Risperidone: Revised PBS restrictions for behavioural and psychological symptoms of dementia

• On 1 January 2020, changes were made to risperidone listings on the PBS General Schedule
  Changes apply to risperidone for behavioural and psychological symptoms of dementia (BPSD) of the Alzheimer type to reduce inappropriate prescribing beyond 12 weeks.

• The previous Authority Required (STREAMLINED) listing was changed to an initial treatment phase
  The listing provides up to 12 weeks of initial treatment with risperidone.

• A new Authority Required (telephone) listing was added
  This item is for a treatment phase of continuing treatment, or a trial of reduction or cessation of treatment.

• Antipsychotics are only effective for one in five people with dementia for short-term management
  Risperidone has minimal evidence of efficacy beyond 3 months and is associated with an increased risk of adverse events and mortality.

• Non-pharmacological methods of treatment should be used first line for BPSD
  If risperidone treatment is required, the lowest dose possible should be used for a short period only.

On 1 January 2020, changes were made to the General Schedule (Section 85) listing for risperidone for patients who have:^1,2

• behavioural disturbances characterised by psychotic symptoms and aggression

AND

• dementia of the Alzheimer type

These included changes to the existing Authority Required (STREAMLINED) listing and adding a new Authority Required listing.¹

Authority Required (STREAMLINED)

The previous Authority Required (STREAMLINED) listing was the only listing on the General Schedule for risperidone for this condition. The clinical criteria stated ‘the patient must have failed to respond to non-pharmacological methods of treatment’ and ‘the treatment must be limited to a maximum duration of 12 weeks’.^3,4

The listing was changed on 1 January 2020 to include a treatment phase of ‘initial treatment’. For the clinical criteria, instead of a maximum treatment duration, it stated that ‘the patient must not receive more than 12 weeks of treatment under this restriction.²

In addition, a patient may now only qualify for PBS-subsidised treatment under this restriction once in a 12-month period.²

There was also a listing for grandfathered treatment for the trial of dose reduction or cessation of treatment in a patient prescribed risperidone before 1 January 2020.¹

Authority Required (Telephone)

The new Authority Required (Telephone) listing was added for risperidone for this condition with a treatment phase of continuing treatment, or a trial of reduction or cessation of treatment, where:²

• the patient must have responded to an initial course of treatment with this drug for this condition

AND

• the patient must have failed to respond to non-pharmacological methods of treatment

AND

• the treatment must be for dose-tapering purposes as part of a trial of treatment reduction or cessation

OR

• the patient must have trialled a period of treatment reduction or cessation with this drug for this condition and experienced worsening or re-emergence of symptoms during this trial, and retrials are considered periodically

AND

• the patient must be optimised on non-pharmacological methods of treatment.

The new Authority Required (Telephone) listing also provides instructions for management and definitions of terms used in the restrictions, including:²

• response to treatment and trial of treatment reduction or cessation must be discussed formally with a psychiatrist or geriatrician or in a documented clinical review process involving a least one other medical practitioner, or the patient has been reviewed by a psychiatrist or geriatrician
• response to treatment is defined as a significant reduction in symptoms of psychosis or aggression
• patients must cease treatment if there is no improvement in symptoms of psychosis and aggression or worsening of symptoms with therapy
• patients must be monitored for adverse effects such as falls, drowsiness leading to reduced self-care, incontinence, reduced nutrition, reduced ability to communicate needs or wishes and participate in activities
• therapy must be ceased if harms outweigh benefits of treatment
• trials of reduction or cessation of therapy should be considered periodically with the intention of maintaining symptom control through non-pharmacological measures wherever possible and/or lowest effective dose therapy
• evidence of patient benefit from therapy, failure of non-pharmacological approaches to manage symptoms in the absence of therapy, and recurrence of symptoms following reduction or cessation of therapy, trialled on at least one occasion, must be documented in the patient’s medical records.

See the PBS website for more information on PBS restrictions on risperidone prescribing

May be prescribed by nurse practitioners

Authorised nurse practitioners may prescribe this medicine when the care of a patient is shared with a medical practitioner in a formal arrangement with a management plan.²

See the PBS website for more information on nurse practitioner PBS prescribing

Risperidone is an atypical antipsychotic medicine belonging to the benzisoxazole-derivative class.⁵

Antipsychotic effects are thought to be achieved (at least in part) through blocking dopaminergic transmission in different parts of the brain such as the limbic system. All antipsychotics block D2 receptors, and other receptors such as the serotoninergic 5-hydroxytryptamine2 (5HT2) receptors may also have a role.^5,6

However the mechanism of action for BPSD has not been clearly established.⁷

Risperidone is indicated for the treatment of psychotic symptoms, or persistent agitation or aggression that is not responsive to non-pharmacological approaches, for patients with moderate to severe dementia of the Alzheimer type.⁸

The above symptoms and behavioural disturbances are also referred to as behavioural and psychological symptoms of dementia (BPSD). BPSD is defined by the International Psychogeriatric Association (IPA) as ‘symptoms of disturbed perception, thought content, mood, behaviour frequently occurring in patients with dementia’.⁹ Most behavioural complications of dementia are intermittent and may not persist beyond 3 months.¹⁰

Risperidone may be recommended for patients with severe BPSD where there is a severe and complex risk of harm.¹¹

Comprehensive, holistic and individualised management approach

BPSD is often an expression by the patient of unmet needs. Guidelines emphasise the importance of a comprehensive and holistic assessment to identify underlying factors that may be contributing to behavioural issues, including physical health issues, pain or discomfort, mental health comorbidities, interacting medicines and difficulty communicating. They also recommend considering environmental factors, cultural background, personal history and beliefs, as well as both verbal and non-verbal communication that may be increasing distress in the patient^9,12,13,14 and the overall context for the individual patient, to determine and target any underlying causes.⁹

An individually tailored approach that involves the patient, their family and other carers to allow for shared decision-making in the care process is imperative when managing BPSD.¹⁵

Non-pharmacological methods of treatment for BPSD

Non-pharmacological methods should be used as first-line treatment for BPSD. When pharmacological treatment is required, it should be used to complement non-pharmacological methods.¹⁴

Non-pharmacological interventions have evidence of efficacy for reducing some behavioural symptoms.^16,17 A meta-analysis of non-pharmacological interventions delivered by caregivers showed reduced BPSD, with agitation and aggression more likely to improve than psychosis.¹⁶ Interventions such as good pain management have also been shown to reduce distressing behaviours.^9,17,18 Other examples of non-pharmacological interventions include therapeutic use of music and dancing, massage and reminiscence therapy.¹⁴

Risperidone for treatment of BPSD

Antipsychotic medicines, including risperidone, can be helpful in the short term when non-pharmacological approaches are not working, but should not be first line therapy. However, this needs to be balanced against increased risk of adverse events.^7,19,20 These medicines should only be given when non-pharmacological methods have not alleviated symptoms that are distressing for the patient as well as family, staff or co-residents (in a residential aged care facility).^14,15 Pharmacological treatments should be used to complement, rather than replace non-pharmacological methods.¹⁴ Guidelines (including the Clinical Practice Guidelines and those by the Dementia Collaborative Research Centres) state that atypical antipsychotics have small but statistically significant positive effects on BPSD, with the strongest evidence for risperidone.^9,14

If a health professional considers that medication may need to be prescribed, informed consent should be obtained before prescribing. It is important that the risks and benefits of prescribing medication to a person with dementia is discussed with and understood by the person and/or their decision maker.^11,21

Risperidone is the only medicine that is PBS-listed for the management of BPSD in Australia.³

A significant body of evidence has shown a modest benefit for risperidone in the short-term reduction of BPSD.²⁰

For example, in a 2006 Cochrane review, there was benefit seen with risperidone 1 mg per day compared to placebo on psychosis (intention to treat [ITT], mean deviation [MD] –0.14, 95% CI –0.03 to –0.03, p = 0.0.01).²⁰ This review also found that risperidone had a beneficial effect on aggression for approximately 20% of people. However very high placebo response rates and high risk of adverse events have been recorded.^20,22 In addition, the majority of studies were of short duration.^20,23 Longer term efficacy beyond 12 weeks has not been established in clinical trials.^10,23

Trials of risperidone have indicated modest improvement in aggressive behaviours and psychosis (effect size approximately 0.2) over a treatment period of 6–12 weeks.⁷ But there is minimal evidence of efficacy of antipsychotic treatment extending beyond 3 months, as trial data beyond 12 weeks is lacking and inconsistent.³ A study by Devanand et al 2012 found an increased risk of symptom relapse in patients with Alzheimer disease whose psychosis or agitation had responded to risperidone treatment for 4 to 8 months, following discontinuation of risperidone.²⁴ The time to relapse was shorter for patients who discontinued risperidone and received placebo for 16 weeks compared to those who continued to receive risperidone treatment. However, a large proportion of patients (23 of 70 patients, p = 0.004) who continued to receive risperidone had a relapse. Although discontinuation of risperidone increased the risk of symptom relapse, it was not highly effective in achieving and maintaining a reduction in symptoms of psychosis and agitation.²⁴

Low-quality evidence from a Cochrane review in 2018, which included the above 2012 Devanand study, suggests that antipsychotics may be discontinued successfully for patients with dementia experiencing behavioural disturbances.¹⁰ Discontinuation may have little or no major effect on behavioural symptoms for patients who have been receiving treatment for at least 3 months. Additionally, the review found that antipsychotic discontinuation may have little or no effect on adverse events and quality of life.¹⁰

Compared to placebo, risperidone was associated with improvement in outcomes on the Cohen-Mansfield Agitation Inventory (CMAI) (standardised mean difference [SMD], –0.26; 95% CI –0.37 to –0.15). The median duration of follow-up in the included studies was 10 weeks (range, 6–32 weeks).²⁵ The CMAI is a questionnaire with 29 types of agitated behaviour to assess agitation in an older person.²⁶

The variation in study findings suggest that an individualised approach is important when considering when to deprescribe risperidone. One of the sponsors of risperidone has also stated there is no evidence to support treatment beyond 12 weeks for patients with moderate to severe Alzheimer disease with BPSD.⁸

More information

Additional information, resources and tools on the management of BPSD can be found on the Dementia Training Australia website. A resource for steps involved in safe prescribing is available on the Australian Government Department of Health website.

Comparative efficacy and safety information is lacking for data comparing risperidone with non-pharmacological interventions to manage BPSD. However some randomised control trials have indicated that non-pharmacological methods such as social interaction and staff training on person-centred care may have a greater effect size than antipsychotics and may also be a viable alternative to antipsychotics for management of behavioural symptoms.^7,17

A meta-analysis published in 2019 examined the comparative effectiveness and safety of atypical antipsychotics for the treatment of BPSD. Atypical antipsychotics include aripiprazole, olanzapine, quetiapine and risperidone.²⁵

Seventeen randomised clinical trials comparing any atypical antipsychotic with another atypical antipsychotic or with placebo were included in the meta-analysis, which included 5373 patients. The median duration of follow up was 10 weeks, with a range of 6 to 32 weeks.²⁵

The mean (SD) age of all study participants was 80.8 (3.1) years and included mostly women (69.8%). All study participants had diagnoses of BPSD. The studies included a mix of nursing homes and outpatient settings.²⁵

Risperidone was also associated with an increased risk of cerebrovascular adverse events (odds ratio [OR], 3.85; 95% CI 1.55 to 9.55), as well as increased risk of extrapyramidal side effects (OR 2.23; 95% CI 1.56 to 3.18) compared to placebo.²⁵ Risperidone treatment has also been associated with an increased risk of falls.²⁷

Differences between atypical antipsychotics were not significant for effectiveness, death or cerebrovascular adverse events.²⁵

Increased risk of cerebrovascular events

Several trials, reviews and meta-analyses have identified increased risk of cerebrovascular adverse events as a concern for patients taking atypical antipsychotics including risperidone.^20,28,29 A meta-analysis of 15 trials that included risperidone, olanzapine, quetiapine and aripiprazole found that patients taking an antipsychotic were more than twice as likely to experience a cerebrovascular event compared to those taking placebo. The risk of cerebrovascular adverse events with risperidone was significantly higher, with an odds ratio of 3.43 (95% CI 1.60 to 7.32, p = 0.001).¹⁹ The 2019 meta-analysis (described above) also showed an increased risk of cerebrovascular events with use of risperidone compared to placebo (OR 3.85; 95% CI 1.55–9.55).²⁵

This finding is supported by a Cochrane review which reported that, compared to placebo, risperidone was associated with significantly increased likelihood of serious adverse cerebrovascular events (37/1175 vs 8/779, OR 3.64, 95% CI 1.72 to 7.69, p = 0.0007).²⁰

However much of the published trial data from the original clinical trials grouped all dementia patients together,^30,31 making it difficult to identify specific sub-groups at increased risk. When the sponsor of Risperdal^® re-analysed the data regarding patients taking risperidone, there was an increased risk of cerebrovascular adverse events among patients with vascular or mixed dementia (OR 5.26, 95% CI 1.18 to 48.11), compared to patients with dementia of the Alzheimer type (OR 2.23, 95% CI 0.85 to 6.88).⁵ Despite this comparison, there is still an increased risk in patients with dementia of the Alzheimer type.⁵

Minimising cerebrovascular risk

The cerebrovascular risk is highest in patients with dementia who have poorly controlled vascular risk factors such as atrial fibrillation, diabetes, hypertension, or history of previous stroke.¹⁵

Therefore, limit risperidone to patients with low to moderate risk of stroke. Refer patients with high risk of stroke if considering risperidone treatment to a psychiatrist with expertise in the psychiatry of old age.¹⁵

Increased risk of extrapyramidal symptoms with risperidone

Patients treated with risperidone were 1.78 times (95% CI 1.00 to 3.17, p = 0.05) as likely to experience extrapyramidal symptoms than with placebo, with the incidence substantially higher at 2 mg per day.²⁰ Another meta-analysis which included risperidone, aripiprazole, olanzapine and quetiapine reported that the increased risk of extrapyramidal symptoms seen in the pooled analysis could be attributed to risperidone alone. The odds ratio in the risperidone trials was 1.80 (95% CI 1.35 to 2.42, p < 0.0001) or 17%, compared with 10% in the pooled analysis.²²

A meta-analysis in 2019 also found that the risk of extrapyramidal symptoms was increased with risperidone use compared to placebo (OR, 2.23; 95% CI, 1.56–3.18).²⁵

Increased risk of mortality

Studies have reported varied findings on the comparative mortality risk of specific antipsychotics.²⁸ Most trials have only studied risperidone for 12 weeks or less in patients with dementia. The DART-AD trial randomised patients with dementia living in aged care facilities in the UK who had already been taking antipsychotics for at least 3 months to either continue taking their prescribed antipsychotics for 12 months or to switch to placebo.^24,32,33 In 54 months of follow-up, the trial found increased risk of mortality among those who continued taking risperidone, particularly at 24, 36 and 48 months.³³

Meta-analyses have reported 1.5–1.7 times higher risk of mortality in dementia patients taking atypical antipsychotics to manage behavioural and psychiatric symptoms.^19,34 In an ad hoc analysis published by Schneider et al in 2005, the relative risk of haloperidol (typical antipsychotic) was reported to be 2.07 (95% CI 0.78 to 5.51; p=0.15).³⁴

The DART-AD long-term randomised placebo controlled antipsychotic withdrawal trial found higher mortality among those who continued their treatment for longer than 24 months.³³

Other safety concerns for risperidone

In addition to increased incidence of cerebrovascular events and mortality, risperidone is associated with other adverse events.²⁹ A 2006 meta-analysis of placebo controlled trials found that risperidone significantly increased risk of gait abnormalities, drowsiness, respiratory tract infections, fever and peripheral oedema at 1 and 2 mg/day doses.²⁰

The risk of bone fractures should be considered with use of antipsychotics. Atypical antipsychotics have been associated with hypotension, sedation and gait abnormalities which may contribute to falls, and therefore increase the risk of fractures.³⁵ A Canadian study found a greater risk of falling occurred for patients taking high dose risperidone (greater than 2 mg per day) compared to non-users. The risk of falling was shown to be greater in people with wandering problems for use of antipsychotics as a class (OR = 1.8, 95% CI 1.1–3.1).²⁷

Other common (occurring in greater than 1% of patients) adverse effects of risperidone include insomnia and headache. Less common side effects (occurring in 0.1%–1% of patients) include incontinence, rhinitis, sexual adverse effects and angioedema.⁶

The Pharmaceutical Benefits Advisory Committee (PBAC) was concerned with the overuse of chemical restraints in patients with less severe BPSD as a substitute for first-line non-pharmacological methods of treatment.³ A chemical restraint is defined as a medicine used to control a person’s behaviour, rather than treating their condition.³⁶ The PBAC recommended the PBS listing change for risperidone to reduce inappropriate prescribing of risperidone for BPSD beyond 12 weeks.³⁷ In addition, the changes aim to address the overuse of chemical restraints with less severe BPSD as a substitute for non-pharmacological methods of treatment.³⁷

As there is minimal evidence of risperidone’s efficacy to treat BPSD beyond 3 months,³ the continuing treatment phase listing requires prescribers trial dose reduction or cessation for patients, before considering extended treatment with risperidone.¹ Patients should not continue risperidone treatment if they have not responded to an initial course of treatment.¹

The addition of a new continuing listing will allow prescribers to treat BPSD with risperidone under certain conditions when a patient needs treatment beyond the initial 12 weeks. The PBAC acknowledged that while there is a place in therapy for use of risperidone to control moderate to severe BPSD extending beyond 12 weeks, this would most likely be for a very small group of patients.³

Prescribers instructions in the new Authority Required (Telephone) PBS listing

The new PBS listing states that a patient’s continuing treatment must either be reviewed by a psychiatrist or geriatrician, or involve a documented clinical process review with another medical practitioner, in addition to the prescriber.² The PBAC expressed concern about the availability of psychiatrist and geriatricians to advise whether continuation of risperidone is appropriate, therefore included the option of a review process with another medical practitioner to overcome equity issues around access to specialists. It also noted that prescribers should be familiar with the Guiding principles for medication management in residential aged care facilities in 2012.³

The listing also states that patients must cease risperidone treatment if there is no improvement in symptoms or if symptoms worsen with treatment.² Clinical practice guidelines from the Cognitive Decline Partnership Centre state that if no efficacy of antipsychotics is observed within a relatively short time frame (1 to 2 weeks), treatment should be discontinued.¹⁴

The PBAC stated that the intent of the PBS listing changes is to reduce inappropriate prescribing of risperidone in patients with BPSD. The restriction changes will also allow the Department of Health to undertake retrospective drug utilisation studies of patients continuing on risperidone beyond 12 weeks to help identify inappropriate prescribing.³

The PBAC considered that inappropriate prescribing of chemical restraints is a broader problem that is not confined to risperidone, even though other medicines (such as other antipsychotics or benzodiazepines) may not be PBS-listed or approved by the Therapeutic Goods Administration (TGA) for managing BPSD. It noted that other measures will also be required to improve quality use of medicines for people with dementia in residential aged care.³

The PBAC recommended that a review of the use of risperidone as well as other antipsychotics and benzodiazepines should be conducted within two years of the restriction changes.³

The Therapeutic Guidelines state that an initial daily dose of olanzapine 2.5 mg may be used as an alternative to risperidone, however it is important to note that olanzapine is not approved by the Therapeutic Goods Administration (TGA) for treatment of behavioural disturbances associated with dementia.¹⁵

The NPS MedicineWise program on psychotropic medicines in aged care, due to launch in July 2020, will provide further information and guidance on management of BPSD.

Risperidone may be taken as tablets or an oral solution.

The Product Information for risperidone states treatment should start with a dose of 0.25 mg twice daily. If necessary, adjust gradually, by increments of 0.25 mg twice daily, but not more frequently than every other day. For most patients, the optimum dose is 0.5 mg two times per day. Some patients, however, may benefit from doses up to 1 mg twice daily.⁸

Although effect size is greater at the 2 mg dose than 1 mg, the risk of adverse events is also higher.^7,20

Limited data comparing 2 mg with 1 mg/day doses has shown increased frequency of extrapyramidal disorders, somnolence, falls, urinary tract infections, and fever in the higher dose group.²⁰

The 2 mg dose is associated with a significantly increased drop-out rate both overall, and because of adverse events.²⁰

Once an effective dose is reached, a once-daily dosing regimen can be considered.⁸

Regular review (every 4–12 weeks) to measure the patient’s response to risperidone is important, as symptoms may change, as well as the need for medication.²¹

Tapering of risperidone

Guidelines from Primary Health Tasmania and the New South Wales Therapeutic Advisory Group recommend slowly tapering antipsychotics in collaboration with patients and their carers. This may be achieved by reducing the dose by 25%–50% every 1 to 2 weeks. The patient should be monitored throughout the duration of tapering. This includes for benefits of tapering such as improved alertness, improved gait, reduction in falls and extrapyramidal symptoms, as well as adverse drug withdrawal events such as psychosis, aggression, agitation, delusions and hallucinations.³⁸

A resource to assist tapering of antipsychotics can be found on the NPS website.

Active ingredient prescribing

On 31 October 2019, the National Health (Pharmaceutical Benefits) Regulations 2017 were amended to require the inclusion of active ingredients on most PBS prescriptions. Active ingredient prescribing is part of a wider government strategy to ensure consistent and standardised medicines information.³⁹

Active ingredient prescribing aims to:³⁹

• ensure the identification of active ingredient names on all PBS prescriptions
• increase patient understanding of the medicines they are taking
• promote the uptake of generic medicines.

Under the regulations, prescribers:³⁹

• are required to include the active ingredient on all PBS prescriptions (excluding handwritten prescriptions, paper-based medication charts in residential aged care settings, and medicines with four or more active ingredients or medicines listed as ‘various’ under the PBS and RPBS).
• can include a brand after the active ingredient on a prescription, if the doctor believes the identification of a brand is necessary for the clinical treatment of their patient.

A 12-month transition period has been arranged to ensure prescribers have sufficient time to update prescribing software to versions which meet the new active ingredient prescribing requirements.³⁹

Advise patients and carers:⁴⁰

• the medicine will be trialled to see if it helps, as sometimes it may not help with managing behaviour
• the oral solution can be mixed with water, orange juice, coffee or milk, but not tea (tea may affect the content of risperidone in the solution)⁴¹
• avoid drinking alcohol, as risperidone can increase the effects of alcohol
• in the first few days of starting risperidone, dizziness may occur on standing up so to minimise this, the patient should get up slowly from a sitting or lying position
• other common side effects include drowsiness, falls and headache
• patients undergoing tapering should be monitored for adverse drug withdrawal events such as psychosis, aggression, agitation, delusions and hallucinations.³⁸

Discuss the Risperidone Consumer Medicine Information (CMI) leaflet with the patient.