|Department of Health|
|MEDICINES CONTROL AGENCY|
|Market Towers 1 Nine Elms Lane London SW8 5NQ|
|Telephone 020 7273 0100/0546|
|Facsimile 020 7273 0548||.|
|Dr David Healy, Director|
|University of Wales College of Medicine|
|North Wales Department, Hergest Unit|
|Ysbyty Gwynedd, Bangor, Gwynedd, LL57 2PW||26 July 2000|
Dear Dr Healy,
Thank you for your letters of 3 April and 5 July 2000. I apologise for the delay in responding to your request for information about adverse reactions to Selective Serotonin Reuptake Inhibitors in volunteer studies. A summary of information on adverse events reported by volunteers given SSRIs is attached for your information.
The Committee on Safety of Medicines has recently re-considered the possible association between SSRIs and suicidal behaviour. As you are aware, a number of epidemiological studies and analyses of clinical trial data have failed to find an association between fluoxetine and increased suicidal behaviour. Whist the reporting rate of suicidal behaviour for all SSRIs through the Yellow Card scheme has been low in recent years, there continue to be anecdotal case reports of suicidal behaviour associated with fluoxetine, and CSM will continue to closely monitor this issue.
The CSM noted that it is general clinical experience that the risk of suicide may increase in the early stages of treatment with any antidepressant...The Committee considered that prescribers and patients should be made aware of this in product information, and patients thought to be at risk should be carefully monitored.
The outcome of this review is soon to be published in the bulletin 'Current Problems in Pharmacovigilance' which is sent to all doctors and pharmacists. In addition, we intend to update patient information leaflets in accordance with the recommendations of the CSM.
I trust this provides the information you require.
Yours sincerely Dr Keith Jones Director & Chief Executive
Copy: Lord Hunt, PS(L)
ADVERSE EVENTS FROM SSRI VOLUNTEER STUDIES
There have been 29 studies where fluoxetine was administered
to healthy volunteers. The studies involved 397 subjects who were taking fluoxetine in the dose range lmg/day to 110mg/day for periods ranging from 1-45 days. Some adverse events were reported in these studies, including nervousness, anxiety, irritability and jitteriness. There was no occurrence of suicidal behaviour. There are also 79 publications involving administration of fluoxetine to 1,266 healthy volunteers. The doses ranged from 5 to 80 mg/day for periods ranging from a single dose to 3 months of continued administration. No events relating to suicidal behaviour were reported. Psychological assessments were conducted in 5 studies and demonstrated that fluoxetine has no effect on the mood of healthy individuals.
There were 645 subject sessions (occasions on which a single dose of paroxetine was administered to a volunteer) in single dose studies (dose range 15mg to 70mg) and 381 volunteers were administered paroxetine in repeat dose studies (dose range 20 to 40mg). Most volunteers took paroxetine for between 2 and 28 days, although 16 took paroxetine for 42 days.
There were no reports of suicidal thoughts in any of the volunteer studies. There were a few reports of 'emotional lability', however these reactions were not found to be related to suicidal thoughts or behaviour. Some volunteers reported anxiety, nervousness and agitation while taking paroxetine, however the most commonly reported adverse events were nausea, diarrhoea, drowsiness, somnolence and insomnia.
In studies contained in the sertraline hydrochloride International Registry Dossiers (IRD-1 and -2), Oral Concentrate IRD, and Renal/Hepatic Supplement, there have been over 50 studies in normal healthy volunteers involving over 800 subjects, the majority of subjects were male, although some studies did include females. The sertraline dose range was generally 50 to 200mg and sertraline was administered in both single and multiple doses. The duration of multiple dose studies was normally less than 30 days. There was no occurrence of suicidal ideation, suicide gesture or attempt or completed suicides. There are a few reports of agitation, anxiety, nervousness, abnormal thinking and hyperkinesia among the safety data collected in these studies. These were described as mild or moderate in all cases. No serious psychiatric events were reported.
There have been 95 volunteer studies involving 1300 subjects who received fluvoxamine. Fluvoxamine was administered in single or multiple doses for up to a maximum of 4 weeks. The dosage range administered was 10-300mg/day. A search of the database did not reveal any cases of suicide, suicide attempt, suicidal ideation or related adverse events from spontaneous reporting or rating scale data in non-patient volunteers exposed to fluvoxamine.
There have been 30 volunteer studies involving 421 subjects (176 subjects in single dose, and 245 subjects in multiple dose studies).
There were no cases of suicide or suicide attempt. Adverse events reported which may be relevant were as follows: 4 reports of hyperkinesia, 2 reports of depersonalisation and abnormal thinking and single reports of agitation and depression. From the available data, there was nothing to indicate the occurrence of suicidal thoughts.
There are some reports of mild or moderate psychiatric reactions including nervousness, anxiety and agitation among the safety data from volunteer studies with the SSRIs. However, there is no evidence that suicidal behaviour or severe psychiatric reactions have been reported during healthy volunteer studies involving any of the SSRIs.
CLICK HERE TO READ ON