18th June 2002
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Mrs Heather Simmonds
Code of Practice Authority
12 Whitehall
London SW1A 2DY.

Dear Mrs Simmonds

Case AUTH/1318/5/02 Safety of Seroxat (paroxetine)

We acknowledge receipt on 22 May 2002 of a complaint made by Mr Charles Medawar on 20 May 2002 to the ABPI. The complaint related to comments attributed to Mr Alan Chandler, Director of Corporate Media UK, an employee of the GlaxoSrnithKline 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).

Our response to the complaint is detailed below. However, we do not consider it appropriate to discuss the interpretation of the selection of unverified comments from users of paroxetine supplied as Appendix 2 of the complaint (which has been submitted to our Clinical Safety department for review as part of our standard adverse event reporting process).

INDEPENDENT October 2001
The comment attributed to Mr Chandler in the Independent (October 2001) states (referring to paroxetine and other SSRIs) ‘There’s no reliable scientific evidence to show they cause withdrawal symptoms or dependency’. Mr Chandler corrected this in his letter of 17^th October 2001 (copy enclosed) where he stated that he was not referring to withdrawal symptoms. Contrary to what is stated in the letter of complaint he did not say in that letter that he had been correctly quoted. In response to the reporter, Mr Chandler intended to convey that SSRIs are not reliably shown to cause addiction/dependency.

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 is often used synonymously with the term addiction. In 2000, following a comprehensive review, The European Agency for the Evaluation of Medical Products (EMEA)/The Committee for Proprietary Medicinal Products (CPMP) released a position paper on "Selective Serotonin Uptake Inhibitors (SSRIs) and Dependency/Withdrawal reaction." (copy enclosed). They endorsed the conclusions of the April 1998 Committee on Safety of Medicines (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 that the CPMP consider this issue, further evaluation of the clinical evidence relating to dependence associated with SSRIs was carried out by France and Germany, 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. With respect to discontinuation or withdrawal, they recommended that the key elements of withdrawal reaction statements in the Summaries of Product Characteristics (SmPC) should be harmonised throughout the European Union and recommended the following, among other things:

• A statement that although withdrawal reactions may occur on stopping therapy, the available preclinical and clinical evidence does not suggest that SSRIs cause dependence.

• A list of symptoms reported in association with withdrawal reactions for that product.

• A statement that the majority of withdrawal reactions are mild and self-limiting.

• Advice that prescribers should consider gradual dose reduction when stopping treatment.

In accordance with the recommendations of the CPMP, the Seroxat SmPC states under section 4.8 (undesirable effects),’In common with other SSRIs, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. Dizziness, sensory disturbance (eg paraesthesia), anxiety, sleep disturbances (including intense dreams), agitation, tremor, nausea, sweating and confusion have been reported following abrupt discontinuation 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.’ In accordance with these principles, the relevant sections of the briefing document approved for use in October 2001 were as follows:

Addiction

• Seroxat, unlike for example, smoking or alcohol, 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

• Abrupt stopping of any antidepressant can result in a small number of patients experiencing discontinuation symptoms.

• These symptoms — such as dizziness — are generally mild, short-lasting and self-limiting.

• As recommended by The British National Formulary (BNF) and the EMEA, the likelihood of these symptoms is minimised by gradually tapering the daily dose.

• Seroxat’s high volume of usage compared to other SSRIs means that clinicians may perceive these symptoms occur more frequently with Seroxat. It is important to remember that this is a class effect and can occur with all SSRIs.

• The Seroxat SmPC states: In common with other SSRIs, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. Dizziness, sensory disturbance (eg paraesthesia), anxiety, sleep disturbances (including intense dreams), agitation, tremor, nausea, sweating and confusion have been reported following abrupt discontinuation 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.

MENTAL HEALTH TODAY April 2002
The comments reported in Mental Health Today (Apr 2002), were: ‘You have a product that’s been available for over 10 years and has benefited tens of millions patients. As more patients use the product globally you are bound to get these reports of bizarre side effects’, says Alan Chandler, director of Corporate Media UK. ‘There is no scientific evidence that Seroxat leads to addiction and dependency. There have been one or two reports of discontinuation symptoms with abrupt cessation, which is why our data sheets taper off the medication. The data sheet is a living document and as usage of the product increases the labelling reflects the current usage experience’.

There are two specific parts of this statement that Mr Medawar discusses in his complaint. Firstly, ‘there is no scientific evidence that Seroxat leads to addiction and dependency’. Secondly, ‘there have been one or two reports of discontinuation symptoms with abrupt cessation’

With regard to the first part, we concur with Mr Medawar that this comment is consistent with the Seroxat SmPC, and clearly also with the briefing document enclosed. The relevant sections of this briefing document approved for use in December 2001 and used since then states:

Discontinuation

• Stopping any antidepressant can result in some patients experiencing discontinuation symptoms. The most common of these symptoms may include dizziness, sensory disturbances, agitation, anxiety, nausea and sweating. In most cases these symptoms are mild to moderate in nature and self-limiting.

• As recommended by the BNF and the EMEA, the likelihood of discontinuation symptoms is minimised by gradually tapering the daily dose.

• 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 Seroxat Summary of Product Characteristics (SmPC) states that: "In common with other SSRIs, withdrawal symptoms have been reported on stopping treatment. The available evidence does not suggest these are due to dependence. Dizziness, sensory disturbance (eg paraesthesia), anxiety, sleep disturbances (including intense dreams), agitation, tremor, nausea, sweating and confusion have been reported following abrupt discontinuation 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."

Addiction / Dependence.

• 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.

• The European Regulatory Body the CPMP have recently completed (April 2000) a thorough review of safety data collected following the discontinuation of all SSRIs and other newer serotonergic antidepressant medications. The MCA (Medicines 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.

All these statements are supported by published data and the Seroxat SmPC. As stated above, we believe that the EMEA/CPMP position paper on SSRIs and Dependency/Withdrawal Reactions (2000) provides a comprehensive and clear recommendations that were incorporated within the Seroxat SmPC and hence into our briefing document.

The anecdotal reports of adverse events reported by users of paroxetine from the Social Audit website supplied as Appendix 2 of the complaint, have been reported to our Clinical Safety department as part of our standard adverse event reporting procedure. However, we believe that Social Audit Ltd’s website is not a source of valid and reliable data, presenting many potential biases and containing unverified data. We do not believe it should be considered ‘available evidence’ within the meaning of the Code of Practice. We hope that Social Audit Ltd advise any patients reporting adverse events, that their treating physicians should be notified in order that they can complete appropriate Yellow Card reporting of their symptoms to the Committee on Safety of Medicines (CSM).

With regard to the specific comment attributed to Mr Chandler that ‘There have been one or two reports of discontinuation symptoms with abrupt cessation’ the position of GlaxoSmithKline (GSK) with respect to discontinuation of Seroxat is clearly enunciated in the relevant briefing document (December 01) given above. We acknowledge that the statement attributed to Mr Chandler by Mental Health Today is not consistent with this briefing document. This statement was attributed to Mr Chandler as part of a ‘long conversation with Catherine Jackson initiated by media interest in changes to the product data sheet and patient leaflet for the antidepressant Seroxat’ (letter to Mr Medawar 3^rd May 2002 enclosed). Mr Chandler explains in his letter to Mr Medawar, that he could not remember the precise details of the conversation with the journalist, but that if detailed figures had been required, referral to an appropriate medical expert in the company would have been made.

In summary, the statement ~there have been one or two reports of discontinuation symptoms with abrupt cessation’ attributed to Mr Chandler is not consistent with the briefing document. However, the information in our briefing document is consistent with our Seroxat SmPC and published data, being a factual and balanced document, which underwent the required internal approval process.

As no transcripts are available, there is difficulty in ascertaining exactly what was said in the conversation between Mr Chandler and the journalists. Nevertheless, the statement in the Independent (Oct 01), referring to paroxetine and other SSRIs, as made by Mr Chandler (see letter of 17th October 2001) is consistent with our SmPC and briefing document and we do not believe this statement has led to a breach of the Code of Practice. The comment reported in Mental Health Today (Apr 02) of ‘There is no scientific evidence that Seroxat leads to addiction and dependency’ is consistent with the briefing document and the Seroxat SmPC. As such, we do not accept that a breach of Clauses 3.2, 7.2, 7.9 and 20.2 of the Code of Practice has occurred, with respect to that specific comment. However, the comment ‘There have been one or two reports of discontinuation symptoms with abrupt cessation’ is not consistent with either the appropriate briefing document (Dec 01) nor the Seroxat SmPC.

Hence we accept that, if the statement was made by Mr Chandler, a breach of Clauses 3.2, 7.2, 7.9 and 20.2 of the Code of Practice has occurred with respect to this specific comment.

Finally, GSK has fully accepted the previous IFPMA ruling and Mr Chandler has been fully compliant with all of Mr Medawar’s regular requests, with appropriate written responses within adequate timelines. GSK takes this very seriously and we deny that a breach of Clause 2 of the Code of Practice has occurred.

Yours sincerely

E Gray
General Manager & Senior Vice President

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