UK Antidepressant Report Reinforces NZ Actions

UK Antidepressant Report Reinforces NZ Actions

7 December 2004

A long awaited United Kingdom report into the safety of some antidepressants has recommended changes to UK prescribing and monitoring of the drugs - largely in line with the updated advice issued in New Zealand by Medsafe two months ago (October).

The report from the UK Committee on Safety of Medicines Expert Working Group On SSRIs (Selective Serotonin Reuptake Inhibitors) has confirmed that the benefits of treating depression in adults with these medicines outweigh the potential risks. However it recommends that when the medicines are prescribed there should be "careful and frequent patient monitoring by healthcare professionals", particularly in the early stages of treatment, during dose changes or where symptoms worsen.

SSRIs are antidepressant medicines given for the treatment of major depression disorders. They are one of three classes of medicines used for the treatment of depression. The other two classes are called tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).

Ministry of Health spokesperson Dr Stewart Jessamine says the report's key findings and its recommendations for changes to the prescribing and consumer information is consistent with prescribing and packaging advice issued by Medsafe in October. Medsafe directed drug companies to change prescribing and consumer information for all antidepressants, and issued warnings about the need to monitor children and adults using antidepressants.

For adolescents or children with depression the UK report confirms the earlier recommendations against all SSRIs being used apart from fluoxetine (Prozac) where there is some evidence of overall benefit. However the report warns that this drug too, like other SSRIs, is likely to be linked with a small increased risk of self harm or suicidal thoughts. The UK report reiterates that while there is no clear evidence of an increased risk of self harm and suicidal thoughts in young adults aged 18 and over, careful monitoring is recommended. It says patients in this age group are at increased risk of suicidal thinking and action than other age groups with depression.

The UK report recommends tighter restrictions on one particular SSRI called Efexor (venlafaxine) because of the increased risk of heart damage in overdose. The UK restrictions include limiting prescribing of venlafaxine to specialists (rather than GPs), not using venlafaxine in individuals with heart disease and checking patients heart rhythm by electrocardiogram prior to beginning treatment.

Dr Jessamine says venlafaxine is available in New Zealand and funded by Pharmac as a third line treatment for depression and is usually prescribed by specialists. Prescribing information accompanying the drug already includes information that heart problems and heart rhythm disturbances can occur when taking this medication at high doses or in overdose.

He says Medsafe, the Ministry's regulation and safety arm, will be seeking further information from the UK on venlafaxine as well as undertaking a literature review before referring the issues to its Medicines Adverse Reactions Committee to consider whether tighter restrictions should also apply in New Zealand. The issue will be considered by the committee in the new year.

Dr Jessamine says regulatory authorities around the world are consistently taking a more precautionary approach in their advice with respect to antidepressants.

Background

(SSRIs are antidepressant medicines given for the treatment of major depression disorders. SSRIs are on of three classes of medicines used for the treatment of depression. The other two classes are called tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).

The SSRI medicines available in New Zealand are:

Citalopram (brand names: Cipramil, Celapram)
Escitalopram (brand name: Lexapro, Cipralex)
Fluoxetine (brand names: Fluox, Prozac, Apo-fluoxetine, Lovan, Plinzene, Flexetor, Fluohexal)
Fluvoxamine (brand name: Luvox) - not marketed
Paroxetine (brand name: Aropax)
Sertraline (brand name: Zoloft)
Venlafaxine (brand name: Efexor)

TCAs currently available in New Zealand are:

Amitriptyline (brand name: Amitrip)
Clomipramine (brand name: Anafranil, Apo-clomipramine, Clopress)
Desipramine (brand name: Pertofran)
Doxepin (brand name: Anten)
Dothiepin (brand name: Dopress)
Imipramine (brand name: Tofranil)
Maprotiline (brand name: Ludiomil)
Mianserin (brand name: Tolvon)
Noritriptyline (brand name: Norpress)
Trimipramine (brand name: Tripress, Surmontil)

Other antidepressants available in New Zealand are:

Mirtazapine (brand name: Remeron)
Moclobemide (brand name: Aurorix, Apo-moclobemide)
Reboxetine (brand name: Edronax)
Tranylcypromine (brand name: Parnate)

In New Zealand, none of the SSRIs have ever been licensed for use in those aged less than 18 years (however, it is recognised that off-label use occurs in this age group). All NZ data sheets (information provided for medicine prescribers) for all SSRIs currently state that "Safety and effectiveness in children has not been established". All but fluoxetine and sertraline go further to state that "use is not recommended in children". Data sheets are available on the Medsafe web site www.medsafe.govt.nz.

In June 2003, the UK Committee on Safety of Medicines issued a letter to UK prescribers advising against the use of paroxetine as therapy for children and adolescents with depressive illness. This advice was based on new data from GlaxoSmithKline (GSK)-sponsored clinical trials of Aropax in paediatric patients. At this time, the New Zealand data sheet for paroxetine (Aropax) was updated to advise that clinical trials do not support the use of paroxetine in the treatment of children with major depressive disorder (MDD). In addition, GlaxoSmithKline issued a related Dear Doctor letter to New Zealand prescribers.

In June 2003, Medsafe and the Medicines Adverse Reactions Committee (MARC; an expert advisory committee to the Minister of Health) reviewed the 'Technical document summaries - Summary of clinical safety data' for paroxetine provided to Medsafe by GSK. The Committee agreed that the data were not of sufficient quality to justify any additional regulatory action (beyond that already taken by GSK) regarding the use of paroxetine at that time. The decision was made to keep a watching brief on this issue.

In August 2003, Wyeth updated the New Zealand data sheet for venlafaxine (Effexor) to advise against prescribing venlafaxine as therapy for children and adolescents with depressive illness. This was based on data from paediatric trials, which showed increased reports of suicide-related adverse events in paediatric patients receiving venlafaxine treatment for MDD. In addition, Wyeth issued a related Dear Doctor letter to New Zealand prescribers. Venlafaxine Data Sheet

In December 2003, the UK Committee on Safety of Medicines (CSM) issued a letter to UK health professionals informing them that a CSM Expert Working Group had completed a review of the safety and efficacy of SSRIs in the treatment of paediatric MDD. On the basis of this review of the available clinical trial data, the CSM advised prescribers that paroxetine, citalopram, escitalopram, sertraline, and venlafaxine are contraindicated (meaning should not be used) in paediatric MDD. The balance of risks and benefits of fluoxetine in these patients was deemed to be favourable.

In March 2004, the Medicines Adverse Reactions Committee decided there was not enough information to warrant changing the existing advice about the prescribing of SSRIs to people under the age of 18. There was a commitment to place a high priority on reviewing the safety of SSRIs as more data became available.

In September 2004, two FDA advisory committees discussed an analysis of paediatric suicidality information based on new data and concluded that there is some increased risk of suicidal thoughts and behaviours associated with all SSRIs studied. The MARC is in broad agreement with this conclusion but notes that there is no clinical trial evidence to associate SSRIs with risk of completed suicide in any age group.

In September 2004, the MARC recommended that datasheets for Tricyclic Antidepressants currently approved for use in treating MDD in children and adolescents be updated to say these medicines are not recommended for use in patients under 18 years of age unless upon the advice of an appropriate specialist (and contraindicated in children under 13 years of age). In addition, the MARC have recommended updates to all antidepressant medicine datasheets (including SSRIs, TCAs, and MAOIs) to provide advice on monitoring for clinical worsening and warn of possible increased suicide risk with all antidepressant treatments. An excerpt of the draft MARC minutes (22 September meeting) is available on the Medsafe web site: www.medsafe.govt.nz/Profs/adverse.htm

The key findings of the 6 December 2004 report from the UK Committee on Safety of Medicines (www.mhra.gov.uk) Expert Working Group On SSRIs are available in a letter sent to UK health professionals at www.mhra.gov.uk/news/2004/SSRIs_061204.pdf and a questions and answers document at www.mhra.gov.uk/news/2004/SSRIs_QA_061204.pdf.

On 6 December 2004 the report of the Committee on Safety of Medicines Expert Working Group on Selective Serotonin Reuptake Inhibitors (SSRI) antidepressants was released in the UK. The key messages and "Dear Doctor" letter released in the UK can be found at www.mhra.gov.uk

Related information

Review of prescribing SSRI antidepressants to young people (media release 24 March 2004)