holder (RCH) Pfizer Limited must submit an application for a variation under the worksharing procedure (worksharing variation), within which Germany acts as rapporteur, providing for a comprehensive review and discussion of pharmacokinetic interactions between methotrexate and anticonvulsant medicinal products (in particular levetiracetam, phenytoin, valproate and carbamazepine), including the consequences of such interaction for both methotrexate and the relevant anticonvulsant medicinal product. As part of this review, it should be assessed whether there is a justified need to update the instructions for medical use or to take specific clinical measures, distinguishing between the use of methotrexate at low doses (in inflammatory diseases) and at high doses (in hematological oncology indications).
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1Update of the sections “Special warnings and precautions for use” and “Adverse reactions” of the package insert. The risk assessment report and PRAC recommendations are forwarded to the CHMP for a decision.
List of medicinal products containing methotrexate and approved for medical use in Ukraine (according to the State Register of Medicinal Products as of 15.09.2026). (16 KB) (Downloaded: 16.09.2026 12:57:49)
TO ANALYZE THE PUBLISHED INFORMATION AND SUBMIT THE RELEVANT APPLICATION FOR AMENDMENTS TO THE REGISTRATION MATERIALS, THE APPLICANT MUST USE THE ORIGINAL TEXT AVAILABLE AT THE FOLLOWING LINKS:
