Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in March 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Aripiprazole prolonged-release suspension for injection is licensed for maintenance treatment of schizophrenia in adults whose condition has been stabilised with oral aripiprazole. It was launched in the UK in January 2014. In 2 double-blind, randomised controlled trials (RCTs; n=403 and n=662), once-monthly aripiprazole 400 mg prolonged-release injection was shown to be superior to placebo and non-inferior to oral aripiprazole 10–30 mg daily in preventing relapse in adults with stabilised schizophrenia. The tolerability profile of the injectable formulation was similar to that of oral aripiprazole; the only new adverse event was injection-site reactions.

Effectiveness

  • In a double-blind RCT (n=403), aripiprazole prolonged-release injection statistically significantly delayed time to impending relapse compared with placebo (p<0.0001).

  • In a double-blind RCT (n=662), aripiprazole prolonged-release injection was non-inferior to oral aripiprazole 10–30 mg daily for the proportion of participants experiencing impending relapse (7.12% and 7.76% respectively).

  • No RCTs have directly compared aripiprazole prolonged-release injection with other antipsychotics.

Safety

  • Overall adverse event profile of aripiprazole prolonged-release injection was similar to that of oral aripiprazole, apart from injection-site reactions.

  • Common adverse events in the RCTs included weight gain (9%), akathisia (7.9%), insomnia (5.8%) and injection-site pain (5.1%).

User factors

  • Frequency of intramuscular injection is once every month into the gluteal muscle, compared with every 2 weeks for some other prolonged-release antipsychotic injections.

  • Side effect profile of aripiprazole may differ from that of other atypical antipsychotics. The BNF chapter on antipsychotic drugs describes the relative efficacy and adverse effects of different antipsychotics. A National Prescribing Centre patient decision aid provides a guide to the relative adverse effects of different antipsychotics, based on information available at that time (2009).

Resource implications

  • Annual drug acquisition cost of aripiprazole 400 mg prolonged-release injection is £2,645.

  • Annual drug acquisition cost of alternative depot antipsychotics (first and second-generation) ranges from £13 to £5,789, depending on the drug and dose. See the costs of selected treatment alternatives section for more information.

Key points

Schizophrenia is a major psychiatric disorder, or cluster of disorders, characterised by psychotic symptoms that alter a person's perception, thoughts, affect and behaviour.

In November 2013, aripiprazole prolonged-release suspension for injection (Abilify Maintena; a new, once-monthly formulation of aripiprazole) was granted a European marketing authorisation. It is licensed for maintenance treatment of schizophrenia in adults whose condition has been stabilised with oral aripiprazole. It was launched in the UK in January 2014.

The recommended starting and maintenance dose is 400 mg, administered once a month into the gluteal muscle as a single intramuscular injection. After the first injection, treatment with oral aripiprazole (10–20 mg/day) should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy. If adverse events occur, reduction of the monthly dose to 300 mg should be considered. For people who have never taken aripiprazole, tolerability to oral aripiprazole should be established before starting treatment with aripiprazole prolonged-release injection.

This evidence review is based on 2 double-blind RCTs involving people with schizophrenia (Kane et al. 2012, Study 31-07-247 reported in the European public assessment report [EPAR] for Abilify Maintena). In the first study (Kane et al. 2012), 403 people whose condition had been stabilised on aripiprazole (oral for 4 to 12 weeks followed by prolonged-release injection for 12 to 36 weeks) were randomised to receive aripiprazole prolonged-release injection (400 mg with an option to decrease to 300 mg according to tolerability) or placebo injection once every 4 weeks for up to 52 weeks. Time to impending relapse in the double-blind phase (primary end point) was statistically significantly longer in people treated with aripiprazole prolonged-release injection than in those treated with placebo (p<0.0001). Treatment with aripiprazole prolonged-release injection was associated with statistically significantly lower impending relapse rates compared with placebo (10% compared with 39.6%).

In the second study (Study 31-07-247, reported in the EPAR for Abilify Maintena), 662 people whose condition had been stabilised on oral aripiprazole for at least 8 consecutive weeks were randomised to receive treatment with aripiprazole 400 mg prolonged-release injection once monthly (stepping down to 300 mg depending on tolerability), oral aripiprazole 10–30 mg daily, or aripiprazole 50 mg injection once monthly (stepping down to 25 mg depending on tolerability) . The aripiprazole prolonged-release 50 mg or 25 mg dose is an unlicensed dose and was included as a 'pseudo placebo' to test assay sensitivity for the non-inferiority design. Aripiprazole 400 mg or 300 mg prolonged-release injection was found to be non-inferior to oral aripiprazole for the primary outcome of the proportion of participants meeting impending relapse criteria at week 26 (7.12% and 7.76% respectively, estimated treatment difference −0.64%, 95% confidence interval [CI] −5.26 to 3.99). The secondary end points of time to impending relapse, proportion of people whose schizophrenia responded (defined as 'stabilised patients' at week 38), and proportion of people achieving remission did not differ significantly between the aripiprazole 400 mg or 300 mg prolonged-release injection and the oral aripiprazole groups. Aripiprazole 400 mg or 300 mg injection was associated with a longer time to all-cause medication discontinuation than oral aripiprazole (figures not reported, p<0.05).

The adverse events profile of aripiprazole prolonged-release injection was similar to that of oral aripiprazole. The most frequently reported adverse events were weight gain, akathisia, insomnia and injection-site pain. Injection-site reactions were generally mild to moderate in severity and resolved over time. Extrapyramidal symptoms were reported more frequently with aripiprazole 400 mg or 300 mg prolonged-release injection than oral aripiprazole (18.4% compared with 11.7% patients, p value not reported).

Psychosis and schizophrenia in adults: treatment and management (NICE clinical guideline 178) recommends that depot or long-acting antipsychotics may be offered to people who would prefer such treatment after an acute episode of schizophrenia, or where avoiding covert non-adherence (either intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan. NICE recommends that treatment with antipsychotic medication should be considered an explicit individual therapeutic trial (see Psychosis and schizophrenia in adults for more information).

The Medicines and Healthcare Products Regulatory Agency has warned that there is an increased risk of stroke and a small increased risk of death when antipsychotics are used in older people with dementia. The summary of product characteristics for Abilify Maintena states that it is not indicated for the treatment of people with dementia-related psychosis.

The place in therapy for this treatment is likely to be as an alternative treatment option to the currently available second-generation prolonged-release depot antipsychotics for maintenance treatment of schizophrenia. Local decision makers will need to consider the available evidence on efficacy and safety, as well as cost and individual factors for people with schizophrenia, when making decisions about using aripiprazole prolonged-release injection.

Key evidence

Kane JM, Sanchez M, Perry PP et al. (2012) Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. The Journal of Clinical Psychiatry 73: 617–24

European Medicines Agency (2013) European public assessment report: Abilify Maintena (EMEA/H/C/002755/0000) [online; accessed 15 January 2014]

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.