Metamizole (dipyrone)

Is metamizole safe?

For most people who take it for a few days, metamizole works well and causes few side effects. The exception is rare but serious: agranulocytosis, a sudden collapse in the white blood cells that fight infection. It does not depend on the dose, can start after a single course or weeks into treatment, and was fatal in about 16% of suspected cases reported to the EU's safety database between 1985 and 2017. We score metamizole 66, below ibuprofen (74) and acetaminophen (77), mainly for that risk and its regulatory history.

Metamizole, also called dipyrone, is a non-opioid painkiller that also lowers fever and relaxes cramping muscle. The EMA lists it as authorised in 19 EU countries, including Germany (Novalgin), Spain (Nolotil), Poland (Pyralgin), Italy, Romania and the Czech Republic, for severe pain and fever that other treatments do not control. It is also widely used in Latin America. It is not sold in the US.

EU doses were aligned in 2019. People aged 15 and over can take up to 1,000 mg by mouth per dose, up to four times a day (4,000 mg a day), or up to 5,000 mg a day by injection, starting with the lowest dose. Children's doses go by weight. Individual products differ: Spain's Nolotil 575 mg capsules allow one capsule up to six times a day, a maximum of 3,450 mg.

How common is agranulocytosis?

Estimates vary widely, which is part of the controversy. A prospective study in all 51 Berlin hospitals found 0.96 cases per million people a year from 2000 to 2010. Other studies cited in a 2023 review put it as high as 1 in 1,602 prescriptions. A Spanish cohort of 444,972 new users found agranulocytosis about four to seven times more often than with NSAIDs, although only 26 cases occurred across all groups.

What the studies agree on:

• It can occur at any dose, at any time during treatment, and shortly after stopping.
• It can occur in people who took metamizole before without problems, and comes on faster after re-exposure (median 6 days against 15 days in EU reports).
• Older people and those also taking methotrexate had more fatal outcomes.
• Early warning signs are fever, chills, sore throat and painful mouth or genital sores.

The 2024 EU review

The Finnish medicines agency asked for a review because cases were still being reported despite stricter national measures. On 18 September 2024 the CMDh endorsed the recommendations of the EMA's safety committee (PRAC), and the European Commission made them legally binding on 22 November 2024.

The PRAC concluded that the benefits continue to outweigh the risks, but the product information was strengthened:

• Patients must be told to stop the medicine and seek immediate medical help if symptoms of agranulocytosis appear, during treatment or shortly after.
• A full blood count must be done straight away, with treatment stopped while waiting for the result.
• Metamizole must not be used by people with past agranulocytosis from metamizole or related pyrazolones, bone marrow problems or disorders of blood cell production.
• Prescribers are warned that fever may be masked when metamizole is taken for fever or with antibiotics.

Other risks and interactions

EU product information also lists severe allergic reactions including anaphylactic shock, sudden drops in blood pressure (especially in people who are dehydrated or have unstable circulation) and drug-induced hepatitis, which has occasionally needed a liver transplant. It must not be used in the last three months of pregnancy or while breastfeeding.

Important interactions include methotrexate (combination to be avoided), lower levels of bupropion, efavirenz, methadone, valproate, ciclosporin, tacrolimus and sertraline, a weaker antiplatelet effect of low-dose aspirin, severe hypothermia with chlorpromazine, and stronger effects of alcohol. In overdose it causes nausea, kidney failure and, more rarely, seizures, coma or shock; there is no antidote. In the UK call 111, or in the US Poison Control on 1-800-222-1222.

How we scored it

Dependence (95), track record (85) and overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (75) are reasonable. Interactions (60) and serious side effects (55) reflect agranulocytosis, anaphylaxis and several drug interactions. Regulatory warnings (30) is the weakest factor: withdrawn in the US and other countries, with stronger EU warnings in 2024. Anyone prescribed metamizole should know the warning signs above; talk to your doctor or pharmacist about whether it suits you.