Social Audit   Ltd
P O Box 111 London NW1 8XG
Telephone/Fax 44 (0) 207 586 7771
[email protected]


Dr June Raine, Director
Post-Licensing Division
Medicines Control Agency
Market Towers, 1 Nine Elms Lane
London SW8 5NQ

12 October 2002

       Dear Dr Raine,

Paroxetine: withdrawal symptoms and dependence

I should have written before now to acknowledge with thanks your letters of 20 August,
3 September and 13 September. I did also very much appreciate your prompt response to my query about use of that term "discontinuation." Apologies for not coming back to you sooner; I hope my silence wasn’t too burdensome for you.

I am now writing about a number of matters arising in connection with [a] "The Important Safety Message: MCA response to ‘Panorama’ programme on Seroxat"; and [b] from our Appeal against GlaxoSmithKline’s promotion of Seroxat (paroxetine) under the industry code of marketing practice. Please treat these as formal requests for information.

1. The MCA Response to Panorama states, "there have been isolated reports of more serious symptoms on withdrawal …". On what basis does the MCA suggest that more serious reactions have been "isolated", given that [a] the assessment of severity of withdrawal reactions to paroxetine (reported by Price et al., 1996) identified 21% of reported reactions were "severe"? and [b] that the MCA wrote to the manufacturers of Seroxat on 17 April 1998, noting that: "studies had not been carried out of an appropriate design to allow an estimation of the frequency of withdrawal reactions." Have the results of any appropriately designed studies become available since then?

2. The MCA statement suggests that the European Committee on Proprietary Medicinal Products "concluded (that SSRIs) are not drugs of dependence." What the EMEA/CPMP actually said was that, "The available clinical evidence does not suggest that the SSRIs cause dependence. However the lack of evidence does not prove the absence of a problem…"; "For the majority of compounds, evidence from well-designed preclinical studies with respect to dependency and withdrawal was incomplete …". On what basis does the MCA believe these two statements compatible? Would the Agency maintain that there is no risk here that it is both misrepresenting the EMEA/CPMP and misleading the public?

3. The MCA response states, "It is generally accepted that withdrawal reactions on stopping a drug are not sufficient, or necessary, for a diagnosis of drug dependence" Does the MCA have any evidence that this definition is "generally accepted" either by [i] users of antidepressants; and/or [b] prescribers?

The following questions arise from our Appeal against GlaxoSmithKline’s promotion of Seroxat (paroxetine) under the industry code of marketing practice. The Prescriptions Medicines Code of Practice Authority has yet to publish the reasons for its decision, but the key findings are known. Please see our background note (attached) plus the linked correspondence on our website.

Specifically, these questions concern statements made in the "Reactive Key Messages and Issues Document" (19 December 2001). This document is intended for use by company employees responding to requests for information about Seroxat from the lay press and media – that is to say, it contains messages for onward transmission to the general public:

4. This document states: "Seroxat is clearly shown as being neither addictive nor causing dependence." We contend that - even more than the MCA’s, Response to Panorama - this is highly misleading and inconsistent with the Summary of Product Characteristics No such thing has been "clearly shown": the lack of available evidence clearly precludes any such finding (EMEA, 2000). Does the MCA consider this statement is compatible with the required wording in section 4.8 of the SPC for all SSRIs, that: "the available pre-clinical and clinical evidence does not suggest SSRIs cause dependence"? If the Agency does consider that the company’s statement is unacceptable, what can it credibly do about it, when the MCA’s Response to Panorama also seek to persuade that lack of evidence of risk is equivalent to evidence of lack of risk?

5. The GSK briefing document also states that "Discontinuation symptoms are completely different to addiction or dependence …" In this document, the word, "discontinuation" is used three times, the only reference to "withdrawal symptoms" being in the passage quoted verbatim from the SPC. We contend that the company greatly increases the risk of misleading drug users and prescribers by persisting in use of the term "discontinuation" and that this is not consistent with the SPC. The CPMP/EMEA (2000) evaluation on which GSK otherwise relies states: "The term ‘withdrawal reactions’ should be used, not ‘discontinuation reactions’, as has been proposed by some marketing authorisation holders." Similarly, the CSM/MCA (1998) concluded, "that it would be inappropriate to change medical terminology in this way." In effect, the Company is claiming: "Withdrawal symptoms are completely different to addiction or dependence". This is clearly untrue and the notion that withdrawal is unrelated to dependence is inconsistent with the ICD-10 diagnostic guidelines. Withdrawal symptoms are a prime indicator of dependence (WHO, 1998). Would the MCA not accept this and, if so, what action will it take?

In this connection, we specifically request that the Medicines Control Agency makes representations not only to GlaxoSmithKline, but also to the Prescription Medicines Code of Practice Authority. For reasons unknown, their Appeal Board rejected Social Audit’s complaint under Clause 3.2 of their Code, indicating that they believe that the GlaxoSmithKline "Reactive Key Messages and Issues Document" (19 December 2001) is consistent with the marketing authorisation terms and the SPC. Will the MCA undertake to do this?

It seems to me that the outcome of the 21 November review by the Committee on Safety of Medicines of the SSRIs is already entirely predictable: the MCA’s Response to Panorama seems to completely tie their hands. Even so, please will you also add this letter to the papers they will receive?

Finally, I note that over 1% of the words in the MCA’s Important Safety Message, Response to Panorama, are incorrectly spelt (televison styages psycological syptoms aboput suidcide), presumably the result of rushing out a "response" two days before the programme appears. I have corrected these in the version posted on our website.

Yours sincerely,
Charles Medawar


Contents page
List of correspondence with MCA/CSM