Metamizole-containing medicinal products - referral

Current status

European Commission final decision

Overview

Measures to minimise serious outcomes of known side effect with painkiller metamizole

Product information to be updated to raise awareness of known risk of agranulocytosis and facilitate its early detection and diagnosis

On 18 September 2024, the CMDh¹ endorsed the measures recommended by EMA’s safety committee, PRAC, to minimise the serious outcomes of agranulocytosis, a known side effect caused by the painkiller metamizole. Agranulocytosis involves a sudden and sharp decrease in granulocytes, a type of white blood cell, that can lead to serious or even fatal infections.

Metamizole-containing medicines are authorised in a number of EU countries for treating moderate to severe pain and fever. The authorised uses vary from country to country, ranging from the treatment of pain following surgery or injuries to the treatment of cancer-related pain and fever.

Agranulocytosis is a known side effect with metamizole-containing medicines that can occur at any time during treatment or shortly after stopping the medicine, and in people who have used metamizole previously without problems. This serious side effect is not related to the dose of metamizole used. Existing measures in place to minimise this risk vary across countries.

The review was started at the request of the Finnish medicines agency, as cases of agranulocytosis were still being reported with metamizole despite the recent strengthening of risk minimisation measures in Finland.

After reviewing data on the risk of agranulocytosis for metamizole, the PRAC concluded that the existing warnings in the product information needed to be updated. The changes are intended to increase awareness of this serious side effect among patients and healthcare professionals and facilitate its early detection and diagnosis.

The committee recommended that healthcare professionals must inform patients to stop taking these medicines and seek immediate medical attention if they develop symptoms of agranulocytosis. These include fever, chills, sore throat and painful sores on the moist, inner body surfaces (mucosa), especially in the mouth, nose and throat or in the genital or anal regions. Patients must remain alert for these symptoms both during and shortly after stopping treatment.

If metamizole is taken for fever, some early symptoms of agranulocytosis may go unnoticed. Similarly, when antibiotics are used together with metamizole, these symptoms may also be masked.

If patients develop symptoms of agranulocytosis, a test to measure their levels of blood cells, including the levels of different types of white blood cells, must be done immediately. Treatment must be stopped while awaiting the results.

PRAC also recommended that metamizole must not be used in patients who are at increased risk of, or susceptible to, agranulocytosis. This includes patients who previously experienced agranulocytosis caused by metamizole, or similar medicines known as pyrazolones or pyrazolidines, who have problems with their bone marrow or who have a condition that affects how their blood cells are made or work.

The recommendations follow a review of all available evidence, including data from the scientific literature, post-marketing safety data and information submitted by stakeholders such as patients and healthcare professionals. During the review, PRAC sought advice from an expert group of specialists experienced in pain management, haematologists, general practitioners, pharmacists and a patient representative.

The PRAC concluded that the benefits of metamizole medicines continue to outweigh the risks. However, the product information for all metamizole-containing medicines will be updated with these recommendations. The PRAC recommendations were sent to the CMDh, which endorsed them and adopted its position on 18 September 2024.

The European Commission issued a final legally binding decision applicable across the EU on 22 November 2024.

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¹The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

Background

On 18 September 2024, the CMDh¹ endorsed the measures recommended by EMA’s safety committee, PRAC, to minimise the serious outcomes of agranulocytosis, a known side effect caused by the painkiller metamizole. Agranulocytosis involves a sudden and sharp decrease in granulocytes, a type of white blood cell, that can lead to serious or even fatal infections.

Metamizole-containing medicines are authorised in a number of EU countries for treating moderate to severe pain and fever. The authorised uses vary from country to country, ranging from the treatment of pain following surgery or injuries to the treatment of cancer-related pain and fever.

Agranulocytosis is a known side effect with metamizole-containing medicines that can occur at any time during treatment or shortly after stopping the medicine, and in people who have used metamizole previously without problems. This serious side effect is not related to the dose of metamizole used. Existing measures in place to minimise this risk vary across countries.

The review was started at the request of the Finnish medicines agency, as cases of agranulocytosis were still being reported with metamizole despite the recent strengthening of risk minimisation measures in Finland.

After reviewing data on the risk of agranulocytosis for metamizole, the PRAC concluded that the existing warnings in the product information needed to be updated. The changes are intended to increase awareness of this serious side effect among patients and healthcare professionals and facilitate its early detection and diagnosis.

The committee recommended that healthcare professionals must inform patients to stop taking these medicines and seek immediate medical attention if they develop symptoms of agranulocytosis. These include fever, chills, sore throat and painful sores on the moist, inner body surfaces (mucosa), especially in the mouth, nose and throat or in the genital or anal regions. Patients must remain alert for these symptoms both during and shortly after stopping treatment.

If metamizole is taken for fever, some early symptoms of agranulocytosis may go unnoticed. Similarly, when antibiotics are used together with metamizole, these symptoms may also be masked.

If patients develop symptoms of agranulocytosis, a test to measure their levels of blood cells, including the levels of different types of white blood cells, must be done immediately. Treatment must be stopped while awaiting the results.

PRAC also recommended that metamizole must not be used in patients who are at increased risk of, or susceptible to, agranulocytosis. This includes patients who previously experienced agranulocytosis caused by metamizole, or similar medicines known as pyrazolones or pyrazolidines, who have problems with their bone marrow or who have a condition that affects how their blood cells are made or work.

The recommendations follow a review of all available evidence, including data from the scientific literature, post-marketing safety data and information submitted by stakeholders such as patients and healthcare professionals. During the review, PRAC sought advice from an expert group of specialists experienced in pain management, haematologists, general practitioners, pharmacists and a patient representative.

The PRAC concluded that the benefits of metamizole medicines continue to outweigh the risks. However, the product information for all metamizole-containing medicines will be updated with these recommendations. The PRAC recommendations were sent to the CMDh, which endorsed them and adopted its position on 18 September 2024. The CMDh position will now be sent to the European Commission, which will take an EU-wide legally binding decision.

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¹ The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

Information for patients

• Agranulocytosis, a sudden and sharp decrease in granulocytes (a type of white blood cell) that can lead to serious or even fatal infections, is a known side effect with metamizole-containing medicines.
• This side effect can occur at any time during treatment or shortly after stopping the medicine, and in people who have used metamizole previously without problems. It is not related to the dose of metamizole used.
• You must remain alert to the onset of symptoms of agranulocytosis, including fever, chills, sore throat and painful sores in the moist, inner body surfaces (mucosa), especially in the mouth, nose and throat or in the genital or anal regions, both during and shortly after stopping treatment with metamizole-containing medicines.
• If you develop these symptoms, stop taking the medicine and seek urgent medical assistance.
• If metamizole is taken for fever, some early symptoms of agranulocytosis may go unnoticed. Similarly, symptoms may also be masked if you are taking metamizole together with an antibiotic.
• If you develop symptoms of agranulocytosis, your healthcare provider will do a blood test immediately to check your levels of blood cells.
• You must not take these medicines if you have previously experienced agranulocytosis caused by metamizole or similar medicines known as pyrazolones or pyrazolidines, if you have problems with your bone marrow or if you have a condition that affects how your blood cells are made or work.
• The product information of the various metamizole-containing medicines lists agranulocytosis as a rare or very rare side effect, and in some cases a side effect whose frequency is not known. Although warnings are already in place to minimise this risk, the product information will be updated with more detailed information on how to recognise the symptoms of agranulocytosis and when to consult your doctor.
• If you have any questions or concerns about your medicines, speak with your doctor or pharmacist.

Information for healthcare professionals

• Metamizole-induced agranulocytosis is not dose-dependent and can occur at any time during treatment or shortly following discontinuation, even in patients who have used these medicines previously without complications.
• Patients treated with metamizole must be instructed to discontinue treatment and seek immediate medical attention if they develop symptoms of agranulocytosis and to remain vigilant for these symptoms throughout treatment and shortly following discontinuation, as agranulocytosis may have a delayed onset.
• If metamizole is taken for fever, some early symptoms of agranulocytosis may go unnoticed. Similarly, symptoms may also be masked if metamizole is taken concomitantly with an antibiotic.
• If patients develop symptoms of agranulocytosis, a blood count (including differential blood count) should be performed immediately, and treatment must be discontinued before test results are available. If agranulocytosis is confirmed, treatment must not be reintroduced.
• Routine monitoring of blood counts in patients is no longer recommended as the review did not identify any evidence to support its effectiveness for early detection of metamizole-induced agranulocytosis.
• Metamizole is contraindicated in patients with a previous episode of metamizole-induced agranulocytosis or agranulocytosis induced by other pyrazolones or pyrazolidines, impaired bone marrow function or diseases of the haematopoietic system.
• Warnings are already in place to minimise this risk. However, the product information will be updated to strengthen the existing warnings to raise awareness among patients and healthcare professionals and facilitate early detection and diagnosis of metamizole-induced agranulocytosis.

A direct healthcare professional communication (DHPC) including the above recommendations will be sent in due course to healthcare professionals prescribing, dispensing or administering these medicines. The DHPC will also be published on a dedicated page on the EMA website.

More about the medicine

Metamizole (also known as dipyrone) is an analgesic medicine (painkiller). It has been used in the EU since the 1920s and is taken by mouth, suppository or injection, to treat moderate to severe pain and fever. The review includes both medicines containing metamizole alone and those containing metamizole in combination with other active substances.

Metamizole-containing medicines are authorised in a number of EU countries: Austria, Belgium, Bulgaria, Croatia, Czech Republic, Germany, Hungary, Italy, Latvia, Lithuania, Luxembourg, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia and Spain. In Finland, the only authorised metamizole-containing medicine was withdrawn.

They are available under a range of names including Afexil, Algifen, Algifen Neo, Algi-Mabo, Algocalmin, Algopyrin, Algozone, Alindor, Alkagin, Alvotor, Analgin, Benlek, Berlosin, Buscapina Compositum, Dialginum, Dolocalma, Flamborin, Gardan, Hexalgin, Locamin, Metagelan, Metalgial, Metamistad, Metamizol, Metapyrin, Natrijev, Nodoryl, Nofebran, Nolotil, Novalgin, Novalgina, Novalgine, Novaminsulfon, Novocalmin, Panalgorin, Piafen, Piralgin, Pyralgin, Pyralgina, Quarelin, Scopolan Compositum, Spasmalgon and Tempalgin.

More about the procedure

The review of metamizole-containing medicines was initiated on 13 June 2024 at the request of the Finnish medicines agency, under Article 107i of Directive 2001/83/EC.

The review has been 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 Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted its position. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. As the CMDh position was adopted by majority vote, it was sent to the European Commission, which issued a final legally binding decision applicable in all EU Member States.

Metamizole-containing medicinal products article 107i referral - Measures to minimise serious outcomes of known side effect with painkiller metamizole

Reference Number: EMA/407900/2024

Key facts

About this medicine

• Approved name:
  Metamizole-containing medicinal products
• International non-proprietary name (INN) or common name:
  metamizole

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-107i/1537
• Type:
  Article 107i procedures

  This type of procedure is triggered when a Member State or the European Commission consider that urgent action is necessary because of a safety issue. Situations that fall under this procedure include consideration for suspension or revocation of the marketing authorisation for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorisation such as deletion of indications, reduction of the recommended dose or new contraindications. The procedure is also applicable in case of a safety issue with a class of medicines.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  13/06/2024
• PRAC recommendation date:
  05/09/2024
• CMDh position date:
  18/09/2024
• EC decision date:
  22/11/2024

Data submission

The Agency invites all stakeholders (e.g. healthcare professionals, patients' organisations, the general public) to submit data relevant to this procedure. This is in accordance with Article 107j(1) of Directive 2001/83/EC.

The following requirements apply for data to be considered:

• Submissions must be accompanied by the submission form, with all fields completed:

  Metamizole-containing medicinal products article 107i referral - Stakeholders submission form

  This form needs to be opened with a PDF reader. EMA advises to save the document first, and then open with a PDF reader, such as Acrobat Reader.

• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions.
• The submission of all data should take place by 1 July 2024

Submitting data

Send the completed form electronically to the stakeholders' submission inbox ([e-mail]). Specify the name of the medicine in the subject line of the e-mail.

The size of the submission file should not exceed 25 MB. If your attempt to send your data package to the dedicated e-mail address is unsuccessful, please use alternative submission means.

It is of the utmost importance that data are provided promptly, to avoid undermining the safety review. Due to the urgent nature of the procedure, you are strongly advised to submit your data in English.

Protection of personal data

Personal data submitted are subject to data-protection rules as established by Regulation (EC) 45/2001. They will be treated in accordance with the European Medicines Agency’s privacy statement public and targeted consultations.

Treatment and publication of data

Data submitted will be received and recorded by the Agency.

The Agency will prepare a list of all submissions received, which will be published as an annex to the PRAC assessment report for transparency purposes and public awareness.

Please note that all data submitted in the context of this procedure may be shared and disclosed in the public domain.

All documents

Procedure started

Metamizole-containing medicinal products article 107i referral - Notification

Metamizole-containing medicinal products article 107i referral - Stakeholders submission form

Metamizole-containing medicinal products article 107i referral - Timetable for the procedure

Reference Number: EMA/PRAC/264725/2024 Rev. 2

Metamizole-containing medicinal products article 107i referral - Scientific background

Metamizole-containing medicinal products article 107i referral - List of questions to marketing authorisation holder(s)

Reference Number: EMA/PRAC/264726/2024

Metamizole-containing medicinal products article 107i referral - Review of painkiller metamizole started

Metamizole-containing medicinal products article 107i referral - List of questions to stakeholders

Reference Number: EMA/PRAC/264723/2024

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Metamizole-containing medicinal products article 107i referral - EMA recommends measures to minimise serious outcomes of known side effect with painkiller metamizole

Reference Number: EMA/407900/2024

Position provided by CMDh

Metamizole-containing medicinal products article 107i referral - Annex II

Metamizole-containing medicinal products article 107i referral - Assessment report

Adopted Reference Number: EMA/470471/2024

Metamizole-containing medicinal products article 107i referral - Divergent positions to CMDh position

Metamizole-containing medicinal products article 107i referral - Annex III

Metamizole-containing medicinal products article 107i referral - Annex I

Draft Reference Number: EMA/280148/2024 Rev. 1

Metamizole-containing medicinal products article 107i referral - Measures to minimise serious outcomes of known side effect with painkiller metamizole

Reference Number: EMA/407900/2024

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.