Seroxat Litigation - Report of the Committee on Safety of Medicines Expert Working Group on SSRI Antidepressants, 2004 - ‘Regulatory History’

The much publicised Committee on Safety of Medicines (CSM) Expert Working Group (EWG) report “On the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants” published December 2004 has been haled as a victory in raising awareness about the problems associated with the drug class – which it was.

Mark Harvey of Hugh James, BBC Panorama’s Shelley Jofre, the Seroxat User Groups and Campaigners have laid claim to this as their achievement - although the drug regulatory and safety authorities were aware of, and investigating the issues of the drug class’ safety, propensity to cause suicide, dependency and withdrawal problems from the early 1990’s.

The issue of dependency associated with the SSRIs had already been discussed at European level by the Committee on Proprietary Medicinal Products (CPMP) and its Pharmacovigilance Working Party (PhVWP), in December 1998 the PhVWP decided France and Germany should further evaluate this issue resulting in a CPMP position paper published April 2000;

“The conclusion of the CSM and the CPMP was that all SSRIs are associated with withdrawal reactions; however, they are not drugs of dependence.”

on completion of the review on SSRIs drug class safety profile in relation to the dependence, withdrawal reactions and review of suicidal behaviour with SSRIs issue, a further article covering both aspects was published in 'Current Problems in Pharmacovigilance' September 2000.

As a result of the CPMP position paper (2000) product information for all SSRIs throughout Europe were changed in relation to inclusion of withdrawal reactions, UK product information for all SSRI, SNRIs were updated accordingly.

The following excerpt from the CSM EWG report briefly explains the history of the concerns, investigations and actions, early 1990’s to date of it’s publication December 2004

“2 REGULATORY HISTORY

This chapter outlines the regulatory history of SSRIs in the UK with particular referenceto the two mains areas of concern - withdrawal reactions and suicidal behaviour.

2.1 Withdrawal reactions in association with SSRIs

It has been known for many years that symptoms can occur on the withdrawal of antidepressants. Syndromes occurring on the withdrawal of tricyclic antidepressants (TCAs) have been defined and severe reactions have been noted on the withdrawal of monoamine oxidase inhibitors (MAOIs)[1]. Since the early 1990s, it has become clear that the SSRIs can also be associated with withdrawal reactions, although different SSRIs appear to cause withdrawal reactions to different extents[2]. The greatest number of spontaneous reports of withdrawal reactions have been associated with paroxetine. An article in 'Current Problems in Pharmacovigilance' in 1993 highlighted the risk of withdrawal reactions associated with paroxetine[3].

In late 1997, an article entitled 'The Antidepressant Web' by Charles Medawar raised concern that some people may become dependent on SSRIs[4]; this prompted a review of withdrawal reactions and dependence with these drugs. The related antidepressants venlafaxine and nefazodone (which is no longer marketed within Europe) were also included in the review. The CSM considered this issue in early 1998.

The issue was also discussed at European level by the Committee on Proprietary Medicinal Products (CPMP) and its Pharmacovigilance Working Party (PhVWP). At the December 1998 meeting of the PhVWP it was decided that France and Germany should carry out further evaluation of the issue of dependence associated with the SSRIs. The outcome of this review was a CPMP position paper which was published in April 2000[5].
The conclusion of the CSM and the CPMP was that all SSRIs are associated with withdrawal reactions; however, they are not drugs of dependence. Following the completion of a class review of the safety profile of SSRIs and a review of suicidal behaviour with SSRIs, a further article covering these aspects and the issue of withdrawal reactions was published in 'Current Problems in Pharmacovigilance' in September 2000[6].

The CPMP position paper (2000) contained key principles in relation to withdrawal reactions for inclusion in the product information for all SSRIs throughout Europe. The UK product information for all SSRIs and venlafaxine was updated accordingly.

Concern about withdrawal reactions with SSRIs continued and more recently has focused primarily on paroxetine. The BBC's Panorama programmes in October 2002 and May 2003 highlighted the level of public concern.”

The issue of all drugs in the SSRI, SNRI class causing dependency or being addictive had been addressed in the UK and Europe, both the CSM and CPMP had opined that the drugs including Seroxat did not meet the World Health Organisation (WHO) criteria for addiction by April 2000.

This opinion was not changed by the CSM EWG investigation as described in the earlier post “The "Addiction” Issue & Hugh James’ need to change the Patient Information Leaflet (PIL)” that can be found here.

The closing paragraph of the above excerpt draws attention to the recent (2002 to 2004) primary focus being placed on paroxetine (Seroxat) and the “BBC's Panorama programmes in October 2002 and May 2003 highlighted the level of public concern”.

Although the CSM EWG report is quite explicitly centred on all SSRIs and venlafaxine (Efexor) - the media, Hugh James’ Mark Harvey, the Seroxat User Group and Seroxat Campaigners’ selective interpretation of this statement is that Seroxat is the worse drug in the class because recent (2002 to 2004) concern about all drugs had shifted and “focused primarily on paroxetine”;  However, would it be more reasonable to say the drug Seroxats’ notoriety was generated by the “level” of adverse media coverage and the BBC Panorama’s two Seroxat focused programs?


CMS EWG Quote References

1 - Lejoyeux M et al (1996) ‘Antidepressant withdrawal syndromes’ CNS Drugs 5: 278-292.

2 - Stoukides J A & Stoukides C A (1991) ‘Extrapyramidal symptoms upon discontinuation of fluoxetine (letter).’ Am J Psychiatry 148(9): 1263.

3 - MCA/CSM (1993) Current Problems in Pharmacovigilance 19

4 - Medawar C (1997) ‘The Antidepressant Web.’ Int J Risk Safety Med 10: 75-126.

5 - http://www.emea.eu.int/pdfs/human/press/pp/277599en.pdf

6 - MCA/CSM (2000) Current Problems in Pharmacovigilance 26

7 - Teicher MH et al (1990) ‘Emergence of intense suicidal preoccupation during fluoxetine treatment.’ Am J Psychiatry 147:207-210

8 - MCA/CSM (1992) Current Problems in Pharmacovigilance 18.

9 - Healy D (1999): ‘A Failure to Warn [editorial].’ Int J Risk Safety Med 12: 151-6

10 - Lane RM (1998). ‘SSRI-induced extrapyramidal side effects and akathisia: implications for treatment.’ J Psychopharmacology. 12: 192-214.