ABILIFY MAINTENA 720 mg / 960 mg Prolonged-release suspension for injection Ref.[116141] Active ingredients: Aripiprazole

Pharmacotherapeutic group: Psycholeptics, other antipsychotics
ATC code: N05AX12

Mechanism of action

It has been proposed that aripiprazole's efficacy in schizophrenia is mediated through a combination of partial agonism at dopamine D₂ and serotonin 5-HT_1A receptors and antagonism at serotonin 5-HT_2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties of dopaminergic hypoactivity. Aripiprazole exhibits high binding affinity in vitro for dopamine D₂ and D₃, serotonin 5-HT_1A and 5-HT_2A receptors and has moderate affinity for dopamine D₄, serotonin 5-HT_2C and 5-HT₇, alpha-1 adrenergic, and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for cholinergic muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole oral doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of ¹¹C-raclopride, a D₂/D₃ receptor ligand, to the caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety

Maintenance treatment of schizophrenia in adults

The efficacy of Abilify Maintena 960 mg, administered once every two months, was established in part, on the basis of pharmacokinetic bridging through an open-label, multiple-dose, randomized, parallel-arm multi-centre study. The study demonstrated that Abilify Maintena 960 mg provides similar aripiprazole concentrations, and thus similar effectiveness, to Abilify Maintena 400 mg over the dosing interval (see section 5.2). The similarity of aripiprazole plasma concentrations of Abilify Maintena 960 mg to Abilify Maintena 400 mg is presented in table 1.

Table 2. Geometric mean ratio and confidence interval (CI) following the fourth administration of Abilify Maintena 960 mg or the seventh and eighth Abilify Maintena 400 mg in the open-label study:

The effectiveness of Abilify Maintena 960 mg/720 mg in the treatment of schizophrenia is further supported by the established effectiveness of Abilify Maintena 400 mg/300 mg, as summarised below:

Efficacy of Abilify Maintena 400 mg/300 mg

The efficacy of Abilify Maintena 400 mg/300 mg in the maintenance treatment of patients with schizophrenia was established in two randomised, double-blind, long-term trials.

The pivotal trial was a 38 week, randomised, double-blind, active-controlled trial designed to establish the efficacy, safety, and tolerability of this medicinal product administered as monthly injections compared to once daily oral aripiprazole tablets 10 mg to 30 mg as maintenance treatment in adult patients with schizophrenia. This trial consisted of a screening phase and 3 treatment phases: Conversion phase, oral stabilisation phase, and double-blind, active-controlled phase.

Six-hundred and sixty-two patients eligible for the 38-week double-blind, active-controlled phase were randomly assigned in a 2:2:1 ratio to double-blind treatment to one of 3 treatment groups: 1) Abilify Maintena 2) the stabilisation dose of oral aripiprazole 10 mg to 30 mg, or 3) aripiprazole long-acting injectable 50 mg/25 mg. The aripiprazole long-acting injectable 50 mg/25 mg dose was included as a low dose aripiprazole to test assay sensitivity for the non-inferiority design.

The results of analysis of the primary efficacy endpoint, the estimated proportion of patients experiencing impending relapse by end of week 26 of the double-blind, active-controlled phase, showed that Abilify Maintena 400 mg/300 mg is non-inferior to aripiprazole oral tablets 10 mg to 30 mg.

The estimated relapse rate by end of week 26 was 7.12 % for Abilify Maintena 400 mg/300 mg, and 7.76 % for oral aripiprazole tablets 10 mg to 30 mg, a difference of −0.64 %.

The 95 % CI (−5.26, 3.99) for the difference in the estimated proportion of patients experiencing impending relapse by end of week 26 excluded the predefined non-inferiority margin, 11.5 %.

Therefore, Abilify Maintena 400 mg/300 mg is non-inferior to aripiprazole oral tablets 10 mg to 30 mg.

The estimated proportion of patients experiencing impending relapse by end of week 26 for Abilify Maintena 400 mg/300 mg was 7.12 %, which was statistically significantly lower than in aripiprazole long-acting injectable 50 mg/25 mg (21.80 %; p = 0.0006). Thus, superiority of Abilify Maintena 400 mg/300 mg over the aripiprazole long-acting injectable 50 mg/25 mg was established, and the validity of the trial design was confirmed.

The Kaplan-Meier curves of the time from randomisation to impending relapse during the 38-week, double-blind, active-controlled phase for Abilify Maintena 400 mg/300 mg, oral aripiprazole 10 mg to 30 mg, and aripiprazole long-acting injectable 50 mg/25 mg are shown in figure 1.

Figure 1. Kaplan-Meier product limit plot for time to exacerbation of psychotic symptoms/impending relapse:

NOTE: ARIP IMD 400/300 mg = Abilify Maintena; ARIP 10 mg to 30 mg = oral aripiprazole; ARIP IMD 50/25 mg = Aripiprazole long-acting injectable

Further, the non-inferiority of Abilify Maintena compared to oral aripiprazole 10 mg to 30 mg is supported by the results of the analysis of the positive and negative syndrome scale score (PANSS).

Table 3. PANSS total score – change from baseline to week 38-Last Observation Carried Forward (LOCF): randomised efficacy sample^a,b:

^a Negative change in score indicates improvement.
^b Only patients having both baseline and at least one post baseline were included. P-values were derived from comparison for change from baseline within analysis of covariance model with treatment as term and baseline as covariate.

The second trial was a 52-week, randomised, withdrawal, double-blind, trial conducted in US adult patients with a current diagnosis of schizophrenia. This trial consisted of a screening phase and 4 treatment phases: Conversion, oral stabilisation, IM stabilisation, and double-blind placebo-controlled. Patients fulfilling the oral stabilisation requirement in the oral stabilisation phase were assigned to receive, in a single-blind fashion, Abilify Maintena 400 mg/300 mg and began an IM phase for a minimum of 12 weeks and a maximum of 36 weeks. Patients eligible for the double-blind, placebo-controlled phase were randomly assigned in a 2:1 ratio to double-blind treatment with Abilify Maintena 400 mg/300 mg or placebo, respectively.

The final efficacy analysis included 403 randomised patients and 80 exacerbations of psychotic symptoms/impending relapse events. In the placebo group 39.6% of the patients had progressed to impending relapse, whilst in the Abilify Maintena 400 mg/300 mg group impending relapse occurred in 10% of the patients; thus, patients in the placebo group had a 5.03-fold greater risk of experiencing impending relapse.

Prolactin

In the double-blind, active-controlled phase of the 38-week trial, from baseline to last visit there was a mean decrease in prolactin levels in Abilify Maintena 400 mg/300 mg (−0.33 ng/mL) compared with a mean increase in oral aripiprazole tablets 10 mg to 30 mg (0.79 ng/mL; p<0.01). The incidence of Abilify Maintena 400 mg/300 mg patients with prolactin levels >1 time the upper limit of normal range (ULN) at any assessment was 5.4% compared with 3.5% of the patients on oral aripiprazole tablets 10 mg to 30 mg.

Male patients generally had a higher incidence than female patients in each treatment group.

In the double-blind placebo-controlled phase of the 52-week trial, from baseline to last visit there was a mean decrease in prolactin levels in Abilify Maintena 400 mg/300 mg (−0.38 ng/mL) compared with a mean increase in placebo (1.67 ng/mL). The incidences of Abilify Maintena 400 mg/300 mg patients with prolactin levels >1 time the ULN was 1.9% compared to 7.1% for placebo patients.

Acute treatment of schizophrenia in adults

The efficacy of Abilify Maintena 400 mg/300 mg in acutely relapsed adult patients with schizophrenia was established in a short-term (12-week), randomised, double-blind, placebo-controlled trial (n=339). The primary endpoint (change in PANSS total score from baseline to week 10) showed superiority of Abilify Maintena 400 mg/300 mg (n=167) over placebo (n=172). Similar to the PANSS total score, both the PANSS positive and negative subscale scores also showed an improvement (decrease) from baseline over time.

Table 4. PANSS total score – change from baseline to week 10: randomised efficacy sample:

^a Data were analysed using a mixed model repeated measures (MMRM) approach. The analysis included only subjects who were randomly assigned to treatment, given at least one injection, had baseline and at least one post-baseline efficacy assessment.
^b Difference (Abilify Maintena minus placebo) in least squares mean change from baseline.

Abilify Maintena 400 mg/300 mg also showed statistically significant improvement in symptoms represented by Clinical Global Impressions Severity, CGI-S (CGI-S) score change from baseline to week 10.

Personal and social functioning were evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g. work and study), personal and social relationships, self-care, and disturbing and aggressive behaviours. There was a statistically significant treatment difference in favour of Abilify Maintena 400 mg/300 mg compared to placebo at week 10 (+7.1, p<0.0001, 95% CI: 4.1, 10.1 using an ANCOVA model (LOCF)).

The safety profile was consistent with that known to Abilify Maintena 400 mg/300 mg. Nevertheless, there were differences from what has been observed with maintenance use in the treatment of schizophrenia. In a short-term (12-week), randomised, double-blind, placebo-controlled trial with Abilify Maintena 400 mg/300 mg treated subjects the symptoms which had at least twice the incidence of placebo were increased weight and akathisia. The incidence of weight gain of ≥7% from baseline to last visit (week 12) was 21.5% for Abilify Maintena 400 mg/300 mg compared with the placebo group 8.5%. Akathisia was the most frequently observed EPS symptom (Abilify Maintena 400 mg/300 mg 11.4% and placebo group 3.5%).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Abilify Maintena in all subsets of the paediatric population in schizophrenia (see section 4.2 for information on paediatric use).