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Generic Name: Aripiprazole
Class: Atypical Antipsychotics
Chemical Name: 3,4-dihydro-7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-2(1H)-Quinolinone
Molecular Formula: C23H27Cl2N3O2
CAS Number: 129722-12-9

Warning(s)

Special Alerts:

[Posted 05/03/2016]

AUDIENCE: Psychiatry, Internal Medicine, Patient

ISSUE: FDA is warning that compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex have been reported with the use of the antipsychotic drug aripiprazole (Abilify, Abilify Maintena, Aristada, and generics). These uncontrollable urges were reported to have stopped when the medicine was discontinued or the dose was reduced. These impulse-control problems are rare, but they may result in harm to the patient and others if not recognized.

Although pathological gambling is listed as a reported side effect in the current aripiprazole drug labels, this description does not entirely reflect the nature of the impulse-control risk FDA identified. In addition, FDA has become aware of other compulsive behaviors associated with aripiprazole, such as compulsive eating, shopping, and sexual actions. These compulsive behaviors can affect anyone who is taking the medicine. As a result, FDA is adding new warnings about all of these compulsive behaviors to the drug labels and the patient Medication Guides for all aripiprazole products.

See the FDA Drug Safety Communication (available @ ) for additional information, including a Data Summary.

BACKGROUND: Aripiprazole is used to treat certain mental disorders, including schizophrenia, bipolar disorder, Tourette's disorder, and irritability associated with autistic disorder. It may also be used in combination with antidepressants to treat depression. Aripiprazole can decrease hallucinations and other psychotic symptoms such as disorganized thinking. It can stabilize mood, improve depression, and decrease the tics of Tourette's disorder.

RECOMMENDATION: Health care professionals should make patients and caregivers aware of the risk of these uncontrollable urges when prescribing aripiprazole, and specifically ask patients about any new or increasing urges while they are being treated with aripiprazole. Closely monitor for new or worsening uncontrollable urges in patients at higher risk for impulse-control problems. These include those with a personal or family history of obsessive-compulsive disorder, impulse-control disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors. Consider reducing the dose or stopping the medicine if such urges develop.

Patients and caregivers should be alert for uncontrollable and excessive urges and behaviors while taking aripiprazole. It is important to talk with a health care professional as soon as possible if you or a family member experiences any of these uncontrollable urges, in order to prevent or limit possible harm. Patients should not suddenly stop taking their aripiprazole medicine without first talking to their health care professional.

See for additional information regarding this MedWatch alert.

For more information regarding the MedWatch program, visit the FDA website at: and .

Warning(s)

  • Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 28 73 113 114

  • Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.1 73 113

  • Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).1 73

  • Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.1 28 113

  • Antipsychotic agents, including aripiprazole, are not approved for the treatment of dementia-related psychosis.1 73 113

  • Suicidality
  • Antidepressants may increase risk of suicidal thinking and behavior (suicidality) compared with placebo in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.1 76 77 Aripiprazole is not approved for treatment of depression in pediatric patients.1 (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.1 76 77

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.1 76 77 78

  • Appropriately monitor and closely observe all patients who are started on aripiprazole therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.1 76 77 78 (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Quinolinone derivative;2 5 atypical or second-generation antipsychotic agent.1 2 7 28 89 98

Uses for Abilify

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Used orally for acute and maintenance treatment of schizophrenia.1 2 3 9 89 91 93

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes).28

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.28 70 71 72 115

Used IM for acute management of agitation in patients with schizophrenia for whom treatment with aripiprazole is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).1 86 87

Bipolar Disorder

Used orally alone or in conjunction with lithium or valproate for acute treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic features; also used orally as monotherapy or as adjunctive therapy with lithium or valproate for longer-term maintenance monotherapy.1 67 90 112

Used IM for acute management of agitation in patients with bipolar I disorder, manic or mixed, for whom treatment with aripiprazole is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).1 88

Adjunctive Therapy of Major Depressive Disorder

Used orally as adjunctive therapy to antidepressants for acute treatment of major depressive disorder.1 85

Irritability Associated with Autistic Disorder

Used orally for acute treatment of irritability associated with autistic disorder.1 109 110

Abilify Dosage and Administration

General

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.1 76 77 78 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

  • When switching from other antipsychotic agents to aripiprazole, abrupt discontinuance of previous agent may be acceptable for some patients with schizophrenia, but gradual discontinuance may be most appropriate for others.1 In all cases, minimize period of overlapping antipsychotic administration.1

Administration

Administer aripiprazole orally or by IM injection.1

Oral Administration

Administer orally as conventional tablets, orally disintegrating tablets, or oral solution once daily without regard to meals.1

Orally Disintegrating Tablets

Just prior to administration, peel open blister package; with dry hands, remove orally disintegrating tablet.1 Do not push tablet through foil.1

Place tablet on tongue to dissolve; manufacturer recommends taking without liquid, but may take with liquid, if necessary.1

Do not divide orally disintegrating tablet.1

IM Administration

Administer aripiprazole injection only by IM injection slowly and deeply into the muscle mass.1

Do not administer IV or sub-Q.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Aripiprazole oral solution may be given at same dose on mg-per-mg basis as the tablet strengths of the drug up to a dose of 25 mg.1 However, if oral solution is used in patients receiving 30-mg tablets, use a dose of 25 mg of the oral solution.1

Dosing of aripiprazole orally disintegrating tablets is the same as for conventional tablets of the drug.1

If used with CYP3A4 inhibitors, CYP2D6 inhibitors, and/or CYP3A4 inducers, dosage adjustment may be required.1 (See Interactions.)

Pediatric Patients

Schizophrenia
Oral

Adolescents ≥13 years of age: Recommended target dosage for acute treatment is 10 mg once daily.1 Therapy has been initiated at 2 mg once daily, with subsequent titration to 5 mg once daily after 2 days and to 10 mg once daily after 2 additional days.1 75 91

Subsequent dosage increases should be made in 5-mg, once-daily increments.1

Dosages of 10 and 30 mg once daily evaluated in clinical trials; the 30-mg daily dosage was not more effective than the 10-mg daily dosage.1 75 91

Although efficacy as maintenance treatment not systematically evaluated in adolescents with schizophrenia, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.1 Pediatric patients responding to aripiprazole therapy should continue to receive the drug as long as clinically necessary and tolerated, but at the lowest possible effective dosage; periodically reassess need for continued therapy.1 (See Pediatric Use under Cautions.)

Bipolar Disorder
Manic or Mixed Episodes: Monotherapy or Combination Therapy
Oral

Children and adolescents ≥10 years of age: Target dosage for acute treatment is 10 mg once daily.1 Recommended initial dosage when given as monotherapy is 2 mg once daily, with subsequent titration to 5 mg once daily after 2 days and to the target dosage of 10 mg once daily after 2 additional days.1

Recommended dosage when aripiprazole is given as adjunctive therapy with lithium or valproate is the same as that for monotherapy.1

Daily dosage may be increased, if necessary, in 5-mg increments.1 In pediatric clinical studies, dosages of 10 and 30 mg daily were effective.1

Although efficacy as maintenance treatment in bipolar disorder not evaluated in the pediatric population, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.1 Recommended dosage for maintenance therapy, whether given as monotherapy or as adjunctive therapy with lithium or valproate, is same dosage needed to stabilize patients during acute treatment.1 Pediatric patients responding to aripiprazole therapy should continue to receive the drug as long as clinically necessary and tolerated, but at the lowest possible effective dosage; periodically reassess need for continued therapy.1 (See Pediatric Use under Cautions.)

Irritability Associated with Autistic Disorder
Oral

Children and adolescents 6–17 years of age: Initially, 2 mg once daily, then increase dosage to 5 mg daily, with subsequent increases to 10 or 15 mg daily, if necessary.1 Increase dosage gradually, at intervals of ≥1 week.1 Individualize dosage based on tolerability and response.1 Efficacy established within a dosage range of 5–15 mg daily in clinical studies.1 109 110

Efficacy as maintenance treatment not evaluated, and optimum duration is not known; periodically reassess need for continued therapy.1

Adults

Schizophrenia
Oral

Initial and target dosage for acute treatment is 10 or 15 mg once daily.1

Dosages ranging from 10–30 mg once daily were effective in clinical trials; dosages exceeding 10–15 mg daily did not result in greater efficacy.1

Adjust dosage at intervals of ≥2 weeks, the time needed to achieve steady-state concentrations.1

Efficacy as maintenance therapy for ≤26 weeks has been demonstrated;1 other clinical experience indicates may be effective for up to 52 weeks.2 9 10 Optimum duration of therapy is not known, but maintenance therapy with antipsychotics is well established.1 28

In patients responding to aripiprazole therapy, continue the drug as long as clinically necessary and tolerated, but at lowest possible effective dosage; periodically reassess need for continued therapy.1

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.28 Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while taking antipsychotic.28 Indefinite maintenance treatment is recommended if multiple previous psychotic episodes or 2 episodes within 5 years.28

Bipolar Disorder
Manic or Mixed Episodes: Monotherapy or Combination Therapy
Oral

Monotherapy: Initially, 15 mg once daily.1

Adjunctive therapy to lithium or valproate: Initial dosage of 10–15 mg once daily.1

Recommended target dosage for maintenance therapy is 15 mg daily whether the drug is given as monotherapy or as adjunctive therapy with lithium or valproate.1 Based on patient response, may increase dosage to 30 mg once daily.1

Safety of dosages >30 mg daily not established.1

Efficacy as monotherapy and as combination therapy for long-term maintenance therapy established in clinical studies.1 74 112 Recommended dosage for maintenance therapy, whether given as monotherapy or as adjunctive therapy with lithium or valproate, is same dosage needed to stabilize patients during acute treatment.1 Periodically reevaluate long-term risks and benefits of the drug for the individual patient.1

Major Depressive Disorder
Oral

Initially, 2–5 mg once daily as adjunctive acute therapy.1

Gradually adjust dosage in increments of ≤5 mg daily at ≥1-week intervals; the recommended dosage is 5–10 mg once daily.1 Dosages of 2–15 mg daily were effective in clinical trials.1

Long-term (i.e., >6 weeks) efficacy for adjunctive treatment of major depressive disorder not established and the optimum duration of maintenance therapy is not known; periodically reassess need for continued therapy.1

Manufacturer does not recommend aripiprazole dosage adjustment when administered as adjunctive therapy for major depressive disorder concurrently with CYP2D6 inhibitors.1 (See Interactions.)

Acute Agitation in Schizophrenia and Bipolar Mania
IM

Initially, 9.75 mg as a single dose.1 Consider lower dose of 5.25 mg when clinically warranted.1

In clinical trials, efficacy was demonstrated with doses of 5.25–15 mg.1 86 87 88 Additional benefit not demonstrated with 15-mg dose compared with 9.75-mg dose.1

Efficacy of repeated doses not systematically evaluated.1 If agitation persists following the initial dose, may administer subsequent doses up to a cumulative daily dose of 30 mg.1 Safety of total doses >30 mg daily or administration more frequently than every 2 hours not systematically evaluated in controlled trials.1

If continued aripiprazole therapy is clinically indicated, oral therapy should replace IM therapy as soon as possible.1

Prescribing Limits

Pediatric Patients

Schizophrenia
Oral

Safety and efficacy of dosages >30 mg daily not established.1 91

Bipolar Disorder
Manic or Mixed Episodes
Oral

Safety and efficacy of dosages >30 mg daily not established.1

Irritability Associated with Autistic Disorder
Oral

Safety and efficacy of dosages >15 mg daily not established.1

Adults

Schizophrenia
Oral

Safety and efficacy of dosages >30 mg daily not established.1

Bipolar Disorder
Manic or Mixed Episodes
Oral

Safety and efficacy of dosages >30 mg daily not established.1

Adjunctive Therapy of Major Depressive Disorder
Oral

Safety and efficacy of dosages >15 mg daily not established.1

Acute Agitation in Schizophrenia and Bipolar Mania
IM

Safety of total dosages >30 mg daily or IM doses given more frequently than every 2 hours not established.1

Special Populations

Hepatic Impairment

Dosage adjustment not required.1 95

Renal Impairment

Dosage adjustment not required.1 95

Geriatric Patients

Dosage adjustment not required.1

Gender, Race, or Smoking Status

Dosage adjustment not required.1

Poor CYP2D6 Metabolizer Phenotype

Reduce initial dosage to 50% of the usual dosage, then adjust dosage to achieve favorable clinical response.1

If patients with poor metabolizer phenotype are concomitantly receiving a potent CYP3A4 inhibitor, reduce aripiprazole dosage to 25% of the usual dosage.1 (See Interactions.)

Cautions for Abilify

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Known hypersensitivity (e.g., pruritus, urticaria, anaphylaxis) to aripiprazole or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.1 28 73 113 114

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with aripiprazole in several placebo-controlled studies of dementia-related psychosis.1 28

Antipsychotic agents, including aripiprazole, are not approved for the treatment of dementia-related psychosis.1 73 113 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, and see Dysphagia under Cautions.)

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.1 76 77 78 79 (See Boxed Warning and also see Pediatric Use under Cautions.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1 76 77 78

Appropriately monitor and closely observe patients receiving aripiprazole for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 76 77 78

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.1 77 78 Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.1 76 77 78

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.1 77

Sensitivity Reactions

Allergic reactions (e.g., anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, oropharyngeal spasm) reported rarely.1 (See Contraindications under Cautions.)

Other Warnings and Precautions

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including aripiprazole.1 99 100 101

Immediately discontinue therapy and initiate supportive and symptomatic treatment if NMS occurs.1 Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.1

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including aripiprazole.1 96 97

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.1

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.28 Consider discontinuance of aripiprazole if signs and symptoms of tardive dyskinesia appear.1 However, some patients may require treatment despite the presence of the syndrome.1

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.1 11 12 14 15 16 17 18 20 21 22 23 25 40 41 42 46 65

Periodically monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control and perform fasting glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).11 12 If manifestations of hyperglycemia occur in any aripiprazole-treated patient, perform fasting blood glucose testing.1 11 12 14 15 16 17 18 19 20 21 22 23 (See Advice to Patients.)

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.1 11 12 14 15 16 17 18 19 20 21 22 23 46

Orthostatic Hypotension

Risk of orthostatic hypotension associated with adverse effects, including postural dizziness and syncope, perhaps because of aripiprazole's α1-adrenergic blocking activity.1

Use with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose them to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).1

If parenteral benzodiazepine therapy is necessary in patients receiving IM aripiprazole, monitor patients for possible excessive sedation and orthostatic hypotension.1 (See Specific Drugs under Interactions.)

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia temporally related to antipsychotic agents, including aripiprazole, reported during clinical trial and/or postmarketing experience.1 102 103 Agranulocytosis also has been reported.1

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.1 102 103 Monitor CBC frequently during the first few months of therapy in patients with such risk factors.1 Discontinue aripiprazole at the first sign of a decline in WBC count in the absence of other causative factors.1

Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.1 Discontinue aripiprazole if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.1

Seizures

Seizures/convulsions reported in 0.1 and 0.2% of adult and pediatric patients (6–17 years of age), respectively, treated with oral aripiprazole, and in 0.2% of adults treated with IM aripiprazole.1

Use with caution in patients with a history of seizures or with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer’s type, geriatric patients).1

Cognitive and Motor Impairment

Judgment, thinking, or motor skills may be impaired.1

Somnolence (including sedation) reported in 11 and 9% of adults treated with oral or parenteral aripiprazole, respectively, compared with 6% of those receiving placebo in short-term clinical trials; somnolence (including sedation) reported in 24% of pediatric patients (6–17 years of age) receiving aripiprazole compared with 6% of those receiving placebo.1 (See Advice to Patients.)

Body Temperature Regulation

Antipsychotic agents may disrupt ability to reduce core body temperature.1

Use appropriate caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).1

Suicide

Attendant risk with psychotic illnesses; closely supervise high-risk patients.1 Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents, including aripiprazole.1

Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer’s dementia.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.) Use with caution in patients at risk for aspiration pneumonia.1

Phenylketonuria

Each 10- or 15-mg Abilify Discmelt orally disintegrating tablet contains aspartame (NutraSweet), which is metabolized in the GI tract to provide about 1.12 or 1.68 mg of phenylalanine, respectively.1 80 81 82 83 84

Concomitant Illnesses

Limited experience in patients with certain concomitant diseases (e.g., patients with a recent MI or unstable heart disease).1 Use with caution in patients with conditions that would predispose them to hypotension.1 (See Orthostatic Hypotension under Cautions.)

Specific Populations

Pregnancy

Category C.1

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.1 106 107 108 111 Symptoms varied in severity; some neonates recovered within hours to days without specific treatment, while others have required intensive care unit support and prolonged hospitalization.1 106 107 108

Lactation

Distributed into milk in humans.111 Women receiving aripiprazole should not breast-feed.1

Pediatric Use

Safety and efficacy of aripiprazole not established in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania.1

Safety and efficacy of oral aripiprazole for acute management of schizophrenia in pediatric patients 13–17 years of age established in a placebo-controlled study of 6 weeks' duration.1 91 Efficacy for maintenance treatment not established, but can be extrapolated from adult data and pharmacokinetic comparisons between adult and pediatric populations.1

Safety and efficacy of oral aripiprazole for acute management of bipolar mania in pediatric patients 10–17 years of age established in a placebo-controlled study of 4 weeks' duration.1 Efficacy for maintenance treatment not established, but can be extrapolated from adult data and pharmacokinetic comparisons between adult and pediatric populations.1

Efficacy of oral aripiprazole as adjunctive therapy to lithium or valproate for management of manic or mixed episodes associated with bipolar disorder in pediatric patients not evaluated.1 However, efficacy can be extrapolated from adult data and pharmacokinetic comparisons between adult and pediatric populations.1

Safety and efficacy of oral aripiprazole for treatment of irritability associated with autistic disorder in pediatric patients 6–17 years of age established in 2 placebo-controlled clinical studies of 8 weeks’ duration.1 109 110 Efficacy as maintenance treatment for irritability associated with autistic disorder in pediatric patients not evaluated.1

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).1 77 However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.79 No suicides occurred in these pediatric trials.1 77 79

Initiate drug therapy for pediatric schizophrenia, bipolar I disorder, and irritability associated with autistic disorder only after performing a thorough diagnostic evaluation and carefully considering risks associated with medication treatment.1 Medication treatment should be only part of a total treatment program that often includes psychological, educational, and social interventions.1

Geriatric Use

Insufficient experience with oral and IM aripiprazole in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Manufacturer states that dosage adjustment in geriatric patients is not necessary.1

Tolerability profile may differ in patients ≥65 years of age with dementia-related psychosis, including psychosis in association with dementia of the Alzheimer’s type, compared with that in younger patients with schizophrenia.1 Possible increased risk of death.1 73 (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1 76 77 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Common Adverse Effects

Oral aripiprazole (adults): Nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, restlessness.1

Oral aripiprazole (pediatric patients): Somnolence, extrapyramidal disorder, headache, fatigue.1

IM aripiprazole: Nausea.1

Interactions for Abilify

Extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by CYP2D6 and CYP3A4.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction.1 Reduce aripiprazole dosage to 50% of usual dosage; increase to usual dosage after discontinuance of CYP3A4 inhibitor.1 In patients with poor CYP2D6 metabolizer phenotype, reduce aripiprazole dosage to 25% of usual dosage.1 (See Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration.)

Moderate CYP3A4 inhibitors: Effects not studied.1

Concomitant use with potent inhibitors of CYP3A4 and CYP2D6: Reduce aripiprazole dosage to 25% of usual dosage.1 When the CYP3A4 and/or CYP2D6 inhibitor is withdrawn, increase aripiprazole dosage.1

Concomitant use with combination of potent, moderate, and weak CYP3A4 and CYP2D6 inhibitors (e.g., potent CYP3A4 inhibitor with moderate CYP2D6 inhibitor; moderate CYP3A4 inhibitor with moderate CYP2D6 inhibitor): Reduce initial aripiprazole dosage to 25% of usual dosage, then adjust to achieve favorable clinical response.1

CYP2D6 inhibitors: Reduce aripiprazole dosage to ≤50% of usual dosage.1 Dosage adjustment not recommended if aripiprazole administered concurrently with CYP2D6 inhibitors as adjunctive therapy for major depressive disorder.1 When CYP2D6 inhibitor is discontinued, increase aripiprazole dosage to usual dosage.1

CYP3A4 inducers: Double aripiprazole dosage when potential CYP3A4 inducer is initiated;1 105 base additional dosage escalation on clinical evaluation.1 Decrease aripiprazole dosage to 10–15 mg daily if CYP3A4 inducer is discontinued.1 105

Inhibitors or inducers of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2E1: Pharmacokinetic interaction unlikely.1

Substrates of Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4: Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible additive CNS effects1

Avoid concomitant use1

Anticholinergic agents

Possible disruption of body temperature regulation1

Use with caution1

Benzodiazepines, parenteral (e.g., lorazepam)

Possible increased sedative and orthostatic hypotensive effects1

Lorazepam: No clinically important effects on pharmacokinetics of either aripiprazole or lorazepam with IM administration1

If concomitant use of IM aripiprazole and parenteral benzodiazepines considered necessary, monitor for excessive sedation and orthostatic hypotension1

Lorazepam: Aripiprazole dosage adjustment not necessary during concurrent administration1

Carbamazepine

Carbamazepine (potent CYP3A4 inducer) decreased peak plasma concentrations and AUCs of aripiprazole and dehydro-aripiprazole1 105

Double aripiprazole dosage when carbamazepine is added; base additional aripiprazole dosage increases on clinical evaluation1 105

If carbamazepine is discontinued, reduce aripiprazole dosage to 10–15 mg daily1 105

Clarithromycin

Potent CYP3A4 inhibitors (e.g., clarithromycin) may increase AUCs of aripiprazole and its active metabolite1

Reduce aripiprazole dosage to 50% of usual dosage; when clarithromycin is withdrawn, increase aripiprazole dosage1

CNS agents

Possible additive CNS effects1

Use with caution1

Dextromethorphan

No change in dextromethorphan metabolism observed1

Dextromethorphan dosage adjustment not necessary1

Escitalopram

No substantial effect on pharmacokinetics of escitalopram (CYP2C19 and CYP3A4 substrate)1 104

Escitalopram dosage adjustment not necessary1

Famotidine

Potential decreased aripiprazole absorption; not clinically important1

Aripiprazole dosage adjustment not necessary1

Fluoxetine

Fluoxetine (CYP2D6 inhibitor) expected to increase aripiprazole AUC1

Aripiprazole did not substantially affect fluoxetine pharmacokinetics1 104

Reduction of aripiprazole dosage recommended except when used as adjunctive therapy for major depressive disorder1

Reduce aripiprazole dosage to ≤50% of usual dosage; when fluoxetine is withdrawn, increase aripiprazole dosage1

Hypotensive agents

Possible additive hypotensive effects1

Use with caution1

Itraconazole

Potent CYP3A4 inhibitors (e.g., itraconazole) may increase AUCs of aripiprazole and its active metabolite1

Reduce aripiprazole dosage to 50% of usual dosage; when itraconazole is withdrawn, increase aripiprazole dosage1

Ketoconazole

Ketoconazole (potent CYP3A4 inhibitor) substantially increased AUCs of aripiprazole and its active metabolite1

Reduce aripiprazole dosage to 50% of usual dosage; when ketoconazole is withdrawn, increase aripiprazole dosage1

Lamotrigine

Concomitant use with aripiprazole apparently well tolerated;1 92 pharmacokinetic interaction unlikely1 92

Lamotrigine dosage adjustment not necessary1 92

Lithium

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment of aripiprazole and lithium not necessary1

Omeprazole

No substantial effect on pharmacokinetics of omeprazole (CYP2C19 substrate)1

Omeprazole dosage adjustment not necessary1

Paroxetine

Paroxetine (CYP2D6 inhibitor) expected to increase aripiprazole AUC1

Aripiprazole did not substantially affect paroxetine pharmacokinetics1 104

Reduction of aripiprazole dosage recommended except when used as adjunctive therapy for major depressive disorder1

Reduce aripiprazole dosage to ≤50% of usual dosage; when paroxetine is withdrawn, increase aripiprazole dosage1

Quinidine

Quinidine (potent CYP2D6 inhibitor) increased aripiprazole AUC but decreased AUC of dehydro-aripiprazole1

Reduce aripiprazole dosage to ≤50% of usual dosage; when quinidine is withdrawn, increase aripiprazole dosage1

Sertraline

Aripiprazole did not substantially affect sertraline pharmacokinetics1 104

Smoking

Pharmacokinetic interaction unlikely1

Aripiprazole dosage adjustment not necessary1

Valproate

Clinically important pharmacokinetic interaction unlikely1

Dosage adjustment of aripiprazole and valproate not necessary1

Venlafaxine

No effect on pharmacokinetics of venlafaxine (CYP2D6 substrate) or O-desmethylvenlafaxine1 104

Venlafaxine dosage adjustment not necessary1

Warfarin

No clinically important effect on warfarin pharmacokinetics or INR1

Warfarin dosage adjustment not necessary1

Abilify Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability of conventional tablets is 87%.1

Peak plasma concentrations achieved within 3–5 hours after administration of conventional tablets; steady-state concentrations achieved within 14 days.1

Orally disintegrating tablets and conventional tablets are bioequivalent.1

Well absorbed when administered as oral solution; plasma aripiprazole concentrations are higher after administration of oral solution than conventional tablets at equivalent doses.1 (See Dosage under Dosage and Administration.)

Oral solution-to-tablet ratios of geometric mean maximum plasma concentrations and AUCs were 122 and 114%, respectively.1

Absolute IM bioavailability of a 5-mg dose is 100%.1 Systemic exposure over 24 hours is similar following IM and oral administration; however, AUC was 90% higher within first 2 hours after IM than after oral tablet administration.1

Food

Administration of conventional tablets with a high-fat meal delayed rate but not extent of absorption.1

Distribution

Extent

Large volume of distribution following IV administration indicates extensive extravascular distribution.1

Distributed into milk.111

Plasma Protein Binding

Aripiprazole and its major metabolite, dehydro-aripiprazole, are >99% bound, principally to albumin.1

Elimination

Metabolism

Extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by CYP2D6 and CYP3A4.1

Elimination Route

Following oral administration, approximately 18% and <1% excreted unchanged in feces and urine, respectively; IM administration is not expected to alter metabolic pathways.1

Half-life

Aripiprazole: 75 hours.1

Dehydro-aripiprazole: 94 hours.1

Special Populations

In patients with the poor metabolizer CYP2D6 phenotype (approximately 8% of Caucasians), exposure to aripiprazole is increased by about 80%, while exposure to its active metabolite is decreased by approximately 30%.1 Aripiprazole elimination half-life in poor metabolizers is approximately 146 hours.1

Pediatric patients 10–17 years of age: Pharmacokinetics similar to those in adults after correcting for body weight differences.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Orally Disintegrating Tablets

25°C (may be exposed to 15–30°C).1

Oral Solution

25°C (may be exposed to 15–30°C).1 After opening, can use for up to 6 months (but not beyond expiration date).1

Parenteral

Injection

25°C (may be exposed to 15–30°C).1 Store in original carton until time of use; protect from light.1 Discard any unused portion.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility
Syringe CompatibilityHID

Compatible

Lorazepam

Actions

  • Exact mechanism of action has not been fully elucidated; may involve the drug’s activity at dopamine D2 and serotonin type 1 (5-HT1A) and type 2 (5-HT2A) receptors.1 2 3 4 5 6 7

  • Demonstrates partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.1 2 3 4 5 6 7 89 The major active metabolite, dehydro-aripiprazole, exhibits affinity for D2 receptors similar to that of the parent compound.1

  • Antagonism at other receptors (e.g., α1-adrenergic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).1 89

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of providing copy of written patient information (medication guide) each time aripiprazole is dispensed.1 76 77 78 Importance of advising patients to read the patient information before taking aripiprazole and each time the prescription is refilled.1 76

  • Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 28 73 98 113 Inform patients and caregivers that aripiprazole is not approved for treating geriatric patients with dementia-related psychosis.1 73 98

  • Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, manic or hypomanic symptoms, irritability, agitation, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.1 76 77 78

  • Risk of somnolence and impairment of judgment, thinking, or motor skills; avoid driving, operating machinery, or performing hazardous tasks until effects on the individual are known.1

  • Importance of avoiding alcohol during aripiprazole therapy.1

  • Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.1

  • Importance of informing patients of risk of tardive dyskinesia if chronic use is contemplated.1 98 Importance of informing patients to report any muscle movements that cannot be stopped to a healthcare professional.98

  • Risk of leukopenia/neutropenia.1 Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia of need for CBC monitoring during aripiprazole therapy.1

  • Importance of patients being aware of the symptoms of hyperglycemia and diabetes mellitus (e.g., increased thirst, increased urination, increased appetite, weakness).1 Importance of informing patients who are diagnosed with diabetes that they should have their blood glucose monitored regularly.1 Importance of informing patients with risk factors for diabetes (e.g., obesity, family history of diabetes) that they should have their blood glucose monitored at the beginning of and periodically during aripiprazole treatment; patients who develop symptoms of hyperglycemia during therapy should have their blood glucose assessed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1 98

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 108 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).1 108 Importance of advising patients not to stop taking aripiprazole if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications.108 Importance of advising patients not to breast-feed during aripiprazole therapy.1

  • Importance of avoiding overheating or dehydration.1

  • For patients taking aripiprazole orally disintegrating tablets, importance of not removing a tablet from the blister package until just before administering a dose; importance of peeling blister open with dry hands and placing tablet on tongue to dissolve and be swallowed with saliva.1

  • Importance of informing patients with phenylketonuria that aripiprazole orally disintegrating 10- and 15-mg tablets contain 1.12 and 1.68 mg of phenylalanine, respectively.1

  • Importance of being aware that aripiprazole oral solution contains 400 mg of sucrose and 200 mg of fructose per mL.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Aripiprazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

5 mg/5 mL*

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

Tablets

2 mg*

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

5 mg*

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

10 mg*

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

15 mg*

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

20 mg*

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

30 mg*

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

Tablets, orally disintegrating

10 mg*

Abilify Discmelt

Otsuka (also promoted by Bristol-Myers Squibb)

15 mg*

Abilify Discmelt

Otsuka (also promoted by Bristol-Myers Squibb)

Parenteral

Injection, for IM use only

7.5 mg/mL (9.75 mg)

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

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