Dear Mr Medawar,

Thank you for your letters dated 16 April 1998 and 17 June 1998 about withdrawal reactions or dependency-related problems with SSRls antidepressants such as fluoxetine. As explained in our earlier letter sent on 18 February 1998 in reply to your letter dated 2 December 1997, the new European system of Pharmacovigilance for medicinal products relies on the cooperation between the national competent authorities of the Member States and the EMEA.

It is the direct responsibility of the EMEA/CPMP to assess the pharmacovigilance issues relative to centrally authorised products. The centralised authorisation procedure is used for innovative medicinal products derived from biotechnology and new chemical substances.

Nationally authorised products, such as all the Selective Serotonin Reuptake Inhibitors (SSRIs) marketed in Europe, are retained under the responsibility of the Member States where the marketing authorisations are held. However, in specific cases where the interests of the Community are concerned in terms of public health, such matters may be referred to the EMEA for an opinion of its scientific committee, the Committee for Proprietary Medicinal Products (CPMP). A referral for arbitration can also be addressed to the EMEA when no agreement can be reached about the mutual recognition of a national authorisation that is assumed to present a risk for public health.

For your information. such an arbitration has taken place concerning the mutual recognition of a national authorisation for FLUOXETIN NM, a generic medicinal product containing fluoxetine. The subject of this arbitration was not linked to withdrawal reactions or dependency, and it was concluded that the benefit/risk balance for Fluoxetin NM remains positive. However the CPMP has considered appropriate to require a number of changes in the SPC for this product including the addition of a warning against withdrawal reactions to SSRIs. The CPMP was of the opinion that no statement on dependency should be included in the SPC. This CPMP opinion has been transmitted to the European Commission for decision.

The warning adopted by the CPMP is as follows:

"Withdrawal reactions have been reported in association with Selective Serotonin Reuptake Inhibitors (SSRIs). Symptoms typically include nausea and dizziness. Avoid abrupt discontinuation of treatment."

When the decision is taken, a summary of the procedure and the adopted SPC for this generic product will be available to the public on the EMEA web site. The decision will be addressed to all Member States concerned and the Marketing Authorisation Holders. The Member States concerned will have to vary the Marketing Authorisations as necessary to comply with the decision, including the implementation of the revised SPC.

As explained above, variations of the SPC for other fluoxetine containing medicinal products and any other SSRIs marketed in Europe which have been authorised through National procedures remain under the responsibility of the Member States where the marketing authorisations are held. As national ongoing or planned changes in the SPC for such products are not notified to the EMEA, we are not in a position to provide such information. It would have to be requested from the Competent National Health Authorities.

The lists of CPMP members and of Competent National Health Authorities are attached for your information and are also available to the public on the EMEA web site http://www.eudra.org/emea.html The CPMP members are nominated by each national authority by reason of their role and expertise in the evaluation of medicinal products. Their declaration of interest and curriculum vitae are available to the public at the EMEA.

Yours sincerely

Prof Rolf Bass

Head of Human Medicines Evaluation Unit