Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 2-5 September 2024
EMA recommends measures to minimise serious outcomes of known side effect with painkiller metamizole
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EMA recommends 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
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.
After reviewing data on the risk of agranulocytosis for metamizole, the PRAC concluded that the existing warnings in the product information need 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.
More information is available in EMA’s public health communication and in the section “New safety information for healthcare professionals” below.
New recommendations to minimise the risk of meningioma with medicines containing medroxyprogesterone acetate
Increased risk of meningioma seen in people taking high doses of medroxyprogesterone acetate for several years
The PRAC has recommended measures to minimise the risk of meningioma, a type of brain tumour, with medicines containing medroxyprogesterone acetate.
These medicines are used for gynaecological (including contraception and endometriosis) and oncological indications.
Meningiomas are tumours of the tissue layer surrounding the brain and spinal cord. Usually they are benign (non-cancerous) and grow slowly but, depending on the size or location, they can cause serious problems.
The committee’s recommendations followed a review of data from epidemiological studies, case studies from the medical literature and cases reported in the pharmacovigilance database of the European Union. These data show an increased risk of meningioma in people taking high doses of medroxyprogesterone acetate (injectables and ≥100 mg tablets) for several years. Although the relative risk of meningioma is significantly increased with the use of high-dose medroxyprogesterone acetate, the absolute risk is very small.
PRAC recommended that, in patients who have a meningioma or have had one in the past, medicines containing high-dose medroxyprogesterone acetate must not be used, unless medroxyprogesterone acetate is needed for the treatment of an oncological indication.
PRAC also recommended that patients taking high doses of medroxyprogesterone should be monitored for symptoms of meningioma, which can include change in vision, hearing loss or ringing in ears, loss of smell, headaches, memory loss, seizures and weakness in arms and legs. If a patient treated for a non-oncological indication is diagnosed with meningioma, treatment with high-dose medroxyprogesterone acetate must be stopped. If a patient treated for an oncological indication is diagnosed with meningioma, the need for further treatment with high-dose medroxyprogesterone should be carefully considered, on a case-by-case basis, taking into account individual benefits and risks.
The product information for medicines containing high-dose medroxyprogesterone acetate will be updated to include meningioma as a possible side effect of unknown frequency.
More information is available in the section “New safety information for healthcare professionals” below.
PRAC elects Liana Martirosyan as vice-chair
The PRAC has elected Dr Liana Martirosyan, from the Medicines Evaluation Board in the Netherlands, as its vice-chair for a three-year mandate which will take effect from 30 September 2024. Dr Martirosyan started serving as an alternate PRAC member as of September 2018 and has been a PRAC member from the Netherlands since December 2023. She is a medical doctor, holds a master degree in Public Health and a PhD in pharmacoepidemiology. She follows Dr Martin Huber, from BfArM – the Federal Institute for Drugs and Medical Devices in Germany - who has been in the role of vice-chair for a total of six years.
New safety information for healthcare professionals
Metamizole: measures to minimise the serious outcomes of known risk of agranulocytosis
This DHPC will inform healthcare professionals on important measures to minimise serious outcomes of the known risk of idiosyncratic agranulocytosis, which may be fatal, with metamizole-containing medicines. 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. However, the condition may occur at any time during treatment and even shortly after treatment discontinuation.
Metamizole is contraindicated in patients who had metamizole-induced agranulocytosis or agranulocytosis caused by similar medicines known as pyrazolones or pyrazolidines, impaired bone marrow function or diseases of the haematopoietic system.
Patients treated with metamizole-containing medicines should be informed of the early symptoms of agranulocytosis including fever, chills, sore throat and painful mucosal changes, especially in the mouth, nose and throat or in the genital or anal region. Patients should also remain vigilant for these symptoms throughout treatment and shortly following treatment discontinuation, as agranulocytosis may have a delayed onset. They need to discontinue treatment and seek immediate medical attention if they develop these symptoms.
In patients receiving concomitant antibiotic therapy, agranulocytosis may be asymptomatic.
If agranulocytosis is suspected, 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.
Medroxyprogesterone: increased risk of meningioma with high doses and after prolonged use
The PRAC has agreed a direct healthcare professional communication (DHPC) to inform healthcare professionals of the increased risk of developing meningioma with high doses of medroxyprogesterone acetate (all injectable and ≥100 mg oral formulations), primarily after prolonged use (several years). The DHPC will highlight that medicines containing high doses of medroxyprogesterone acetate, when used for contraception or non-oncological indications, are contraindicated in patients with meningioma or with a history of meningioma. If a meningioma is diagnosed in a patient treated with high doses medroxyprogesterone acetate, treatment must be stopped.
If a meningioma is diagnosed in an oncological patient treated with high doses medroxyprogesterone acetate, the need to continue the treatment should be carefully reconsidered, on a case-by-case basis taking into account individual benefits and risks.
Patients treated with high doses medroxyprogesterone acetate should be monitored for signs and symptoms of meningioma in accordance with clinical practice.
Medicines for chemotherapy containing 5-fluorouracil: in patients with moderate or severe renal impairment, phenotyping for dihydropyrimidine dehydrogenase (DPD) deficiency by measuring blood uracil levels should be interpreted with caution
Medicines for chemotherapy containing 5-fluorouracil (5-FU)are part of the standard therapy for various cancers, including colorectal, pancreatic, gastric, breast, and head and neck cancer.
The enzyme dihydropyrimidine dehydrogenase (DPD) is made up in the liver and helps the body break down thymine and uracil. Patients with impaired DPD enzyme function are at increased risk of severe or life-threatening toxicity when treated with 5-FU or one of its prodrugs.
To identify these patients, pre-treatment testing for DPD deficiency is recommended, despite uncertainties regarding optimal testing methodology.
Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with 5-FU or other medicines of the same class (fluoropyrimidines).
Patients with partial DPD deficiency are at increased risk of severe and potentially life‑-threatening toxicity. To limit the risk of severe toxicity, a reduced starting dose should be considered. Subsequent doses may be increased in the absence of serious toxicity, as the efficacy of a reduced dose has not been established.
The PRAC has agreed a DHPC to inform healthcare professionals about the fact that if blood uracil levels are used to determine the DPD phenotype, the phenotype result must be interpreted with caution in patients with moderate or severe renal impairment, as renal impairment can lead to increased blood uracil levels. This could result in an incorrect diagnosis of DPD deficiency and consequently underdosing of 5-FU or other fluoropyrimidines in these patients.
Once adopted, the DHPCs for metamizole, medroxyprogesterone and 5-fluorouracil will be disseminated to healthcare professionals by the marketing authorisation holders, according to an agreed communication plan, and published on the Direct healthcare professional communications page and in national registers in EU Member States.
Agenda
PRAC statistics: September 2024
Glossary
- Safety signal assessments. A safety signal is information which suggests a new potentially causal association, or a new aspect of a known association between a medicine and an adverse event that warrants further investigation. Safety signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature. More information can be found under 'Signal management'.
- Periodic safety update reports, abbreviated as PSURs, are reports prepared by the marketing authorisation holder to describe the worldwide safety experience with a medicine in a defined period after its authorisation. PSURs for medicinal products that contain the same active substance or the same combination of active substances but have different marketing authorisations and are authorised in different EU Member States, are jointly assessed in a single assessment procedure. More information can be found under 'Periodic safety update reports: questions and answers'.
- Risk management plans, abbreviated as RMPs, are detailed descriptions of the activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicines. Companies are required to submit an RMP to EMA when applying for a marketing authorisation. RMPs are continually updated throughout the lifetime of the medicine as new information becomes available. More information is available under 'Risk-management plans'.
- Post-authorisation safety studies, abbreviated as PASSs, are studies carried out after a medicine has been authorised to obtain further information on its safety, or to measure the effectiveness of risk-management measures. The PRAC assesses the protocols (aspects related to the organisation of a study) and the results of PASSs. More information can be found under 'Post-authorisation safety studies'.
- Referrals are procedures used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines. In a referral related to safety of medicines, the PRAC is requested by a Member State or the European Commission to conduct a scientific assessment of a particular medicine or class of medicines on behalf of the EU. More information can be found under referral procedures.
Ongoing referrals
| Procedure | Status | Update |
|---|---|---|
| Metamizole containing medicinal products - referral | Under evaluation | PRAC continued its assessment |