Subject: Are commonly available antidepressants bad for the health?

E-1975/03EN

Answer given by Mr Liikanen

on behalf of the Commission

(1 August 2003)

The United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) informed the Commission that new data from clinical trials of paroxetine (Seroxat) in children and adolescents were received at the end of May 2003. These new data have been reviewed by an Expert Working Group on SSRIs (selective inhibitor of serotonin reuptake) and the Committee on Safety of Medicines (CSM) of the European Agency for the Evaluation of Medicinal Products. The data do not demonstrate efficacy in depressive illness in this age group and show an increase in the risk of episodes of self-harm and potentially suicidal behaviour in the Seroxat group compared to placebo. Various analyses suggest that the risk of these events is between 1.5 and 3.2 times greater with Seroxat compared to placebo.

On the basis of these data, CSM has advised that Seroxat should not be used in children and adolescents under the age of 18 years to treat depressive illness. Seroxat is not licensed for use in this population under 18 but it is used in this age group outside its licensed indications where prescribers make a judgement on their own responsibility that it is the right treatment for a particular patient.

This advice was communicated to health professionals via the Public Health Link 10 June 2003 and was placed on the MHRA website, along with information for patients. Revised patient information leaflets containing the new advice are being sent to prescribers and pharmacists.

This new safety signal in the paediatric population raises concerns about the balance of risks and benefits of paroxetine. The United Kingdom considers that in the interests of the Community, the balance of risk and benefits of paroxetine should be reassessed.

A referral to the Committee for Proprietary Medicinal Products (CPMP) of the European Medicines Evaluation Agency (EMEA) based on Article 31 of Directive 2001/83 EEC [1] was initiated by the United Kingdom on 12 June 2003. This was discussed at the June 2003 meeting of the CPMP and the procedure has been started.

The issue of withdrawal reactions and suicidal behaviour for Prozac (fluoxetine) was reviewed at European level by the Committee on Proprietary Medicinal Products (CPMP) of the EMEA. This Committee reached the following conclusions in September 2002:

“Based on the information available and the discussion within the Committee, the CPMP considered that the benefit/risk ratio of Prozac is favourable for the use relating to major depressive episodes, obsessive-compulsive disorder and as a complement of psychotherapy in the treatment of bulimia nervosa.”

In the Summary of Product Characteristics the following information must be included:

“4.4 Special warnings and special precautions for use

Suicide:

As improvement may not occur during the first few weeks of treatment, in common with all antidepressants, patients should be closely monitored during this period. The possibility of suicide attempt is inherent in depression and may persist until significant remission occurs. It is general clinical experience with all therapies for depression that the risk of suicide may increase in the early stage of recovery.

4.8 Undesirable effects

When stopping treatment, withdrawal symptoms have been reported in association with SSIRs (selective inhibitor of serotonin reuptake) although the available evidence does not suggest this is due to dependence. Common symptoms include dizziness, paraethesia, headache, anxiety and nausea, the majority of which are mild and self-limiting.

Plasma fluoxetine and norfluoxetine concentrations decrease gradually at the conclusion of therapy, which makes dosage tapering unnecessary in most patients.

4.2 Posology and method of administration

In agreement with the consensus statement of the WHO (World Health Organisation), antidepressant medication should be continued for at least 6 months.

Children: The use of fluoxetine in children and adolescents (under the age of 18) is not recommended, as safety and efficacy have not been established”.

The information is available on the EMEA website. (www.emea.eu.int)

The Pharmacovigilance Working Group of the Scientific Committee of the EMEA is monitoring closely all medicinal products of the class of selective inhibitor of serotonin reuptake (SSRI), including fluoxetine. Previously, in 2000, CPMP agreed core safety warnings for SSRIs in relation to withdrawal symptoms.