Safety Alerts

Revised indication on the use of risperidone for treatment of dementia

Audiences

Healthcare professional

Industry member

Product type

Therapeutic Products

20 December 2016

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HSA would like to update healthcare professionals on the outcomes of its benefit-risk assessment on the revised indication of risperidone for the treatment of dementia.

Risperidone is currently approved for the treatment of behavioural disturbances in patients with dementia. In view of increased risk of CVAE associated with its use in MD/VD, the licensed indication of risperidone will be revised to the short-term treatment of persistent aggression in patients with Alzheimer’s Dementia (AD) only. It will no longer be recommended for use in other types of dementia, such as MD/VD. In addition, warnings will be strengthened in the local package inserts (PIs) to mitigate the risk of CVAE. This regulatory action was made in consultation with HSA’s Medicines Advisory Committee (MAC) and clinical experts, following concerns raised internationally on increased risk of CVAE associated with the use of risperidone in MD/VD.

Background

Several other international drug regulatory agencies have similarly restricted the indication of risperidone, following the initiation on the change in the licensed indications submitted by the manufacturer (Janssen Cilag Spa) of the innovator product (Risperdal®). These include Health Canada¹ and the Australian Therapeutics Goods Administration.²The European Medicines Agency has further limited the duration of use of risperidone for short-term treatment (up to 6 weeks) of persistent aggression in patients with moderate to severe AD unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.³

HSA’s benefit-risk assessment

HSA's benefit-risk assessment on the use of risperidone for the treatment of dementia, took into consideration current available scientific evidence, inputs from local clinicians, safety data submitted by product licence holder (Johnson & Johnson Pte Ltd), local adverse drug reaction (ADR) reports and the actions taken by other drug regulatory agencies.

Available data showed that risperidone, at recommended therapeutic doses, demonstrated efficacy in treatment of aggression in elderly patients with moderate to severe dementia (AD, MD or VD) by achieving statistically significantly greater response rates measured by Behaviour Pathology in Alzheimer’s Disease (BEHAVE-AD) and Cohen-Mansfield Agitation Inventory (CMAI) scores versus placebo.

CVAE such as stroke and transient ischemic attack, including fatalities, had been reported in trials of risperidone in elderly patients with dementia-related psychosis. However, the assessment of the post market data showed that there was a higher incidence of CVAE in MD/VD versus AD patients taking risperidone. Pooled results from all placebo-controlled studies showed that CVAE risk was increased 2.1 times in MD/VD patients compared to AD patients. Pooled data from all placebo-controlled studies also showed that the number of serious CVAE could be increased by 2.7 times in MD/VD compared to AD patients. While the cause of the CVAE in these patients is unknown, the increase in CVAE risk in dementia patients had been postulated to be due to orthostatic hypotension, thromboembolic events and dehydration etc.⁴ In addition, concomitant diseases such as poorly controlled diabetes and hypertension as well as underlying cerebral pathology such as in VD also predispose patients to CVAE.

HSA has received one serious ADR report of stroke associated with risperidone. A 92-year old, diagnosed with behavioural and psychotic symptoms of dementia, was prescribed risperidone for behavioural control for 6 months. The patient also had other risk factors such as hyperlipidaemia. In addition, the patient had osteoarthritis of the knees, vestibulobasilar insufficiency and benign prostatic hyperplasia. However, risperidone was the only suspected drug and the causality was assessed by the reporting doctor as possible.

HSA, in consultation with its MAC, concluded that the benefit-risk profile for use of risperidone in treatment of aggression in dementia remains favourable when it is restricted for the short-term treatment of AD. Considerations include the assessment that the CVAE risk for AD had not been shown to be elevated against what is currently known for the drug. In addition, when using risperidone in AD, CVAE risk may be mitigated by the physician’s assessment of cerebrovascular risk factors, tailing off treatment when behavioural and psychotic symptoms of dementia is controlled and regular follow-up to assess patient and need for continued treatment. However, risperidone is no longer recommended for use in other types of dementia, such as MD/VD due to increased CVAE risk.

HSA’s advisory

Healthcare professionals are advised to take note of the following to minimise the risk of CVAE, when considering the use of risperidone for the treatment of dementia:

Risperidone is indicated for the short-term treatment of persistent aggression in patients with moderate to severe dementia of the Alzheimer’s type unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others
The risk of CVAEs was higher in patients on risperidone with mixed or vascular type of dementia when compared to Alzheimer’s dementia.
Physicians are advised to assess the risks and benefits of the use of risperidone in elderly patients with dementia, taking into account risk predictors for stroke in the individual patient.
Patients should be re-assessed regularly to determine the need for continued treatment.

HSA will be working with the companies to update the local package inserts of risperidone products to reflect the restriction in indication and recommendations. A Dear Healthcare Professional Letter was issued on 16 June 2016 to advise healthcare professionals on these recommendations.⁵

Revised indication on the use of risperidone for treatment of dementia

Background

HSA’s benefit-risk assessment

HSA’s advisory

References

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