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 European Medicines Agency (EMA) published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 28 November – 1 December 2022. Following the meeting, a decision was made on the need to introduce safety-related changes to the registration materials/instructions for medical use of certain medicinal products.
Further follow-up of PSUR/PSUSA
Methotrexate (methotrexate) – EMEA/H/C/003983/LEG 005
Scope: Comprehensive reviews of the available evidence on the mechanism of genotoxic action of methotrexate according to the conclusions of the PSUR single assessment procedure (PSUSA) (PSUSA/00002014/202110), completed in June 2022.
Background
Following the assessment of the latest submitted PSUR(s) for the medicinal product(s) containing methotrexate, the registration certificate holders (RCHs) were asked to provide additional data on the mechanism of the genotoxic action of methotrexate. For reference, see the PRAC minutes of June 2022. The responses were assessed in order to provide further PRAC recommendations.
Summary of recommendations and conclusions
- Based on the available data and assessment, and also taking into account the response of the Safety Working Party (SWP) to the question of the Coordination Group for Mutual Recognition and Decentralized Procedures – Human (CMDh) regarding “recommendations on the duration of contraception after the end of treatment with a medicinal product that causes genotoxicity”, the PRAC agreed that the instructions for medical use should be amended to shorten the duration of contraception after the end of treatment with methotrexate for men from six to three months, and the same applies to donor sperm.
- The registration certificate holder must submit the changes within 60 days in order to update1 the instructions for medical use accordingly.
1Update of the sections “Special warnings and precautions for use” and “Use during pregnancy or breastfeeding” of the instructions for medical use.
Safety issues for discussion at the request of a member state of the European Union (EU)
Methotrexate – DE/H/PSUFU/00002014/202110
Scope: PRAC consultation on the PSUR follow-up procedure (PSU FU) with an assessment of comprehensive reviews of the available evidence on the genotoxic mechanism of action of methotrexate, as discussed at the PRAC meeting and agreed by the CMDh following completion of the PSUR single assessment procedure (PSUSA) (PSUSA/00002014/202110), completed in June 2022 at the request of Germany.
Background
Methotrexate is a folic acid analogue indicated for the treatment of various types of cancer, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, breast carcinoma, small cell lung cancer, epidermoid tumors of the head and neck, ovarian carcinoma, and osteosarcoma, as well as autoimmune diseases, such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, and Crohn's disease, under certain conditions.
Based on the evaluation of the latest PSUSA procedure for methotrexate (methotrexate) (PSUSA/00002014/202110), completed in June 2022, PRAC decided that the reviews of available evidence on the mechanism of genotoxic action of methotrexate (methotrexate) require further evaluation. For additional information, see the minutes of the PRAC meeting of June 2022.
At the request of the CMDh, the registration certificate holders of medicinal products containing methotrexate (methotrexate) (registered under the national procedure) provided the necessary safety reviews for evaluation within the PSUR follow-up procedure (PSU FU). In the context of the ongoing evaluation of the PSU FU procedure (DE/H/PSUFU/00002014/202110), Germany, as the lead member state (LMS), asked PRAC to provide advice on its assessment.
Summary of recommendations
- Based on the analysis of the available information and evidence, PRAC supported the LMS assessment that the instructions for medical use should be updated to reflect the duration of contraception for male patients, which should last at least 3 months after the end of treatment with methotrexate, and that the same recommendations should apply to sperm donation. PRAC also agreed that the recommendations on the duration of contraception for female patients should remain unchanged (i.e., for the last 6 months after discontinuation of treatment with methotrexate).
Follow-up assessment report on the PSUR, regarding amendments to the instructions for medical use of medicinal products containing methotrexate
Based on the analysis of the data provided, PRAC considers that the instructions for medical use should be updated as follows:
Registration certificate holders (RCHs) of medicinal products containing methotrexate must adapt the instructions for medical use to ensure that the changed threshold value (3 instead of 6 months) is properly reflected.
Update of the section “Use during pregnancy or breastfeeding” of the instructions for medical use in order to amend the recommendations on contraception for men.
It is recommended to amend the instructions for medical use of medicinal products containing methotrexate (new text is underlined and in bold, deleted text is struck through):
All medicinal products containing methotrexate (methotrexate):
Section “Use during pregnancy or breastfeeding”
Contraception recommendations for men should be amended as follows:
Contraception in men
[…]
As a precaution, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 3 months after discontinuation of methotrexate. Men should not donate sperm during treatment or for 6 3 months after discontinuation of methotrexate.
Changes to the safety information of medicinal products containing methotrexate following the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 7 – 10 June 2022
The European Medicines Agency (EMA) has published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 7 – 10 June 2022. Following the meeting, it was decided that safety-related changes are needed to the registration materials/instructions for medical use of certain medicinal products.
Methotrexate (methotrexate) – PSUSA/00002014/202110
Background
Methotrexate (methotrexate) is a folic acid analogue. For oncological indications, methotrexate (methotrexate) is indicated under certain conditions for the treatment of choriocarcinoma, chorioadenoma, acute lymphoblastic leukemia (ALL), breast cancer, cervical cancer, ovarian carcinoma, testicular carcinoma, bladder cancer, epidermoid tumors of the head and neck, mycosis fungoides, lung cancer, non-Hodgkin lymphomas, meningeal lymphoma, histiocytic and lymphatic lymphoma, Burkitt lymphoma, osteosarcoma, and meningeal leukemia. For non-oncological indications, methotrexate (methotrexate) is indicated under certain conditions for the treatment of active rheumatoid arthritis in adult patients, severe polyarthritic forms, active juvenile idiopathic arthritis when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate, severe psoriasis vulgaris in adult patients that cannot be adequately treated by conventional methods, and mild to moderate Crohn’s disease, either alone or in combination with corticosteroids, in adult patients who are resistant to or intolerant of thiopurines.
Based on the evaluation of Periodic Safety Update Reports (PSURs), the PRAC reviewed the benefit/risk balance of medicinal products containing methotrexate and provided the following 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) in the approved indications remains unchanged.
- The current registration materials/instructions for medical use of medicinal products containing methotrexate remain unchanged.
- In the next PSUR, registration certificate holders of medicinal products containing methotrexate that have indications requiring low-dose methotrexate therapy should provide a review of skin cancer, including melanoma.
Based on the recommendations of the CHMP Safety Working Party (SWP) on "recommendations on the duration of contraception following the end of treatment with a medicinal product that causes genotoxicity" (EMA/CHMP/SWP/74077/2020 corr. 3*) and the received reviews of the available evidence on the mechanism of genotoxic action of methotrexate, the PRAC considers that the current recommendations on the duration of contraception following the end of treatment with methotrexate for men and women should be reviewed further. In addition, the PRAC considers that the findings of Grosen et al. (2021) on the presence of methotrexate in semen should be reviewed further in the context of the use of medicinal products containing methotrexate for indications requiring low-dose methotrexate therapy. Further consideration should be carried out at the CHMP/CMDh level.
Перелік лікарських засобів, що містять метотрексат (methotrexate) та дозволені до медичного застосування в Україні (за даними Державного реєстру лікарських засобів станом на 13.06.2023 року).
For the analysis of published information, the applicant must use the original text posted at the links:
