ABILIFY® (aripiprazole)

ABILIFY® (aripiprazole)

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ABILIFY® (aripiprazole)

Aripiprazole is an atypical antipsychotic drug that is available as ABILIFY® (aripiprazole) Tablets, ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets, ABILIFY® (aripiprazole) Oral Solution, and ABILIFY® (aripiprazole) Injection, a solution for intramuscular injection. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C23H27Cl2N3O2 and its molecular weight is 448.38.

Indications and usage

ABILIFY is an atypical antipsychotic. The oral formulations are indicated for:

  • Schizophrenia
  • Acute Treatment of Manic and Mixed Episodes associated with Bipolar I
  • Adjunctive Treatment of Major Depressive Disorder
  • Irritability Associated with Autistic Disorder
  • Treatment of Tourette’s disorder

The injection is indicated for:

  • Agitation associated with schizophrenia or bipolar mania

Mechanism of Action

The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

Dosage and administration

Schizophrenia:

Adults: The recommended starting and target dose for ABILIFY is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals

Adolescents: The recommended target dose of ABILIFY is 10 mg/day.

Bipolar I Disorder

Acute Treatment of Manic and Mixed Episodes:

Adults: The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with lithium or valproate. ABILIFY can be given without regard to meals.

Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years) as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a target dose of 10 mg/day after 2 additional days. Recommended dosing as adjunctive therapy to lithium or valproate is the same.

Adjunctive Treatment of Major Depressive Disorder

Adults: The recommended starting dose for ABILIFY as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The recommended dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week

Irritability Associated with Autistic Disorder

Pediatric Patients (6 to 17 years): The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is 5 to 15 mg/day. Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week

Tourette’s Disorder

Pediatric Patients (6 to 18 years): The recommended dosage range for Tourette’s Disorder is 5 to 20 mg/day.

  • For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days.
  • For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on day 8.

Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)

Adults: The recommended dose in these patients is 9.75 mg. The recommended dosage range is 5.25 to 15 mg. No additional benefit was demonstrated for 15 mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical factors warrant.

Dosing of Oral Solution

The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution.

Dosing of Orally Disintegrating Tablets

The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral tablets

Contraindications

ABILIFY is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Warnings and precautions

Increased Mortality: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis.

Cerebrovascular Adverse Events, Including Stroke: In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementiarelated psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in ABILIFY-treated patients (mean age: 84 years; range: 78 to 88 years).

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY. Rare cases of NMS occurred during ABILIFY treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

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Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Pathological Gambling and Other Compulsive Behaviors: Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole.

Orthostatic Hypotension: ABILIFY may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism

Falls: Antipsychotics, including ABILIFY, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics including ABILIFY. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Seizures/Convulsions: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold

Potential for Cognitive and Motor Impairment: Use caution when operating machinery

Adverse reactions

  • Adult patients with schizophrenia: akathisia
  • Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor
  • Adult patients (monotherapy) with bipolar mania: akathisia, sedation, restlessness, tremor, and extrapyramidal disorder
  • Adult patients (adjunctive therapy with lithium or valproate) with bipolar mania: akathisia, insomnia, and extrapyramidal disorder
  • Pediatric patients (10 to 17 years) with bipolar mania: somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness
  • Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy): akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision
  • Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and 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

Drug interactions

FactorsDosage Adjustments for ABILIFY
Known CYP2D6 Poor MetabolizersAdminister half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitorsAdminister a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitorsAdminister half of usual dose
Strong CYP2D6(e.g., quinidine, fluoxetine, paroxetine) and CYP3A4 inhibitors (e.g., itraconazole, clarithromycin)Administer a quarter of usual dose
Strong CYP3A4 inducers (e.g., carbamazepine, rifampin)Double usual dose over 1 to 2 weeks

Antihypertensive Drugs: Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

Benzodiazepines (e.g., lorazepam): The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone.

Use in specific populations

Pregnancy: Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including ABILIFY) during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms, and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Lactation: Limited data from published literature report the presence of aripiprazole in human breast milk, at relative infant doses ranging between 0.7% to 8.3% of the maternal weight-adjusted dosage.

There are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ABILIFY and any potential adverse effects on the breastfed infant from ABILIFY or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.

Geriatric Use: No dosage adjustment is recommended for elderly patients

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