A full NPS RADAR review of aripiprazole oral was published in May 2004. This In Brief extends the evidence presented in that review to the new long-acting injection (LAI) formulation and compares safety and efficacy against oral aripiprazole and other LAI antipsychotics. This summary is based on data available to December 2014.


A long-acting injection containing the active ingredient aripiprazole, a second-generation antipsychotic, is now PBS listed for maintenance treatment of schizophrenia in adults in whom tolerability to oral aripiprazole has been established.1, 2

The Authority Required (STREAMLINED) listing was recommended by the Pharmaceutical Benefits Advisory Committee on a cost-minimisation basis compared with the long-acting formulation of paliperidone, another second-generation antipsychotic.1

The recommended dose for aripiprazole long-acting injection (ALAI) is 400 mg once monthly, delivered via a single deep intramuscular gluteal injection.2 It is not for subcutaneous or intravenous use.

Aripiprazole is metabolised predominantly through pathways involving CYP 450 , CYP2D6 and CYP3A4 enzymes. Dose adjustments to ALAI are recommended if strong inhibitors of these enzymes are being taken concomitantly for more than 14 days.2


Place in therapy

Oral aripiprazole has been available for the treatment of schizophrenia in Australia since 2003.3 It has a receptor-binding profile that allows partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.2-4 This mechanism of action is distinct from that of other atypical agents.4, 5

Antipsychotic medicines are the mainstay of pharmacological treatment for patients with schizophrenia.6 Australian guidelines recommend oral second-generation (atypical) antipsychotic agents for first-line treatment in most patients, due to the lower risk of extrapyramidal symptoms (EPS) (ie, akathisia, tardive dyskinesia) compared with typical agents.6, 7

Poor adherence to treatment is a recognised problem in the management of patients with schizophrenia,8 and is predictive of poor outcomes (relapse, aggressive behaviour, suicide, substance abuse) and increased risk of hospitalisation.6, 8

Multiple factors have been identified as increasing the risk of non-adherence, including complex medicines schedules and the use of oral treatments.9 Long-acting formulations of typical and atypical antipsychotic medicines have the potential to improve long-term outcomes due to improved adherence.8, 10

Guidelines suggest that long-acting antipsychotic medicines may be offered to people who would prefer such treatment or in cases where avoiding covert non-adherence to antipsychotic medication (either intentional or unintentional) is a clinical priority within the treatment plan.6, 11

ALAI is already approved for the treatment of schizophrenia in several European countries as well as the US.4, 12

Three other second-generation antipsychotic medicines are currently available on the PBS in long-acting injection formulations — risperidone, olanzapine and paliperidone (Table 1).13

Table 1 Comparison of atypical LAI antipsychotic medicines PBS listed for maintenance treatment of schizophrenia2, 14-16





Available doses

Vial kits: 25, 37.5, 50 mg

Vial kits: 210, 300, 405 mg

Prefilled syringe: 25, 50, 75, 100, 150 mg

Vial kits: 300, 400 mg

Injection interval (weeks)


2 (210, 300 mg)

4 (405 mg)



Injection site

Deltoid or gluteal (maintenance)


Deltoid (initiation)

Deltoid or gluteal (maintenance)


Oral medicine required after first injection

Yes – continue for 3 weeks



Yes – continue for 2 weeks

Recommended starting dose*

25 mg

Varies according to the oral dose initially taken

150 mg (day 1) + 100 mg (day 8) administered in deltoid

400 mg

Recommended maintenance dose

25 mg

Varies according to the oral dose initially taken

75 mg

400 mg

* See 'Dosage and Administration' section of individual Product Information sheets for instruction regarding starting LAI therapy in treatment-naïve patients, those switching from other oral agents, and those switching from other LAI formulations


Efficacy consistent with that of oral aripiprazole

In the double-blind active-controlled ASPIRE EU trial, adult patients with schizophrenia stabilised on oral aripiprazole (minimum of 8 weeks) were randomised 2:2:1 to maintenance treatment with:

  • ALAI (400 mg once monthly, n = 265) or
  • oral aripiprazole (10–30 mg/day, n = 266) or
  • ALAI (50 mg once monthly, n = 131)

and followed out to 38 weeks.17 A double-dummy design ensured all patients, including those randomised to oral aripiprazole, received an injection.

The primary outcome was Kaplan–Meier estimated impending relapse rates at week 26. Trial results demonstrated non-inferiority for ALAI 400 mg compared with oral aripiprazole (7.12% vs 7.76%, treatment difference –0.64%, p = 0.79).17 Both treatments were superior to ALAI 50 mg (21.80%, p ≤ 0.001).

† A dose below the therapeutic threshold for assay sensitivity.


Extrapyramidal symptoms more frequent with long-acting injectable than oral formulation

Overall findings from ASPIRE EU reported that frequency of treatment-emergent adverse events was comparable across all three groups and largely mild to moderate in severity.17

Serious treatment-emergent adverse events were also similar across treatment arms: 5.7% for ALAI 400 mg, 5.6% for oral aripiprazole and 8.4% for ALAI 50 mg.

More patients treated with ALAI 400 mg experienced treatment-emergent EPS and EPS-related adverse effects (21.9%) compared with oral aripiprazole (11.7%) and ALAI 50 mg (12.2%).

Injection-site pain was also more common in the aripiprazole 400 mg group (7.5%) than in the 50 mg (0.8%) group or the oral group receiving placebo injections (2.3%).


No direct comparison available against other long-acting antipsychotic agents

It has been suggested that ALAI may provide some advantage over other available atypical antipsychotic LAIs for patients in whom weight gain, adverse metabolic effects or prolactin increase are a concern.5, 10

However, with no head-to-head trials directly comparing ALAI to other LAI formulations, recommendations regarding the use of one LAI over another cannot be readily made.10, 18

An indirect comparison of ALAI, paliperidone LAI and olanzapine LAI, using placebo-controlled registration trial data, suggests comparable efficacy across the three agents in terms of relapse prevention.10

A comparative study of ALAI versus paliperidone LAI is currently underway (NCT01795547).19


Dose and administration

Two dosage strengths of ALAI are listed on the PBS: 400 mg and 300 mg.2

Both doses are available as a kit containing:2

  • a vial of the active ingredient (in lyophilised powder form)
  • a vial of sterile water for reconstitution
  • a sterile syringe and needle for reconstitution
  • a sterile syringe and safety needles for injection
  • a vial adaptor.

The recommended starting and maintenance dose is 400 mg once monthly, with continued treatment with oral aripiprazole (10–20 mg/day) or other oral antipsychotic for 2 weeks after the first injection.2

If there are adverse reactions with the 400 mg dose, consider reducing the dose to 300 mg once monthly.2

Dose adjustments are recommended in patients known to be CYP2D6 poor metabolisers or if strong inhibitors of CYP2D6 or CYP3A4 are being taken concomitantly for ≥ 2 weeks. The Product Information provides further details.2



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