Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC)

Update to information on psychiatric disorders for chloroquine and hydroxychloroquine

EMA’s safety committee (PRAC) has recommended updating the product information for all chloroquine or hydroxychloroquine-containing medicines following a review of all available data that confirmed a link between the use of these medicines and the risk of psychiatric disorders and suicidal behaviour.

The review was initiated in May 2020 after EMA had been informed by the Spanish Medicines Agency AEMPS of six cases of psychiatric disorders in patients with COVID-19 who were given higher than authorised doses of hydroxychloroquine. Chloroquine and hydroxychloroquine are authorised in the EU for the treatment of certain autoimmune diseases, such as rheumatoid arthritis and lupus, as well as for prophylaxis and treatment of malaria. They are not authorised for the treatment of COVID-19, but both medicines have been used as off-label treatment in patients with the disease. However, chloroquine and hydroxychloroquine have not shown any beneficial effects in treating COVID-19 in large randomised clinical trials.

In view of their use during the COVID-19 pandemic, EMA had reminded healthcare professionals of the risks of these medicines in April and in May 2020. It is already known that chloroquine and hydroxychloroquine, even used in approved doses for authorised indications, can cause a wide spectrum of psychiatric disorders. Psychotic disorders and suicidal behaviour are listed in the product information of some chloroquine or hydroxychloroquine-containing medicines as rare side effects or side effects occurring at an unknown frequency.

The review confirmed that psychiatric disorders have occurred and may sometimes be serious, both in patients with and without prior mental health problems. Based on the available data, the review showed that, for hydroxychloroquine, the side effects may occur in the first month after the start of treatment. For chloroquine, there was not sufficient data to establish a clear timeframe.

The PRAC recommends updating the product information for these medicines to provide better information to healthcare professionals and patients on the risk of suicidal behaviour and psychiatric disorders.

Patients using chloroquine or hydroxychloroquine medicines who experience mental health problems (e.g. irrational thoughts, anxiety, hallucinations, feeling confused or feeling depressed, including thoughts of self-harm or suicide), or others around them who notice these side effects, should contact a doctor straight away.

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.