Methotrexate containing medicinal products - referral

Current status

European Commission final decision

Overview

New measures to avoid potentially fatal dosing errors with methotrexate for inflammatory diseases

On 22 August 2019 EMA recommended new measures to prevent serious and potentially fatal errors with the dosing of methotrexate for treating inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn’s disease. The recommendations result from a review of reports that patients are using methotrexate incorrectly despite previous measures to prevent errors.

For inflammatory conditions, methotrexate must be used just once a week. Using methotrexate more frequently than intended can result in serious side effects. The review found that the error in dosing frequency can occur at any step from prescribing the medicine to the patient taking it.

The new measures to prevent errors include restricting who can prescribe these medicines, making warnings on the packaging more prominent and providing educational materials for patients and healthcare professionals. In addition, to help patients follow the once-weekly dosing, methotrexate tablets will be provided in blister packs and not in bottles (or tubes). The measures were agreed after consultation with patients and healthcare professionals.

Information for patients

• If you are taking methotrexate for rheumatoid arthritis, psoriasis or Crohn’s disease, you must take it just once a week.
• Take your methotrexate medicine on the same day every week.
• Follow the instructions on the packaging of your methotrexate medicine.
• You will receive a patient card with your methotrexate tablets (or oral liquid). Read it carefully because it tells you how to take your medicine.
• Show your patient card to any new healthcare professional who treats you so that they know that you take your methotrexate medicine once a week.
• See your doctor at once if you get a sore throat, fever, mouth ulcers, diarrhoea, vomiting, skin rashes, bleeding or unusual weakness. These can be signs of taking too much methotrexate.
• Always attend your scheduled clinic visits and blood test appointments. They are important for making sure that your methotrexate medicine is working and that it is not causing any concern.
• If you are not sure about how to take your methotrexate medicine or you have any questions about it, talk to your doctor or pharmacist.

Information for healthcare professionals

• Methotrexate for inflammatory conditions is intended for use just once a week. Serious side effects including fatalities have occurred when methotrexate is taken more often.
• Only physicians with expertise in using methotrexate medicines should prescribe them.
• Healthcare professionals who prescribe or dispense methotrexate for inflammatory conditions should:
  • read the educational materials for oral methotrexate medicines;
  • ensure that they are familiar with the latest changes to the summaries of product characteristics for methotrexate medicines used for inflammatory conditions;
  • give clear instructions to the patient (or carer) about once-weekly dosing;
  • check carefully that the patient (or carer) understands that the medicine must be used once a week, and do this each time a new prescription is issued or the medicine is dispensed;
  • decide together with the patient (or carer) on which day of the week the patient uses methotrexate;
  • counsel the patient (or carer) about signs of methotrexate overdose and give instructions to promptly seek medical advice in case of suspected overdose.

More about the medicine

Methotrexate is authorised in the EU for two different groups of indications, each with a different administration schedule:

• treatment of cancer for which the dosing frequency depends on the regimen and can involve daily administration of methotrexate;
• treatment of inflammatory diseases including rheumatoid arthritis, psoriasis and Crohn’s disease, which require once-weekly use of a low dose of methotrexate.

Methotrexate can be taken orally or given by injection.

Most methotrexate-containing medicines have been authorised via national procedures. They are marketed in all EU countries under several brand names including: Ledertrexate, Maxtrex, Metex and Metoject. Jylamvo (for use by mouth) and Nordimet (for injection) are the only centrally authorised medicines containing methotrexate.

More about the procedure

The review of methotrexate medicines was initiated on 22 March 2018 at the request of the Spanish Agency for Medicines and Health Products, under Article 31 of Directive 2001/83/EC.

The review was carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. The PRAC recommendations were sent to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted the Agency’s opinion. The CHMP opinion was forwarded to the European Commission, which issued final legally binding decisions for Nordimet on 17 October, Jylamvo and the nationally authorised methotrexate medicines on 21 October. The decisions are applicable in all EU Member States.

Methotrexate Article-31 referral - New measures to avoid potentially fatal dosing errors with methotrexate for inflammatory diseases

Adopted Reference Number: EMA/587673/2019

Key facts

About this medicine

• Approved name:
  Methotrexate containing medicinal products
• International non-proprietary name (INN) or common name:
  methotrexate
• Associated names:
  • Nordimet
  • Jylamvo
  • Jylamvo
  • Nordimet
  • Ledertrexate
  • Maxtrex
  • Metex
  • Metoject

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1463
• Type:
  Article 31 referrals

  This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

• Authorisation model:
  Centrally and nationally authorised products (mixed)
• Decision making model:
  PRAC-CHMP-EC

Key dates and outcomes

• Procedure start date:
  12/04/2018
• PRAC recommendation date:
  11/07/2019
• CHMP opinion date:
  22/08/2019
• EC decision date:
  21/10/2019
• Outcome:
  Risk minimisation measures

All documents

Procedure started

Methotrexate Article-31 referral - Notification

Methotrexate Article-31 referral - Review started

Methotrexate Article-31 referral - Timetable for the procedure

Reference Number: EMA/PRAC/199744/2018 Rev.3

Methotrexate Article-31 referral - Annex I

Methotrexate Article-31 referral - PRAC list of questions

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Methotrexate Article-31 referral - PRAC recommends new measures to avoid dosing errors with methotrexate

Reference Number: EMA/384938/2019

Opinion provided by Committee for Medicinal Products for human Use

Methotrexate Article-31 referral - Jylamvo : EPAR - Product Information

Methotrexate Article-31 referral - Annex IV

Methotrexate Article-31 referral - Annex II

Methotrexate Article-31 referral - Annex I

Methotrexate Article-31 referral - Annex III

Methotrexate Article-31 referral - New measures to avoid potentially fatal dosing errors with methotrexate for inflammatory diseases

Reference Number: EMA/414775/2019

European Commission final decision

Methotrexate Article-31 referral - Public assessment report - EMEA/H/A-31/1463

Reference Number: EMA/521627/2019

Methotrexate Article-31 referral - New measures to avoid potentially fatal dosing errors with methotrexate for inflammatory diseases

Adopted Reference Number: EMA/587673/2019

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.