ATYPICAL ANTIPSYCHOTIC DRUGS AND STROKE
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St Andrew's House
Edinburgh EH1 3DG
9 March 2004
Dear Care Home Provider
ATYPICAL ANTIPSYCHOTIC DRUGS AND STROKE
I enclose for your information a copy of a letter from Professor Gordon Duff, Chairman, Committee on Safety of Medicines about antipsychotic drugs and an increased risk of stroke particularly when these drugs are used in the treatment of elderly patients with dementia. I am also enclosing Question and Answers provided by the CSM, which you may find helpful.
DR E M ARMSTRONG Dear Colleague,
Chief Medical Officer
ATYPICAL ANTIPSYCHOTIC DRUGS AND STROKE
I am writing to inform you of an important concern about the safety of atypical antipsychotic drugs and provide new prescribing recommendations. Evidence reviewed by the Committee on Safety of Medicines (CSM) indicates an increased risk of stroke which particularly applies when these drugs are used by elderly patients with dementia.
Although no atypical antipsychotic drug is licensed for the treatment of behavioural disturbance in dementia, they are quite frequently used for this purpose and manufacturers have conducted clinical trials in this indication. The Committee has reviewed the available data from trials of risperidone and olanzapine and considered other relevant evidence.
Risperidone is the most extensively studied drug in this context and a meta-analysis of randomized placebo-controlled clinical trials in elderly patients with dementia has shown that, compared with placebo, the risk of stroke with risperidone was approximately three times higher.
A pooled analysis of randomized placebo-controlled clinical trials of olanzapine in elderly patients with dementia has shown a similar increased risk of stroke and a 2-fold increase in all-cause mortality.
The mechanism by which these drugs are associated with stroke is unclear. Although some patients with dementia may have underlying vascular disease, the risk is not confined to this group. Although most of the evidence causing concern comes from patients with dementia, the risk may not be confined to use in this indication and should be considered relevant to any patient with a history of cerebrovascular disease or relevant risk factors (see below).
CSM advice on balance of risks and benefits
The CSM has advised that there is clear evidence of an increased risk of stroke in elderly patients with dementia who are treated with risperidone or olanzapine. The magnitude of this risk is sufficient to outweigh likely benefits in the treatment of behavioural disturbances associated with dementia and is a cause for concern in any patient with a high baseline risk of stroke.
CSM has advised that risperidone or olanzapine should not be used for the treatment of behavioural symptoms of dementia.
Use of risperidone for the management of acute psychotic conditions in elderly patients who also have dementia should be limited to short-term and should be under specialist advice (olanzapine is not licensed for management of acute psychoses).
Prescribers should consider carefully the risk of cerebrovascular events before treating any patient with a previous history of stroke or transient ischaemic attack. Consideration should also be given to other risk factors for cerebrovascular disease including hypertension, diabetes, current smoking and atrial fibrillation.
Although there is presently insufficient evidence to include other antipsychotics in these recommendations, prescribers should bear in mind that a risk of stroke cannot be excluded, pending the availability of further evidence. Studies to investigate this are being initiated.
Patients with dementia who are currently treated with an atypical antipsychotic drug should have their treatment reviewed. Many patients with dementia who are disturbed may be managed without medicines. Treatment guidelines are available at websites listed below.
Prescribing information for risperidone and olanzapine are being amended to reflect the advice given above.
Further information (available from 1pm Tuesday 9 March)
Treatment guidelines are available at the following websites:
Information for patients and carers is available at the following website:
Further information about the CSM advice can be found on the MHRA wesbite:
For any additional information please phone the MHRA on 020 7084 2000
Professor Gordon Duff
Chairman - Committee on Safety of Medicines
ATYPICAL ANTI-PSYCHOTIC DRUGS AND STROKE:
QUESTIONS AND ANSWERS
What are atypical antipsychotic drugs?
Atypical antipsychotic drugs are a group of medicines used to treat conditions such as schizophrenia, agitation, anxiety, mania and aggression. They are "atypical" because they are less likely than standard antipsychotic drugs to cause movement disorders as a side-effect (these may resemble Parkinson's disease). Three atypical antipsychotic drugs were reviewed by the Committee on Safety of Medicines ( CSM) - risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel).
Why have atypical antipsychotic drugs been restricted ?
Clinical trials have been undertaken with risperidone and olanzapine in elderly patients (older than 65 years) with dementia to see if they are useful in controlling symptoms such as agitation. These trials showed a greater rate of cerebrovascular events, including stroke and Transient Ischaemic Attacks, (about 3 times as many) in patients treated with these medicines by comparison with placebo treatment. This increased risk of cerebrovascular events including stroke outweighs the likely benefits in the treatment of behavioural symptoms of dementia. On the basis of this evidence the CSM has now recommended that they be avoided in such patients.
For other indications, prescribers should consider carefully the risk of stroke before using these products in a patient who has had a previous stroke or a transient ischaemic attack. These medicines should also be used with caution in those who have risk factors for stroke (see below).
Regarding quetiapine, fewer studies have been undertaken but an increased risk of stroke cannot be ruled out. At the moment there is insufficient evidence to warrant the same action as for risperidone and olanzapine.
What is a stroke?
A stroke (also known as a cerebrovascular accident) results from a disturbance of circulation of blood to part of the brain. It usually occurs suddenly and produces variable degrees of paralysis affecting one side of the body (depending on which side of the brain is damaged). Speech may also be affected. Some strokes may resolve quite rapidly but others are life-threatening or cause long-term disability. Stroke is not usually an adverse effect of a medicine but the result of arteriosclerosis.
What are the main risk factors for stroke?
Old age, high blood pressure, diabetes, smoking and heart rhythm disorders all increase the risk of stroke.
How do atypical antipsychotic drugs cause stroke?
This is not yet known. In particular, the relationship between dementia, stroke and these treatments requires investigation.
Should a patient taking an atypical antipsychotic drug stop treatment immediately?
No. Treatment should only be stopped on the advice of a doctor. Carers of elderly patients with dementia using olanzapine or risperidone should arrange for their doctor to review treatment within the next few weeks.
What is dementia?
Dementia is a name for a group of degenerative brain diseases which cause profound memory loss, particularly in the elderly. Alzheimer's disease is the commonest form of dementia. Another form, known as vascular dementia, is caused by multiple small strokes.
Are atypical antipsychotic drugs safe in younger patients with other illnesses?
These medicines generally have a good safety record and for this reason are often preferred to standard antipsychotic drugs. In the light of the risk observed in older patients with dementia it is now prudent to use these medicines cautiously if the patient has previously had a stroke or appears to be at high risk.
Do other antipsychotic drugs cause stroke?
At present there is insufficient evidence for this but it is a possibility that needs to be investigated.
Who has made this decision?
The Committee on Safety of Medicines - an independent scientific expert body that advises the government - has reviewed the relevant evidence and issued advice to relevant healthcare professionals.
What alternative treatments are available?
Many patients with dementia who have behavioural disturbances may be managed without medicines. For those who need drug treatment, a number of alternatives are available on the advice of a doctor. Guidance on the management of dementia is available on the following websites:
Further information for patients and carers is available at the website of the Alzheimer's' Society: http://www.alzheimers.org.uk
What is happening abroad regarding these drugs?
Prescribers in the USA and Canada have already been advised by the authorities in those countries. This issue has been under active consideration in Europe and Member States will be issuing advice nationally on risperidone. The European scientific committee, the Committee for Proprietary Medicinal Products (CPMP) is issuing advice on olanzapine for which the European Commission is the licensing authority (further information is available on the website of the European Agency for the Evaluation of Medicinal Products - http://www.emea.eu.int
Where can I get further information?
Further information is available on the MHRA's website (www.mhra.gov.uk) and by calling NHS Direct/ NHS24. Any patients who are concerned should consult their doctor for advice.