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Abilify (aripiprazole) – 5 Indications

Scroll down for additional information on each indication:

• for the treatment of schizophrenia; approved November 2002
• for the treatment of acute manic or mixed episodes associated with Bipolar Disorder; approved September 2004 
• as an adjunctive therapy to antidepressants for treating Major Depressive Disorder; approved November 2007
• for the treatment of irritability associated with autistic disorder in pediatric patients (aged 6 to 17 years); approved November of 2009
• for the treatment of Tourette’s disorder; approved December of 2014

General Information

Abilify (aripiprazole) is an orally administered dopamine partial agonist and a seratonin antagonist. 

Abilify is specifically indicated:

• for the treatment of schizophrenia
• for the treatment of acute manic or mixed episodes associated with Bipolar Disorder
• as an adjunctive therapy to antidepressants for treating Major Depressive Disorder
• for the treatment of irritability associated with autistic disorder in pediatric patients (aged 6 to 17 years)
• for the treatment of Tourette’s disorder

Abilify is supplied as tablets for oral administration and as an intramuscular suspension for monthly (Abilify Maintena) or once every two months (Abilify Asimtufii) administration. 

Scroll down for specific dosing/administration recommendations for each indication.

Mechanism of Action

Abilify ((aripiprazole) is though to work through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

Side Effects

Adverse effects associated with the use of Abilify may include the following:

Adult patients with schizophrenia:

• akathisia

 Pediatric patients (13 to 17 years) with schizophrenia:

• extrapyramidal disorder
• somnolence
• tremor

Adult patients (monotherapy) with bipolar mania: 

• akathisia
• sedation
• restlessness
• tremor
• extrapyramidal disorder

Adult patients (adjunctive therapy with lithium or valproate) with bipolar mania:

• akathisia
• insomnia
• extrapyramidal disorder

Pediatric patients (10 to 17 years) with bipolar mania: 

• somnolence
• extrapyramidal disorder
• fatigue
• nausea
• akathisia
• blurred vision
•  salivary hypersecretion
• dizziness

Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy):

• akathisia
• restlessness
• insomnia
• constipation
• fatigue
• blurred vision

Pediatric patients (6 to 17 years) with autistic disorder:

• sedation
• fatigue
• vomiting
• somnolence
• tremor
• pyrexia
• drooling
• decreased appetite
• salivary hypersecretion
• extrapyramidal disorder
• lethargy

Pediatric patients (6 to 18 years) with Tourette’s disorder:

• sedation
• somnolence
• nausea
• headache
• nasopharyngitis
• fatigue
• increased appetite

Adult patients with agitation associated with schizophrenia or bipolar mania:

•  nausea

Indication 1 – for the treatment of schizophrenia

approved November 2002

Dosing/Administration

	Initial Dose	Recommended Dose	Maximum dose
Adults	10 to 15 mg/day	10 to 15 mg/day	30 mg/day
Pediatrics	2 mg/day	10 mg/day	30 mg/day

Clinical Trial Results

Four short-term, placebo-controlled clinical trials were conducted with Abilify in acute replapsed inpatients with schizophrenia. In three of the four trials, efficacy was measured by the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity of Illness Score (CGI-S). In the three trials, Abilify was statistically superior to placebo using these measures.

In the fourth trial, efficacy was measured by a responder analysis based on the CGI-S and the change in Brief Psychiatric Rating Scale (BPRS). Abilify was statistically superior to placebo based on the CGI-S, but not in the BPRS measure.

Clinical efficacy was demonstrated by the 15mg, 20mg and 30mg doses in two trials each. Clinical efficacy was shown for the 10mg dose in one trial. No evidence of clinical superiority was shown by the higher doses compared to the lowest dose.

Indication 2 – acute manic or mixed episodes associated with Bipolar Disorder

approved September 2004

Dosing/Administration

	Initial dose	Recommended dose	Maximum dose
Bipolar mania – adults: monotherapy	15 mg/day	15 mg/day	30 mg/day
Bipolar mania – adults: adjunct to lithium or valproate	10 to 15 mg/day	15 mg/day	30 mg/day
Bipolar mania – pediatric patients: monotherapy or as an adjunct to lithium or valproate	2 mg/day	10 mg/day	30 mg/day

Clinical Trial Results

Adults- Monotherapy

The efficacy of Abilify as monotherapy in the acute treatment of manic episodes was established in four 3 week, placebo-controlled trials in hospitalized patients who met the DSMIV criteria for bipolar I disorder with manic or mixed episodes.

The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y-MRS), an 11 item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score).

A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) Scale. In the four positive, 3 week, placebo-controlled trials (n=268; n=248; n=480; n=485) which evaluated Abilify in a range of 15 mg to 30 mg, once daily (with a starting dose of 30 mg/day in two studies and 15 mg/day in two studies), Abilify was superior to placebo in the reduction of Y-MRS total score and CGI-BP Severity of Illness score (mania).

In the two studies with a starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint.

Adjunctive Therapy

The efficacy of adjunctive Abilify with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6 week, placebo-controlled study (n=384) with a 2 week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder.

Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 mcg/mL) at therapeutic serum levels and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤25% improvement on the Y-MRS total score) to lithium or valproate were randomized to receive either Abilify (15 mg/day or an increase to 30 mg/day as early as Day 7) or placebo as adjunctive therapy with open-label lithium or valproate.

In the 6 week, placebo-controlled phase, adjunctive Abilify starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0.6 to 1.0 mEq/L or 50 to 125 mcg/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the Y-MRS total score and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6 week endpoint.

Pediatric Patients

The efficacy of Abilify in the treatment of bipolar I disorder in pediatric patients (10 to 17 years of age) was evaluated in one 4 week, placebo-controlled trial (n=296) of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥20 at baseline.

This double-blind, placebo-controlled trial compared two fixed doses of Abilify (10 or 30 mg/day) to placebo. The Abilify dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm, and in 13 days in the 30 mg/day treatment arm.

Both doses of Abilify were superior to placebo in change from baseline to Week 4 on the Y-MRS total score.

Indication 3 – as an adjunctive therapy to antidepressants for treating Major Depressive Disorder

approved November 2007

Dosing/Administration

Initial dose: 2 to 5 mg/day
Recommended dose: 5 to 10 mg/day
Maximum dose: 15 mg/day

Clinical Trial Results

The efficacy of Abilify in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6 week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy. 

The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10 item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3 item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme).

In the two trials (n=381, n=362), Abilify was superior to placebo in reducing mean MADRS total scores. In one study, Abilify was also superior to placebo in reducing the mean SDS score. In both trials, patients received Abilify adjunctive to antidepressants at a dose of 5 mg/day.

Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4 mg/day.

Indication 4 – irritability associated with autistic disorder in pediatric patients (aged 6 to 17 years)

approved November 2009

Dosing/Administration

Initial dose: 2 mg/day
Recommended dose: 5 to 10 mg/day
Maximum dose: 15 mg/day

Clinical Trial Results

The efficacy of Abilify in the treatment of irritability associated with autistic disorder was established in two 8 week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems.

Over 75% of these patients were under 13 years of age. Efficacy was evaluated using two assessment scales: The Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABCI). The ABC-I subscale measured symptoms of irritability in autistic disorder.

In one of the 8 week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or Abilify 2 to 15 mg/day. Abilify , starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo.

The mean daily dose of Abilify at the end of 8 week treatment was 8.6 mg/day. In the other 8 week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of Abilify (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. Abilify dosing started at 2 mg/day and was increased to 5 mg/day after one week.

After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm. All three doses of Abilify significantly improved scores on the ABC-I subscale compared with placebo.

Indication 5 – for the treatment of Tourette’s disorder

approved December of 2014

Dosing/Administration

Patients <50 kg

Initial dose: 2 mg/day
Recommended dose: 5 mg/day
Maximum dose: 10 mg/day

Patients >50 kg

Initial dose: 2 mg/day
Recommended dose: 10 mg/day
Maximum dose: 20 mg/day

Clinical Trial Results

The efficacy of Abilify in the treatment of Tourette’s disorder was established in one 8 week (7 to 17 years of age) and one 10 week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette’s disorder and had a Total Tic score (TTS) ≥20 to 22 on the Yale Global Tic Severity Scale (YGTSS).

The YGTSS is a fully validated scale designed to measure current tic severity. Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information. Over 65% of these patients were under 13 years of age.

 The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS. Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each. Summation of these 10 scores provides a TTS (i.e., 0 to 50).

 The results of these trials are as follows: In the 8 week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette’s disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose Abilify, high dose Abilify, or placebo. The target doses for the low and high dose Abilify groups were based on weight.

Patients <50 kg in the low dose Abilify group started at 2 mg per day with a target dose of 5 mg per day after 2 days. Patients ≥50 kg in the low dose Abilify group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at Day 7.

Patients <50 kg in the high dose Abilify group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at Day 7. Patients ≥50 kg in the high dose Abilify group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at Day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21. 

Abilify (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) and on the CGI-TS scale compared with placebo. 

Approval Date: 2002-11-01

Company Name: Otsuka America Pharmaceutical