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

2 August 2002

       Dear Dr Raine,

Paroxetine: withdrawal symptoms and dependence

1. I would be grateful if you could let me know the date of the meeting when the CSM is likely to consider the two outstanding matters referred to in your letter of 3rd July.

2. Assuming we are still in time, please would you draw Members’ attention to the evidence of abuse of SSRIs outlined in the attachment to this letter? This comes from the Drug Abuse Warning Network (DAWN), operated by the Substance Abuse and Mental Health Services Administration of the US Department of Health & Human Services. DAWN publishes tabulations of reports received from a sample of hospitals operating 24-hour Emergency Departments, in 21 US metropolitan areas, of episodes involving deliberate use of prescribed/diverted pharmaceutical products, (excluding accidental overdose or adverse reactions, unless these occurred in combination with an illicit drug). Benzodiazepines accounted for 8% of mentions; antidepressants for 6% of mentions:  

In 2000, the most frequently mentioned SSRIs and other newer antidepressants were:

Paroxetine (8,020 mentions), which rose 105 % from 1994 to 2000
Fluoxetine (7,939 mentions), which decreased 19 % from 1998 to 2000
Sertraline (6,670 mentions in 2000), which was unchanged from the previous 2 years
Venlafaxine (3,722 mentions), a 129 % increase since 1998; a 992 % increase since 1994
Citalopram (3,458 mentions), which more than doubled from 1999 to 2000
Nefazodone (1,608) mentions
Bupropion (3,809 mentions), a 42 % increase since 1998 and a 403 % increase since 1994
Mirtazepine (2,416 mentions), a 70 % increase since 1999 and a 299 % increase since 1998
Trazodone (9798 mentions)

3. When considering what to do about the obvious and widespread misunderstanding over the meaning/nature of ‘dependence’, the Committee may wish to consider the definition used by DAWN. Unlike the definition the Committee has consistently relied on, this one generally accords with WHO’s meaning (1998) and with public understanding:

"Dependence: A physiological or psychological condition characterized by a compulsion to take the drug on a continuous or periodic basis is order to experience its effects or to avoid the discomfort of its absence (e.g., had to take, had to have, needed a fix)"

4. I would be grateful if you could help with some queries about the current Summary of Product Characteristics (SPC) and Patient Information Leaflets (PIL) for paroxetine. Some years ago, the CSM recommended that the PIL for SSRIs etc, should contain the following additional advice, relating to withdrawal symptoms: "If you experience severe symptoms, contact your doctor." The current PIL for paroxetine gives no such advice and does not acknowledge that withdrawal symptoms may be severe. (See minutes of meeting of 26 March 1998, item 7.4.2). Please could you explain why this wording does not appear.

5. At the same 1998 CSM meeting (item 7.4.4), the CSM recommended that, "the statement ‘symptomatic treatment is seldom warranted’ should be removed from the paroxetine SPC, but this statement still appears. Please could you explain why it still appears, what it means and what evidence it is based on.

6. In its April 2000 review of SSRIs, the EMEA/CPMP (2000) recommended that, "The term ‘withdrawal reactions’ should be used, not ‘discontinuation reactions’, as has been proposed by some marketing authorisation holders." This reinforced the CSM’s conclusion (26 March 1998, item 7.3.3), "that it would be inappropriate to change medical terminology in this way." Given these recommendations, would the MCA be inclined to consider that repeated use of the term "discontinuation" (in place of "withdrawal") in promotional literature is consistent with the SPC? Would the MCA consider the following claim in promotional literature (a company press/PR briefing) to be consistent with the SPC: "Discontinuation symptoms are completely different to addiction or dependence …"?

7. Please may I have a copy of the document(s) sent to the relevant market authorisation holders to communicate the decisions of the CSM and EMEA/CPMP, following the meetings referred to above?

8. Please will you circulate this letter to the CSM? I would want them to be especially aware of the following statements (glaring but not unrepresentative extracts from a GlaxoSmithKline internal briefing paper for its press and public relations people), which the company robustly insists are consistent with the SPC: "The MCA (Medicine Control Agency) and CPMP have concluded that SSRIs do not cause dependency/addiction." …. "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."

Does the MCA/CSM consider such statements in promotional materials, directed at the general public via the press/media, to be consistent with the SPC?

If appropriate, please treat these as formal requests under the Code of Practice on Access to Government Information. Thank you for your attention; I look forward to hearing from you.

Yours sincerely,
Charles Medawar

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List of correspondence with MCA/CSM