22 August 2002 Stockley Park West Uxbridge Middlesex UB11 1BT Tel. +44 (0)20 8990 9000 Fax. +44 (0)20 8990 4321 www.gsk.com
Mr Peter Clift, Executive OfficerDear Mr Clift,
Code of Practice Authority
London SW1A 2DY.
Case AUTH/1318/5/02 Safety of Seroxat (paroxetine)
We acknowledge receipt on 7 August 2002 of an appeal to the above complaint, made by Mr Charles Medawar on 1 August 2002 and appreciate the opportunity to comment.
The original complaint related to comments attributed to Mr Alan Chandler, Director of Corporate Media UK, an employee of the GlaxoSmithKline PLC. These comments were published in a British newspaper, The Independent (October 2001) reported by Anastasia Stephens and in a British journal, Mental Health Today (April 2002) reported by Catherine Jackson. Both articles related to adverse events claimed to be attributable to antidepressants, including Seroxat (paroxetine).
In his appeal, Mr Medawar refers to several separate issues, some of which we do not believe are relevant to the original complaint. Several of these issues relate to our December 2001 briefing document, which we enclosed with our original response.
Regarding Mr Medawars concerns relating to Clause 3.2 of the Code of Practice, this Clause clearly states that the promotion of a medicine must be in accordance with the terms of its marketing authorization and must not be inconsistent with the particulars listed in its summary of product characteristics. This is wholly the case regarding our briefing document and Mr Medawars comments relating to this briefing document, approved for use in December 2001, are unfounded. The statements of concern to Mr Medawar are:Seroxat is not addictive. There are well-defined international criteria for drug dependency and addiction and Seroxat is clearly shown as being neither addictive nor causing dependence. Discontinuation symptoms are completely different to addiction or dependence. Haddad and Young, BMJ 1998 said Discontinuation symptoms do not in themselves indicate drug dependence. Dependence is a syndrome, and diagnosis requires several other features, such as tolerance, inability to control drug use, primacy of drug taking behaviour, and continued use despite harmful consequences. Antidepressants are not associated with these features and are not drugs of dependence. The European Regulatory Body the CPMP (Committee for Proprietary Medicinal Products) have recently completed (April 2000) a thorough review of safety data collected following the discontinuation of all SSRIs and other newer serotonergic antidepressant mediations. The MCA (Medicine Control Agency) and CPMP have concluded that SSRIs do not cause dependency/addiction. There has been no reliable scientific evidence from either preclinical studies, long term clinical trials or clinical experience, to suggest that Seroxat is addictive, shows dependence or is a drug of abuse. As recommended by the British National Formulary (BNF) and the European medicines evaluation agency (EMEA), the likelihood of discontinuation symptoms is minimised by gradually tapering the daily dose.
All these statements from the briefing document are supported by published data and the Seroxat summary of product characteristics (SmPC). Importantly, The European Agency for the Evaluation of Medical Products (EMEA)/ The Committee for Proprietary Medicinal Products (CPMP) position paper on "Selective Serotonin Uptake Inhibitors (SSRIs) and Dependency/Withdrawal reactions" (2000) (copy enclosed) provided comprehensive and clear recommendations that were incorporated within the Seroxat SmPC and hence into our briefing document.
Furthermore, the new evidence that Mr Medawar presents in his appeal letter (the top 20 medicines associated with reports of suspected withdrawal reactions), is taken directly from the UK ADROIT database and represent the total number of suspected withdrawal reactions over time. It is important to note that the unadjusted nature of these data may lead to wide misinterpretation of the relative risks of withdrawal reactions to these antidepressants. In fact, advice is given by the Medicines Control Agency (MCA) in the guidance notes on the ADROIT system, warning against the use of spontaneous reports when making quantitative comparisons between drugs. It states Numerical comparisons should not be made between reactions associated with different drugs on the basis of the data in these prints alone. Comparisons are invalid unless they take account of variations in the level of reporting, the extent of use of the drugs, and a number of other confounding variables. We therefore believe that not only is this evidence not relevant to the original complaint and out of context, but also is misleading, and the detailed analysis and interpretation of such data should be conducted by the MCA. In fact, correspondence (dated from June 2002) between Mr Medawar and the MCA published on the Social Audit website regarding paroxetine/SSRIs and reports of withdrawal/dependence, highlights a potential review of SSRIs by the Committee on Safety of Medicines (CSM), this being the appropriate forum for such a review.
A similar point is made in our original response to Mr Medawars complaint regarding the anecdotal reports of adverse events reported by users of paroxetine from the Social Audit website. The context of the data is of paramount importance and we believe that this website is not a source of valid and reliable data, presenting many potential biases and containing unverified data. We continue to believe that the data on this website should not be considered available evidence within the meaning of the Code of Practice.
Regarding the specific topic of dependence, we would like to reiterate our response to this question in Mr Medawars original complaint, that discontinuation symptoms, also referred to as withdrawal symptoms, comprise a diverse range of symptoms, but do not in themselves indicate drug dependence (1,2). Dependence is a syndrome, and diagnosis requires several other features, such as tolerance, inability to control drug use, primacy of drug taking behaviour, and continued use despite harmful consequences (1). Dependence as it is commonly understood, means the same thing as addiction or substance dependence. In 2000, following a comprehensive review, the EMEA/CPMP released a position paper on SSRIs and Dependency/Withdrawal Reactions (copy enclosed). They endorsed the conclusions of the April 1998 CSM review that had not identified evidence that SSRIs were drugs of dependence, but that the product information for all SSRIs should contain appropriate warnings about well-recognised withdrawal reactions. They noted that, following the request of the European Commission, the CPMP consider this issue and that no evidence that SSRIs were drugs of dependence was found. Based on this and other evidence, the CPMP concluded that the available clinical evidence does not suggest that the SSRIs cause dependence.
We would like to point out that, in accordance with the recommendations of the CPMP, our SITIPC for Seroxat clearly states under Section 4.8 (Undesirable Effects) that In common with other selective serotonin reuptake inhibitors, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. Dizziness, sensory disturbance (e.g. paraesthesia), anxiety, sleep disturbances (including intense dreams), agitation, tremor, nausea, sweating and confusion have been reported following abrupt withdrawal of Seroxat. They are usually mild self-limiting and symptomatic treatment is seldom warranted. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when antidepressive treatment is no longer required, gradual discontinuation by dose-tapering be carried out.
Regarding the issue of Mr Chandlers statements to the journalists, Mr Medawar states that the Panel were unjustified in making their decision because of an inability to determine precisely what had been said. We are not in a position to comment on the actions of the Panel in reaching their decision, but would again refer to our response to Mr Medawars original complaint, acknowledging fully the advice that the Panel have given regarding written back up of oral interviews and good record keeping.
Finally, we welcome your invitation for GlaxoSmithKline to attend the appeal hearing on Thursday 10 October 2002 and would like to put forward Dr Alastair Benbow, Vice President and Head European Clinical Psychiatry and Dr David Briess, Medical Adviser UK Pharma as our representatives. We have no objection to allowing the Director, Secretary and Deputy Secretary to be present during the hearing of the appeal.
General Manager and Senior Vice President
Seroxat (paroxetine) Summary of Product Characteristics (SmPC), June 2002.
The European Agency for the Evaluation of Medical Products (EMEA)/ The Committee for Proprietary Medicinal Products (CPMP) position paper April 2000.
(1)Haddad P, Lejoyeux M, Young A. Antidepressant discontinuation reactions, are preventable and simple to treat. BMJ 1998; 316: 1105-6.
(2)Haddad P. Antidepressant Discontinuation Syndromes, Clinical relevance, Prevention and Management. Drug safety 2001; 24(3): 183-197.
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