EMA’s safety committee, PRAC, has recommended measures 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 will now be sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)1 for consideration at its next meeting in September.
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.
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 is being 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
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 has made a set of recommendations.
The PRAC recommendations will now be sent to Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which will adopt a position. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.
1The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway