The European Medicines Agency (EMA) has published the conclusions of a study on medicines containing metamizole, such as the well-known Nolotil. The report, published by the Spanish Agency for Medicines and Health Products (AEMPS), indicates that the benefit of medicines containing metamizole outweighs the risks in the authorized indications and reinforces measures to facilitate the early identification of symptoms and treatment of agranulocytosis.
The EMA reviewed the risk of agranulocytosis associated with the use of metamizole (alone or in combination with other active substances) in June 2024, at the request of the Finnish Medicines Agency. This review follows the request of the marketing authorisation holder to withdraw the only authorised product containing metamizole in that country, following the reporting of several cases of agranulocytosis.
Based on the assessment of all available scientific evidence, the EMA’s European Pharmacovigilance Risk Assessment Committee (PRAC) has concluded that its withdrawal is not appropriate, while warning that the information available to date does not exclude or confirm a higher risk in populations with specific ethnic or genetic characteristics.
What is agranulocytosis?
Agranulocytosis is a decrease in granulocytes, cells of the immune system that help us defend ourselves against infectious agents. In the most severe cases, it can be fatal, by limiting the body’s defenses against bacteria, viruses or other pathogens. The suspicion that metamizole may trigger this problem is the reason why it is not sold in France, the United Kingdom and Scandinavian countries such as Sweden, Norway or Denmark.
This reaction causes fever, chills, oropharyngeal pain, rhinitis, pharyngitis, genital tract inflammation, and anal inflammation. In severe cases, it can be fatal, by limiting the body’s defenses against bacteria, viruses, or other pathogens. It has also been noted that clozapine, an antipsychotic, can cause agranulocytosis.
These serious adverse effects on the immune system are the reason why metamizole is not available in all European countries: it is not marketed in France, the United Kingdom and Scandinavian countries such as Sweden, Norway or Denmark.
Patient request
In Spain, the lawsuit brought by the Association of People Affected by Drugs (ADAF) against the Spanish Ministry of Health and the Spanish Agency for Medicines and Health Products (AEMPS) for failing to protect British citizens from adverse effects – even fatal ones – linked to the consumption of metamizole has raised concerns, even though the authorities have always insisted that it is a safe medicine.
The EMA and the AEMPS had already issued a warning in 2018 recalling that metamizole is a medicine subject to medical prescription and should only be used for short-term treatments at the minimum effective doses, monitoring the appearance of symptoms suggestive of agranulocytosis.
The new conclusions of the PRAC assessment must be ratified by the EMA Coordination Group (CMDh), which includes all European medicines agencies. The updated information will be included in the technical data sheet (information for healthcare professionals) and the package leaflet (information for citizens) of medicines containing metamizole, available in the Information Centre. Online of the AEMPS Medicine (CIMA).
On sale since 1969
Nolotil has been marketed in Spain since 1969 to treat moderate or severe acute postoperative or post-traumatic pain, such as colic or tumoral pain, as well as high fever that does not respond to other therapeutic measures, including first-line antipyretics. As its technical specifications and package insert clearly indicate, these are its approved indications and, therefore, it should not be used for other types of pain.
Considered a nonsteroidal anti-inflammatory drug (NSAID), its active ingredient is metamizole or dipyrone. NSAIDs, the most commonly used group of anti-inflammatories, produce an analgesic, antipyretic (fever-reducing) and anti-inflammatory effect through the inhibition of cyclooxygenase enzymes, but they can also negatively affect the digestive system.
As Víctor López Ramos, full professor of pharmacology at the San Jorge University, recalled in a recent article, the main problem is that it is often not used correctly, even due to medical malpractice. For example, it is very common to find people who use Nolotil or Metamizole for headaches, musculoskeletal pain or stomach aches. There are even patients who drink the injectable ampoules, practically self-administering a dose four times higher than that contained in a capsule.
In Spain, its use has become popular due to its low price, availability and because the profile of gastrointestinal and renal adverse effects appears more favorable compared to other NSAIDs such as ibuprofen.
Information for healthcare professionals (source: AEMPS)
- Treatment with metamizole may cause agranulocytosis, a very rare but potentially fatal side effect due to infections that may occur.
- Agranulocytosis is not dependent on the dose of metamizole administered and its symptoms may appear at any time during treatment, even shortly after its completion. It can also occur in patients previously treated without complications.
- Patients should be advised to stop treatment and seek medical advice immediately if they develop symptoms suggestive of agranulocytosis, such as fever, chills, sore throat and painful changes in the mucous membranes, particularly of the mouth, nose and throat, or in the throat. The use of metamizole, by reducing fever, may make this symptom go unnoticed. Similarly, in patients receiving antibiotic treatment, symptoms may be less obvious or masked.
- If symptoms suggest agranulocytosis, a complete blood count should be obtained immediately and treatment should be discontinued without waiting for the results.
- Metamizole should not be administered to patients who have previously experienced agranulocytosis due to metamizole or other pyrazolones or pyrazolidines (e.g., drugs containing propyphenazone), or to patients with impaired bone marrow function or diseases of the haematopoietic system.
- Since agranulocytosis may develop unpredictably at any time during treatment and the effectiveness of monitoring blood counts has not been demonstrated, the recommendation to perform such monitoring has been removed.
Information for patients (source: AEMPS)
- Metamizole is a medicine used to treat moderate to severe acute pain and high fever, which may cause agranulocytosis (a sudden decrease in a type of white blood cell, called granulocytes, which play an important role in fighting infections).
- Agranulocytosis, although very rare, is a serious adverse effect that can be fatal because it promotes infections.
- Agranulocytosis can occur at any time during treatment or shortly after stopping treatment, even if treatment has been used previously without problems.
- If you experience the following symptoms, you should stop using metamizole and seek medical advice immediately as they may indicate possible agranulocytosis: chills, fever, sore throat and painful ulcers on the mucous membranes, especially in the mouth, nose and throat, or in the genital or anal area. Your doctor will perform a test to measure the level of blood cells.
- If you take metamizole for fever, some symptoms of agranulocytosis may go unnoticed.
- If you are given antibiotics, the typical symptoms of agranulocytosis may be less obvious or masked, because antibiotics can reduce the manifestation of infections and the characteristic symptoms.
- If you have ever had agranulocytosis or other serious changes in your blood counts after being treated with metamizole or other medicines in the same class, for example propyphenazone, you should never take this medicine.
