valproate (2.2)
`
`As an adjunct to
`antidepressants for the
`treatment of major
`depressive disorder – adults
`(2.3)
`Irritability associated with
`autistic disorder – pediatric
`patients (2.4)
`
`Agitation associated with
`9.75 mg /1.3
`30 mg/day
`
` schizophrenia or bipolar
`mL injected
`injected
`mania – adults (2.5)
`IM
`IM
`
`
`
`Oral formulations: Administer once daily without regard to meals (2)
`•
`
`IM injection: Wait at least 2 hours between doses. Maximum daily dose
`•
`30 mg (2.5)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`Tablets: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg (3)
`•
`
`
`
`
`Orally Disintegrating Tablets: 10 mg and 15 mg (3)
`•
`
`
`
`Oral Solution: 1 mg/mL (3)
`•
`
`
`
`Injection: 9.75 mg/1.3 mL single-dose vial (3)
`•
`------------------------------CONTRAINDICATIONS-------------------------------
`Known hypersensitivity to ABILIFY (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`
`Elderly Patients with Dementia-Related Psychosis: Increased incidence of
`
`•
`cerebrovascular adverse events (eg, stroke, transient ischemic attack,
`
`including fatalities) (5.1)
`Suicidality and Antidepressants: Increased risk of suicidality in children,
`
`adolescents, and young adults with major depressive disorder (5.2)
`Neuroleptic Malignant Syndrome: Manage with immediate discontinuation
`
`and close monitoring (5.3)
`
`Tardive Dyskinesia: Discontinue if clinically appropriate (5.4)
`Hyperglycemia and Diabetes Mellitus: Monitor glucose regularly in
`
`
`patients with and at risk for diabetes (5.5)
`Orthostatic Hypotension: Use with caution in patients with known
`
`cardiovascular or cerebrovascular disease (5.6)
`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 (5.7)
`Seizures/Convulsions: Use cautiously in patients with a history of seizures
`or with conditions that lower the seizure threshold (5.8)
`Potential for Cognitive and Motor Impairment: Use caution when
`
`operating machinery (5.9)
`Suicide: The possibility of a suicide attempt is inherent in schizophrenia
`
`and bipolar disorder. Closely supervise high-risk patients (5.11)
`-------------------------------ADVERSE REACTIONS------------------------------
`
`Commonly observed adverse reactions (incidence ≥5% and at least twice that for
`placebo) were (6.2):
`
`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
`Adult patients with agitation associated with schizophrenia or bipolar
`mania: nausea
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch
`Page 1 of 80
`
`02/2011
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`Indications and Usage, Bipolar I Disorder,
`
`Adjunctive Therapy (1.2)
`
`Dosage and Administration, Bipolar I Disorder,
`
`
`02/2011
`Adjunctive Therapy (2.2)
`
`02/2011
`Dosage and Administration, Dosage Adjustment (2.6)
`---------------------------INDICATIONS AND USAGE----------------------------
`ABILIFY is an atypical antipsychotic indicated
`as oral formulations for the:
`
`Treatment of schizophrenia (1.1)
`
`
`Adults: Efficacy was established in four 4-6 week trials and one
`
`•
`maintenance trial in patients with schizophrenia (14.1)
`
`Adolescents (ages 13-17): Efficacy was established in one 6-week trial in
`
`patients with schizophrenia (14.1)
`
`Acute treatment of manic or mixed episodes associated with bipolar I disorder as
`
`monotherapy and as an adjunct to lithium or valproate (1.2)
`Adults: Efficacy was established in four 3-week monotherapy trials and
`
`•
`one 6-week adjunctive trial in patients with manic or mixed episodes (14.2)
`
`
`Pediatric Patients (ages 10-17): Efficacy was established in one 4-week
`
`monotherapy trial in patients with manic or mixed episodes (14.2)
`
`
`Maintenance treatment of bipolar I disorder, both as monotherapy and as an
`
`adjunct to lithium or valproate (1.2)
`
`
`Adults: Efficacy was established in one maintenance monotherapy trial and
`
`•
`in one maintenance adjunctive trial (14.2)
`Adjunctive treatment of major depressive disorder (MDD) (1.3)
`Adults: Efficacy was established in two 6-week trials in patients with MDD
`who had an inadequate response to antidepressant therapy during the
`current episode (14.3)
`
`Treatment of irritability associated with autistic disorder (1.4)
`
`Pediatric Patients (ages 6-17 years): Efficacy was established in two 8­
`
`•
`week trials in patients with autistic disorder (14.4)
`
`as an injection for the:
`
`Acute treatment of agitation associated with schizophrenia or bipolar I disorder
`(1.5)
`
`•
`
`Adults: Efficacy was established in three 24-hour trials in agitated patients
`with schizophrenia or manic/mixed episodes of bipolar I disorder (14.5)
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`Initial
`Recommended Maximum
`
`Dose
`Dose
`Dose
`10-15 mg
`10-15 mg
`30 mg
`
`/day
`/day
`/day
`2 mg
`10 mg
`30 mg
`/day
`/day
`/day
`15 mg
`15 mg
`30 mg
`/day
`/day
`/day
`10-15 mg
`15 mg
`30 mg
`/day
`/day
`/day
`
`2 mg
`/day
`
`10 mg
`/day
`
`30 mg
`/day
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use ABILIFY
`
`safely and effectively. See full prescribing information for ABILIFY.
`ABILIFY® (aripiprazole) Tablets
`ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets
`
`ABILIFY® (aripiprazole) Oral Solution
`ABILIFY® (aripiprazole) Injection FOR INTRAMUSCULAR USE ONLY
`Initial U.S. Approval: 2002
`
`WARNINGS: INCREASED MORTALITY IN ELDERLY
`
`PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and
`
`
`SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`See full prescribing information for complete boxed warning.
`
`
`• Elderly patients with dementia-related psychosis treated with
`antipsychotic drugs are at an increased risk of death. ABILIFY is
`
`not approved for the treatment of patients with dementia-related
`
`psychosis. (5.1)
`
`• Children, adolescents, and young adults taking antidepressants for
`
`major depressive disorder (MDD) and other psychiatric disorders
`
`are at increased risk of suicidal thinking and behavior. (5.2)
`
`
`2-5 mg
`/day
`
`5-10 mg
`/day
`
`15 mg
`/day
`
`
`
` 2 mg/day
`
`
`
` 5-10 mg/day
`
`
`
` 15 mg/day
`
`
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`Schizophrenia – adults (2.1)
`
`
`Schizophrenia – adolescents
`(2.1)
`Bipolar mania – adults:
`monotherapy (2.2)
`Bipolar mania – adults:
`
`adjunct to lithium or
`
`valproate (2.2)
` Bipolar mania – pediatric
`
`
`patients: monotherapy or as
`
`an adjunct to lithium or
`
`Reference ID: 2912460
`
`

`

`--------------------------------DRUG INTERACTIONS-----------------------------
`
` Strong CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, fluoxetine) inhibitors
`
`•
`will increase ABILIFY drug concentrations; reduce ABILIFY dose to one-
`
`half of the usual dose when used concomitantly (2.6, 7.1), except when
`
`used as adjunctive treatment with antidepressants (2.6). If a strong
`CYP3A4 inhibitor and strong CYP2D6 inhibitor are co-administered or a
`known CYP2D6 poor metabolizer is receiving a concomitant strong
`
`
`
`
`•
`
`CYP3A4 inhibitor, the ABILIFY dose should be reduced to one-quarter
`
` (25%) of the usual dose (2.6, 12.3).
` CYP3A4 inducers (eg, carbamazepine) will decrease ABILIFY drug
`
`concentrations; double ABILIFY dose when used concomitantly (2.6, 7.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`
`
`Revised: 02/2011
`
`Reference ID: 2912460
`
`Page 2 of 80
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS
`
`WITH DEMENTIA-RELATED PSYCHOSIS AND SUICIDALITY
`
`AND ANTIDEPRESSANT DRUGS
`
`INDICATIONS AND USAGE
`
`
`
`Schizophrenia
`
`1.1
`
`
`1.2
`Bipolar I Disorder
`
`
`
`1.3
`Adjunctive Treatment of Major Depressive Disorder
`
`
`
`1.4
`Irritability Associated with Autistic Disorder
`
`
`
`1.5
`Agitation Associated with Schizophrenia or Bipolar Mania
`
`
`1.6
`Special Considerations in Treating Pediatric
`
`Schizophrenia, Bipolar I Disorder, and Irritability
`
`
`
`Associated with Autistic Disorder
`
`
`
`DOSAGE AND ADM NISTRATIONI
`
`
`
`Schizophrenia
`
`2.1
`
`
`2.2
`Bipolar I Disorder
`
`
`
`2.3
`Adjunctive Treatment of Major Depressive Disorder
`
`
`
`2.4
`Irritability Associated with Autistic Disorder
`
`
`2.5
`Agitation Associated with Schizophrenia or Bipolar Mania
`
`
`(Intramuscular Injec on)
`ti
`
`
`
`2.6
`Dosage Adjustment
`
`
`
`2.7
`Dosing of Oral Solution
`
`
`Dosing of Orally Disintegrating T blets
`a
`2.8
`
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`Use in Elderly Patients with Dementia-Related Psychosis
`
`5.1
`
`
`Clinical Worsening of Depression and Suicide Risk
`
`5.2
`
`
`5.3
`Neuroleptic Malignant Syndrome (NMS)
`
`
`
`5.4
`Tardive Dyskinesia
`
`
`
`5.5
`Hyperglycemia and Diabetes Mellitus
`
`
`
`5.6
`Orthostatic Hypotension
`
`
`
`5.7
`Leukopenia, Neutropenia, and Agranulocytosis
`
`
`
`5.8
`Seizures/Convulsions
`
`
`
`5.9
`Potential for Cognitive and Motor Impairment
`
`
`
`5.10
`
`Body T mperature Regulation
`e
`
`
`5.11
`Suicide
`
`
`
`5.12 Dysphagia
`
`
`
`5.13 Use in Patients with Concomitant Illness
`
`
`ADVERSE REACTIONS
`
`
`Overall Adverse Reactions Profile
`
`6.1
`
`
`Clinical Studies Experience
`
`6.2
`
`
`6.3
`Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`
`1
`
`
`2
`
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`
`
`
`
`
`8
`
`
`
`Potential for Other Drugs to Affect ABILIFY
`
`7.1
`
`
`Potential for ABILIFY to Affect Other Drugs
`
`7.2
`
`Drugs Having No Clinically Important Interactions with
`
`7.3
`
`ABILIFY
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`
`8.1
`
`
`8.2
`Labor and Delive y
`r
`
`
`8.3
`Nursing Mothers
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5
`Geriatric Use
`
`
`
`8.6
`Renal Impairment
`
`
`
`8.7
`Hepatic Impairment
`
`
`
`8.8
`Gender
`
`
`
`8.9
`Race
`
`
`
`8.10
`Smoking
`
`
`DRUG ABUSE AND DEPENDENCE
`
`
`Controlled Substance
`
`9.1
`
`
`9.2
`Abuse and Dependence
`
`
`OVERDOSAGE
`
`
`10.1 Human Experience
`
`
`
`10.2 Management of Overdosage
`
`
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2
`Pharmacodynami s
`c
`
`
`12.3
`Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`Animal Toxicology and/or Pharmacology
`
`13.2
`
`CLINICAL STUDIES
`
`
`14.1
`Schizophrenia
`
`
`
`Bipolar Disorder
`
`14.2
`
`
`14.3
`Adjunctive Treatment of Major Depressive Disorder
`
`
`
`14.4
`Irritability Associated with Autistic Disorder
`
`
`
`14.5
`Agitation Associated with Schizophrenia or Bipolar Mania
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`
`16.2
`Storage
`
`
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1
`Information for Patients
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`
`9
`
`
`10
`
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`16
`
`
`17
`
`Reference ID: 2912460
`
`3
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS
`
`WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDALITY AND
`
`ANTIDEPRESSANT DRUGS
`
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs
`are at an increased risk of death. Analyses of seventeen placebo-controlled trials
`(modal duration of 10 weeks), largely in patients taking atypical antipsychotic
`drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times
`the risk of death in placebo-treated patients. Over the course of a typical 10-week
`controlled trial, the rate of death in drug-treated patients was about 4.5%,
`compared to a rate of about 2.6% in the placebo group. Although the causes of
`death were varied, most of the deaths appeared to be either cardiovascular (eg,
`
`heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational
`studies suggest that, similar to atypical antipsychotic drugs, treatment with
`conventional antipsychotic drugs may increase mortality. The extent to which the
`
`findings of increased mortality in observational studies may be attributed to the
`antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
`ABILIFY (aripiprazole) is not approved for the treatment of patients with
`dementia-related psychosis [see WARNINGS AND PRECAUTIONS (5.1)].
`Antidepressants increased the risk compared to placebo of suicidal thinking and
`behavior (suicidality) in children, adolescents, and young adults in short-term
`studies of major depressive disorder (MDD) and other psychiatric disorders.
`Anyone considering the use of adjunctive ABILIFY or any other antidepressant in a
`child, adolescent, or young adult must balance this risk with the clinical need. Short-
`term studies did not show an increase in the risk of suicidality with antidepressants
`compared to placebo in adults beyond age 24; there was a reduction in risk with
`antidepressants compared to placebo in adults aged 65 and older. Depression and
`
`certain other psychiatric disorders are themselves associated with increases in the
`risk of suicide. Patients of all ages who are started on antidepressant therapy should
`
`be monitored appropriately and observed closely for clinical worsening, suicidality,
`or unusual changes in behavior. Families and caregivers should be advised of the
`
`need for close observation and communication with the prescriber. ABILIFY is not
`approved for use in pediatric patients with depression [see WARNINGS AND
`PRECAUTIONS (5.2)].
`
`
`Reference ID: 2912460
`
`4
`
`
`

`

`
`
`INDICATIONS AND USAGE
` 1
`
`1.1 Schizophrenia
`
` ABILIFY is indicated for the treatment of schizophrenia. The efficacy of ABILIFY was
`
`established in four 4-6 week trials in adults and one 6-week trial in adolescents (13 to 17
`years). Maintenance efficacy was demonstrated in one trial in adults and can be
`extrapolated to adolescents [see CLINICAL STUDIES (14.1)].
`
` 1.2 Bipolar I Disorder
`Acute Treatment of Manic and Mixed Episodes
`
`ABILIFY is indicated for the acute treatment of manic and mixed episodes associated
`
` with bipolar I disorder, both as monotherapy and as an adjunct to lithium or valproate.
`
` Efficacy as monotherapy was established in four 3-week monotherapy trials in adults and
`one 4-week monotherapy trial in pediatric patients (10 to 17 years). Efficacy as
`
` adjunctive therapy was established in one 6-week adjunctive trial in adults [see
`CLINICAL STUDIES (14.2)].
`Maintenance Treatment of Bipolar I Disorder
`ABILIFY is indicated for the maintenance treatment of bipolar I disorder, both as
`
` monotherapy and as an adjunct to either lithium or valproate. Maintenance efficacy was
`demonstrated in one monotherapy maintenance trial and in one adjunctive maintenance
`
` trial in adults [see CLINICAL STUDIES (14.2)].
` 1.3 Adjunctive Treatment of Major Depressive Disorder
`
`
` ABILIFY is indicated for use as an adjunctive therapy to antidepressants for the
`
`treatment of major depressive disorder (MDD). Efficacy was established in two 6-week
`trials in adults with MDD who had an inadequate response to antidepressant therapy
`during the current episode [see CLINICAL STUDIES (14.3)].
`
` 1.4 Irritability Associated with Autistic Disorder
`
`ABILIFY is indicated for the treatment of irritability associated with autistic disorder.
`Efficacy was established in two 8-week trials in pediatric patients (aged 6 to 17 years)
`
` with irritability associated with autistic disorder (including symptoms of aggression
`towards others, deliberate self-injuriousness, temper tantrums, and quickly changing
`
` moods) [see CLINICAL STUDIES (14.4)].
`
`Reference ID: 2912460
`
`5
`
`
`

`

`
`
`
`
` 1.5 Agitation Associated with Schizophrenia or Bipolar Mania
`
` ABILIFY Injection is indicated for the acute treatment of agitation associated with
`
`schizophrenia or bipolar disorder, manic or mixed. "Psychomotor agitation" is defined in
`DSM-IV as “excessive motor activity associated with a feeling of inner tension”. Patients
`experiencing agitation often manifest behaviors that interfere with their diagnosis and
`care (eg, threatening behaviors, escalating or urgently distressing behavior, or self-
`exhausting behavior), leading clinicians to the use of intramuscular antipsychotic
`medications to achieve immediate control of the agitation. Efficacy was established in
`
` three short-term (24-hour) trials in adults [see CLINICAL STUDIES (14.5)].
` 1.6 Special Considerations in Treating Pediatric Schizophrenia,
`
`Bipolar I Disorder, and Irritability Associated with Autistic
`Disorder
`
`Psychiatric disorders in children and adolescents are often serious mental disorders with
`variable symptom profiles that are not always congruent with adult diagnostic criteria. It
`is recommended that psychotropic medication therapy for pediatric patients only be
`initiated after a thorough diagnostic evaluation has been conducted and careful
`consideration given to the risks associated with medication treatment. Medication
`treatment for pediatric patients with schizophrenia, bipolar I disorder, and irritability
`associated with autistic disorder is indicated as part of a total treatment program that
`often includes psychological, educational, and social interventions.
`2 DOSAGE AND ADMINISTRATION
`2.1 Schizophrenia
`Adults
`
` Dose Selection: The recommended starting and target dose for ABILIFY is 10 mg/day or
`
` 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY has
`been systematically evaluated and shown to be effective in a dose range of 10 mg/day to
`30 mg/day, when administered as the tablet formulation; however, doses higher than
`10 mg/day or 15 mg/day were not more effective than 10 mg/day or 15 mg/day. Dosage
`
` increases should generally not be made before 2 weeks, the time needed to achieve
`steady-state [see CLINICAL STUDIES (14.1)].
` Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in
`
`a trial involving patients with schizophrenia who had been symptomatically stable on
`other antipsychotic medications for periods of 3 months or longer. These patients were
`discontinued from those medications and randomized to either ABILIFY 15 mg/day or
`
`Reference ID: 2912460
`
`6
`
`
`

`

`
`
`placebo, and observed for relapse [see CLINICAL STUDIES (14.1)]. Patients should be
`periodically reassessed to determine the continued need for maintenance treatment.
`Adolescents
`Dose Selection: The recommended target dose of ABILIFY is 10 mg/day. Aripiprazole
`was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses
`
`of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients
`was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after
`
`2 additional days. Subsequent dose increases should be administered in 5 mg increments.
`
`The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose.
`ABILIFY can be administered without regard to meals [see CLINICAL STUDIES (14.1)].
`Maintenance Treatment: The efficacy of ABILIFY for the maintenance treatment of
`schizophrenia in the adolescent population has not been evaluated. While there is no body
`of evidence available to answer the question of how long the adolescent patient treated
`with ABILIFY should be maintained on the drug, maintenance efficacy can be
`extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic
`parameters in adult and pediatric patients. Thus, it is generally recommended that
`responding patients be continued beyond the acute response, but at the lowest dose
`needed to maintain remission. Patients should be periodically reassessed to determine the
`need for maintenance treatment.
`Switching from Other Antipsychotics
`There are no systematically collected data to specifically address switching patients with
`schizophrenia from other antipsychotics to ABILIFY or concerning concomitant
`administration with other antipsychotics. While immediate discontinuation of the
`previous antipsychotic treatment may be acceptable for some patients with schizophrenia,
`
`more gradual discontinuation may be most appropriate for others. In all cases, the period
`of overlapping antipsychotic administration should be minimized.
`
` 2.2 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. The recommended target dose
`of ABILIFY is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or
`valproate. The dose may be increased to 30 mg/day based on clinical response. The safety
`of doses above 30 mg/day has not been evaluated in clinical trials.
`
`Reference ID: 2912460
`
`7
`
`
`

`

`
`
`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. Subsequent dose increases, if needed, should be administered in
`5 mg/day increments. ABILIFY can be given without regard to meals [see CLINICAL
`STUDIES (14.2)].
`Maintenance Treatment
`The recommended dose for maintenance treatment, whether as monotherapy or as
`adjunctive therapy, is the same dose needed to stabilize patients during acute treatment,
`both for adult and pediatric patients. Patients should be periodically reassessed to
`determine the continued need for maintenance treatment [see CLINICAL STUDIES
`
` (14.2)].
` 2.3 Adjunctive Treatment of Major Depressive Disorder
`
`Adults
`Dose Selection: The recommended starting dose for ABILIFY as adjunctive treatment
`for patients already taking an antidepressant is 2 mg/day to 5 mg/day. The efficacy of
`ABILIFY as an adjunctive therapy for major depressive disorder was established within a
`dose range of 2 mg/day to 15 mg/day. Dose adjustments of up to 5 mg/day should occur
`
` gradually, at intervals of no less than 1 week [see CLINICAL STUDIES (14.3)].
`Maintenance Treatment: The efficacy of ABILIFY for the adjunctive maintenance
`treatment of major depressive disorder has not been evaluated. While there is no body of
`evidence available to answer the question of how long the patient treated with ABILIFY
`should be maintained, patients should be periodically reassessed to determine the
`continued need for maintenance treatment.
`
` 2.4 Irritability Associated with Autistic Disorder
`Pediatric Patients
`Dose Selection: The efficacy of aripiprazole has been established in the treatment of
`pediatric patients 6 to 17 years of age with irritability associated with autistic disorder at
`doses of 5 mg/day to 15 mg/day. The dosage of ABILIFY should be individualized
`according to tolerability and response.
`Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with
`subsequent increases to 10 mg/day 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 [see CLINICAL
`STUDIES (14.4)].
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`Maintenance Treatment: The efficacy of ABILIFY for the maintenance treatment of
`irritability associated with autistic disorder has not been evaluated. While there is no
`body of evidence available to answer the question of how long the patient treated with
`
` ABILIFY should be maintained, patients should be periodically reassessed to determine
`the continued need for maintenance treatment.
`
` 2.5 Agitation Associated with Schizophrenia or Bipolar Mania
`(Intramuscular Injection)
`Adults
`Dose Selection: The recommended dose in these patients is 9.75 mg. The effectiveness
`of aripiprazole injection in controlling agitation in schizophrenia and bipolar mania was
`demonstrated over a dose range of 5.25 mg 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. If agitation warranting a second dose persists
`following the initial dose, cumulative doses up to a total of 30 mg/day may be given.
`However, the efficacy of repeated doses of aripiprazole injection in agitated patients has
`
`not been systematically evaluated in controlled clinical trials. The safety of total daily
`doses greater than 30 mg or injections given more frequently than every 2 hours have not
`been adequately evaluated in clinical trials [see CLINICAL STUDIES (14.5)].
`If ongoing aripiprazole therapy is clinically indicated, oral aripiprazole in a range of
`
`10 mg/day to 30 mg/day should replace aripiprazole injection as soon as possible [see
`DOSAGE AND ADMINISTRATION (2.1 and 2.2)].
`Administration of ABILIFY Injection
`To administer ABILIFY Injection, draw up the required volume of solution into the
`syringe as shown in Table 1. Discard any unused portion.
`
`
`
` Table 1: ABILIFY Injection Dosing Recommendations
`
`Single-Dose
`5.25 mg
`9.75 mg
`15 mg
`
`
` Required Volume of Solution
`0.7 mL
`
`1.3 mL
`
`2 mL
`
`
`ABILIFY Injection is intended for intramuscular use only. Do not administer
`intravenously or subcutaneously. Inject slowly, deep into the muscle mass.
` Parenteral drug products should be inspected visually for particulate matter and
`discoloration prior to administration, whenever solution and container permit.
`
`
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`2.6 Dosage Adjustment
`
`Dosage adjustments in adults are not routinely indicated on the basis of age, gender, race,
`or renal or hepatic impairment status [see USE IN SPECIFIC POPULATIONS (8.4-
`8.10)].
`Dosage adjustment for patients taking aripiprazole concomitantly with strong
`
` CYP3A4 inhibitors: When concomitant administration of aripiprazole with
`strong CYP3A4 inhibitors such as ketoconazole or clarithromycin is indicated,
`
` the aripiprazole dose should be reduced to one-half of the usual dose. When the
`CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole
`dose should then be increased [see DRUG INTERACTIONS (7.1)].
`Dosage adjustment for patients taking aripiprazole concomitantly with potential
`CYP2D6 inhibitors: When concomitant administration of potential CYP2D6
`inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs,
`aripiprazole dose should be reduced at least to one-half of its normal dose. When
`the CYP2D6 inhibitor is withdrawn from the combination therapy, the
`aripiprazole dose should then be increased [see DRUG INTERACTIONS (7.1)].
`
`When adjunctive ABILIFY is administered to patients with major depressive
`
`disorder, ABILIFY should be administered without dosage adjustment as
`specified in DOSAGE AND ADMINISTRATION (2.3).
`
`Dosing recommendation in patients taking aripiprazole concomitantly with strong
`CYP3A4 and CYP2D6 inhibitors: When concomitant administration of aripiprazole
`with strong inhibitors of CYP3A4 (such as ketoconazole or clarithromycin) and
`CYP2D6 (such as quinidine, fluoxetine, or paroxetine) is indicated, the aripiprazole
`dose should be reduced to one-quarter (25%) of the usual dose. When the CYP3A4
`and/or CYP2D6 inhibitor is withdrawn from the combination therapy, the
`aripiprazole dose should be increased [see DRUG INTERACTIONS (7.1)].
`Dosing recommendation in patients taking aripiprazole concomitantly with strong,
`moderate, or weak inhibitors of CYP3A4 and CYP2D6: Patients who may be
`receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and
`
`CYP2D6 (eg, a potent CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a
`moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be
`
`reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve
`a favorable clinical response.
`Dosing recommendation
`in patients who are classified as CYP2D6 poor
`metabolizers (PM): The aripiprazole dose in PM patients should initially be reduced
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`to one-half (50%) of the usual dose and then adjusted to achieve a favorable clinical
`response. The dose of aripiprazole for PM patients who are administered a strong
`
` CYP3A4 inhibitor should be reduced to one-quarter (25%) of the usual dose [see
`CLINICAL PHARMACOLOGY (12.3)].
`
` Dosage adjustment for patients taking potential CYP3A4 inducers: When a
`
`potential CYP3A4 inducer such as carbamazepine is added to aripiprazole
`therapy, the aripiprazole dose should be doubled. Additional dose increases
`should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn
`
` from the combination therapy, the aripiprazole dose should be reduced to 10 mg
`to 15 mg [see DRUG INTERACTIONS (7.1)].
`
` 2.7 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 [see
`CLINICAL PHARMACOLOGY (12.3)].
`
` 2.8 Dosing of Orally Disintegrating Tablets
`
`The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral tablets
`[see DOSAGE AND ADMINISTRATION (2.1, 2.2, 2.3, and 2.4)].
`3 DOSAGE FORMS AND STRENGTHS
`
`ABILIFY® (aripiprazole) Tablets are available as described in .
`
`Table 2:
`
`ABILIFY Tablet Presentations
`
`Tablet
`Strength
`2 mg
`
`
`5 mg
`
`
`10 mg
`
`
`15 mg
`
`20 mg
`
`30 mg
`
`Tablet
`Color/Shape
`green
`modified rectangle
`blue
`modified rectangle
`pink
`modified rectangle
`yellow
`round
`white
`round
`pink
`round
`
`Tablet
`
` Markings
`“A-006”
`and “2”
`“A-007”
`and “5”
`“A-008”
`and “10”
`“A-009”
`and “15”
`“A-010”
`and “20”
`“A-011”
`and “30”
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`
` ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets are available as
`described in Table 3.
`
`Table 3:
`
`ABILIFY DISCMELT Orally Disintegrating Tablet
`Presentations
`
`Tablet
`Strength
`10 mg
`
`
`15 mg
`
`Tablet
`Color/Shape
`pink (with scattered specks)
`
`
`round
`yellow (with scattered specks)
`round
`
`Tablet
`Markings
`
`“A” and “640”
`
`“10”
`“A” and “641”
`
`“15”
`
` ABILIFY® (aripiprazole) Oral Solution (1 mg/mL) is a clear, colorless to light yellow
`
`solution, supplied in child-resistant bottles along with a calibrated oral dosing cup.
`ABILIFY® (aripiprazole) Injection for Intramuscular Use is a clear, colorless solution
`
`available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass
`vials.
`4 CONTRAINDICATIONS
`
`from
`
`ranged
`
`reaction
`Known hypersensitivity
`to ABILIFY. Reactions have
`pruritus/urticaria to anaphylaxis [see ADVERSE REACTIONS (6.3)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Use in Elderly Patients with Dementia-Related Psychosis
` 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 [see BOXED WARNING].
`
`Cerebrovascular Adverse Events, Including Stroke
`In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of
`dementia-related psychosis, there was an increased