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
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
` Schizophrenia – adults (2.1)
`
`
`
`
`
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`
`
`WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL
`
`
`THOUGHTS AND BEHAVIORS WITH 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)
`
`
`
` Increased risk of suicidal thinking and behavior in children,
`
` adolescents, and young adults taking antidepressants. Monitor for
`
`
` worsening and emergence of suicidal thoughts and behaviors. (5.3)
`
`
`
` ---------------------------RECENT MAJOR CHANGES -------------------------­
`
`
`
` Warnings and Precautions (5.5)
`
`
`
` 08/2019
`
`
` --------------------------- INDICATIONS AND USAGE -------------------------­
`
`
`
` ABILIFY is an atypical antipsychotic. The oral formulations are indicated for:
`
`
`
` Schizophrenia (14.1)
`•
`Acute Treatment of Manic and Mixed Episodes associated with Bipolar I
`
`
`
`
`
`•
`(14.2)
`
`Adjunctive Treatment of Major Depressive Disorder (14.3)
`
`
`•
`Irritability Associated with Autistic Disorder (14.4)
`
`
`•
`Treatment of Tourette’s disorder (14.5)
`
`
`•
`The injection is indicated for:
`
`Agitation associated with schizophrenia or bipolar mania (14.6)
`
`
`
`•
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION --------------------­
` Initial Dose Recommended
`Maximum
`
`
`
`
` Dose
` Dose
` 10 to 15 mg/day
`
`
`
` 30
`
` mg/day
`
` 30
`
` mg/day
`
` 30
`
` mg/day
`
` 30
`
` mg/day
`
` 30
` mg/day
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
` ------------------------------ CONTRAINDICATIONS ----------------------------­
`
`Known hypersensitivity to ABILIFY (4)
`
`
`
`•
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
`
`
`Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-
`•
`Related Psychosis: Increased incidence of cerebrovascular adverse
`
`reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.2)
`
`
`Neuroleptic Malignant Syndrome: Manage with immediate
`
`
`
`
`discontinuation and close monitoring (5.4)
`
`
`Tardive Dyskinesia: Discontinue if clinically appropriate (5.5)
`
`
`
`•
`• Metabolic Changes: Atypical antipsychotic drugs have been associated
`
`
`
`
`with metabolic changes that include hyperglycemia/diabetes mellitus,
`
`
`dyslipidemia, and body weight gain (5.6)
`
`
`
`o Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in
`
`
`
`patients with and at risk for diabetes (5.6)
`
`
`o Dyslipidemia: Undesirable alterations in lipid levels have been
`
`
`
`observed in patients treated with atypical antipsychotics (5.6)
`
`
`
`o Weight Gain: Weight gain has been observed with atypical
`
`
`
`
`
`antipsychotic use. Monitor weight (5.6)
`
`Pathological Gambling and Other Compulsive Behaviors: Consider dose
`
`
`
`reduction or discontinuation (5.7)
`
`Orthostatic Hypotension: Monitor heart rate and blood pressure and warn
`
`
`
`patients with known cardiovascular or cerebrovascular disease, and risk of
`
`dehydration or syncope (5.8)
`
`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 (5.10)
`
`Seizures/Convulsions: Use cautiously in patients with a history of seizures
`
`
`
`
`or with conditions that lower the seizure threshold (5.11)
`
`
`
`Potential for Cognitive and Motor Impairment: Use caution when
`
`
`
`operating machinery (5.12)
`
`
`Suicide: The possibility of a suicide attempt is inherent in schizophrenia
`
`
`
`
`and bipolar disorder. Closely supervise high-risk patients (5.14)
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`Commonly observed adverse reactions (incidence ≥5% and at least twice
`
`
`
`
`
`
`
`
`
`
`that for placebo) were (6.1):
`
`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
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Otsuka
`
`
`
`America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800­
`
`
`FDA-1088 or www.fda.gov/medwatch.
`
`
`------------------------------ DRUG INTERACTIONS ----------------------------­
`
`
`
`
`Dosage adjustment due to drug interactions (7.1):
`
`
` Dosage Adjustments for
`
` Factors
`
`
` ABILIFY
`
` Administer half of usual dose
`
` Known CYP2D6 Poor Metabolizers
`
` Known CYP2D6 Poor Metabolizers
`
` Administer a quarter of usual dose
`
` and strong CYP3A4 inhibitors
`
`Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose
`
`
`
`
`
`
`
`
`
`
`
`
`
` 15
`
`
` mg/day
`
` 15
`
` mg/day
`
` 10
`
` mg/day
`
` 20
`
` mg/day
`
` 30
`mg/day
`injected
`
`
` IM
`
`
`
`
` 10 to 15
`
` mg/day
` 2 mg/day
`
`
`
`
`
`
` 10 mg/day
`
`
`
` 15 mg/day
`
`
`
` 15 mg/day
`
`
`
`
` 10 to 15
`
` mg/day
` 2 mg/day
`
`
` 2 to 5
`
`
`
` mg/day
` 2 mg/day
`
`
`
`
` 15 mg/day
`
`
`
`
`
` 10 mg/day
`
`
`
`
`
` 5 to 10 mg/day
`
`
`
`
`
`
`
` 5 to 10 mg/day
`
`
`
`
`
`
`
` 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 valproate (2.2)
`
`
`
` Major Depressive Disorder – Adults
` adjunct to antidepressants (2.3)
`
`
` Irritability associated with autistic
`
`
`
` disorder – pediatric patients (2.4)
`
` Tourette’s
` Patients < 50 kg
`
`
`disorder
`
` (2.5)
`
`
`
`
`
`
`
` –
`
`
`
` Patients ≥ 50 kg
`
`
`
`
`
` 2 mg/day
`
`
`
` 5 mg/day
`
`
`
` 2 mg/day
`
`
`
` 10 mg/day
`
` associated
`Agitation
`
`
` with
`
` schizophrenia or bipolar mania –
`
` adults (2.6)
`
`9.75 mg
`
` /1.3 mL
` injected 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 (2.6)
`Known CYP2D6 poor metabolizers: Half of the usual dose (2.7)
`
`
`
`
`
`•
`--------------------- 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)
`
`
`
`
`•
`
`Reference ID: 4556968
`
`

`

` ----------------------- USE IN SPECIFIC POPULATIONS ---------------------­
`
`
`
`
`
` Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in
` neonates with third trimester exposure (8.1)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`Revised: 2/2020
`
`
`
`
`7.1 Drugs Having Clinically Important Interactions with ABILIFY
`
`
`
`
`
`7.2 Drugs Having No Clinically Important Interactions with ABILIFY
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 CYP2D6 Poor Metabolizers
`
`
`
`8.7 Hepatic and Renal Impairment
`
`
`
`
`8.8 Other Specific Populations
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`9.1 Controlled Substance
`
`
`
`9.2 Abuse
`
`
`
`9.3 Dependence
`
`
`10 OVERDOSAGE
`
`
`10.1 Human Experience
`
`
`
`10.2 Management of Overdosage
`
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`
`
`14.1 Schizophrenia
`
`
`
`14.2 Bipolar Disorder
`
`
`
`14.3 Adjunctive Treatment of Major Depressive Disorder
`
`
`
`14.4 Irritability Associated with Autistic Disorder
`
`
`
`
`14.5 Tourette’s Disorder
`
`
`
`14.6 Agitation Associated with Schizophrenia or Bipolar Mania
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`
`16.2 Storage
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`
`Strong CYP2D6 and CYP3A4
`
`
`
`
` inhibitors
` Strong CYP3A4 inducers
`
`
`
`
`
`
` Administer a quarter of usual dose
`
` Double usual dose over 1 to 2
`
` weeks
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`
`
`WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL
`
`
`
`THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS
`
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Schizophrenia
`
`
`
`2.2 Bipolar I Disorder
`
`
`
`
`2.3 Adjunctive Treatment of Major Depressive Disorder
`
`
`
`2.4
`Irritability Associated with Autistic Disorder
`
`
`
`2.5 Tourette’s Disorder
`
`
`2.6 Agitation Associated with Schizophrenia or Bipolar Mania
`
`
`
`
`
`(Intramuscular Injection)
`
`
`
`2.7 Dosage Adjustments for Cytochrome P450 Considerations
`
`
`
`
`
`2.8 Dosing of Oral Solution
`
`
`
`2.9 Dosing of Orally Disintegrating Tablets
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`Increased Mortality in Elderly Patients with Dementia-Related
`
`5.1
`
`
`
`Psychosis
`
`
`
`5.2 Cerebrovascular Adverse Events, Including Stroke
`
`
`5.3 Suicidal Thoughts and Behaviors in Children, Adolescents, and
`
`
`
`
`
`Young Adults
`
`
`
`5.4 Neuroleptic Malignant Syndrome (NMS)
`
`
`
`5.5 Tardive Dyskinesia
`
`
`
`5.6 Metabolic Changes
`
`
`
`5.7 Pathological Gambling and Other Compulsive Behaviors
`
`
`
`5.8 Orthostatic Hypotension
`
`
`
`5.9 Falls
`
`
`
`5.10 Leukopenia, Neutropenia, and Agranulocytosis
`
`
`
`
`5.11 Seizures/Convulsions
`
`
`
`5.12 Potential for Cognitive and Motor Impairment
`
`
`
`
`5.13 Body Temperature Regulation
`
`
`
`5.14 Suicide
`
`
`
`5.15 Dysphagia
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`Reference ID: 4556968
`
`

`

` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
` WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`
` DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND
`
`
`
`
` BEHAVIORS WITH ANTIDEPRESSANT DRUGS
`
`
` 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 [see Warnings and Precautions (5.1)].
`
`
`
`
`
` Antidepressants increased the risk of suicidal thoughts and behavior in children,
`
` adolescents, and young adults in short-term studies. These studies did not show an
`
` increase in the risk of suicidal thoughts and behavior with antidepressant use in patients
`
`
` over age 24; there was a reduction in risk with antidepressant use in patients aged 65
`
`
`
` and older [see Warnings and Precautions (5.3)].
`
`
`
`
`In patients of all ages who are started on antidepressant therapy, monitor closely for
`
`
`worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
`
`
`caregivers of the need for close observation and communication with the prescriber [see
`Warnings and Precautions (5.3)].
`
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
`
` ABILIFY Oral Tablets, Orally-Disintegrating Tablets, and Oral Solution are indicated for the
`
` treatment of:
`
`
`
` • Schizophrenia [see Clinical Studies (14.1)]
`
`
`
`
`
`• Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder [see
`
`
`
`
`
`
`Clinical Studies (14.2)]
`
`
`
`
`
`
`• Adjunctive Treatment of Major Depressive Disorder [see Clinical Studies (14.3)]
`
`
`
` Irritability Associated with Autistic Disorder [see Clinical Studies (14.4)]
`
`
`
`
`•
` • Treatment of Tourette’s Disorder [see Clinical Studies (14.5)]
`
`
`
`
`
`
`
`
`
`
`ABILIFY Injection is indicated for the treatment of:
`
` • Agitation associated with schizophrenia or bipolar mania [see Clinical Studies (14.6)]
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4556968
`
`

`

`
`
`
` 2 DOSAGE AND ADMINISTRATION
` 2.1 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. ABILIFY has been systematically evaluated and
`
` shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet
`
` formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 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 placebo, and observed
`
`
`for relapse [see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine
`
`
`
` the continued need for maintenance treatment.
`
`
` Adolescents
`
`
`
`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)]. 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.
`
`
`Reference ID: 4556968
`
`

`

` 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.
`
`
`
`
` 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)].
`
`
`
`
`
`
` 2.3 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 [see
`
`
`
`
`Clinical Studies (14.3)]. Patients should be periodically reassessed to determine the continued
`
`
`
`need for maintenance treatment.
`
`
`
` 2.4 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 [see Clinical Studies (14.4)]. Patients should
`
`
`
`
`
`
`
`be periodically reassessed to determine the continued need for maintenance treatment.
`
`
` 2.5 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. The dose can be increased to 10 mg/day in patients who do
`
`
`
`
`
`
`
`Reference ID: 4556968
`
`

`

`
`
` not achieve optimal control of tics. Dosage adjustments should occur gradually at
`
`
` intervals of no less than 1 week.
`
`
`
`
`
` 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. The
`
`
`
`
` dose can be increased up to 20 mg/day for patients who do not achieve optimal control of
`
`
`
`
`
` tics. Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of
`
`
`
`
`
`
`
` no less than 1 week. [See Clinical Studies (14.5)].
`
`
`
`
`
`
`
`
` Patients should be periodically reassessed to determine the continued need for maintenance
` treatment.
`
`
` 2.6 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. 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 ABILIFY 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 (14.6)].
`
`
`
`
`
`
`
`
`
`
`
`If ongoing ABILIFY therapy is clinically indicated, oral ABILIFY in a range of 10 to 30 mg/day
`
`
`should replace ABILIFY 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.
`
`
`
`
`
`Reference ID: 4556968
`
`

`

`
`
` Parenteral drug products should be inspected visually for particulate matter and discoloration
`
` prior to administration, whenever solution and container permit.
`
`
`
` 2.7 Dosage Adjustments for Cytochrome P450 Considerations
`
`
` Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers
` and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4
`
`inducers (see Table 2). When the coadministered drug is withdrawn from the combination
`
`
`therapy, ABILIFY dosage should then be adjusted to its original level. When the coadministered
`CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1
`
`to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak
`
`
`
`inhibitors of CYP3A4 and CYP2D6 (e.g., a strong 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.
`
`
`
`
`Table 2: Dose Adjustments for ABILIFY in Patients who are known CYP2D6 Poor
`
`Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4
`
`Inhibitors, and/or CYP3A4 Inducers
`
` Dosage Adjustments for ABILIFY
` Administer half of usual dose
`
`
`
`
` Factors
`
` Known CYP2D6 Poor Metabolizers
`
` Known CYP2D6 Poor Metabolizers taking
`
`concomitant strong CYP3A4 inhibitors (e.g.,
`
` itraconazole, clarithromycin)
` Strong CYP2D6 (e.g., quinidine, fluoxetine,
`
`paroxetine) or CYP3A4 inhibitors (e.g.,
`
` itraconazole, clarithromycin)
`
`Strong CYP2D6 and CYP3A4 inhibitors
`
`
`Strong CYP3A4 inducers (e.g.,
`
` carbamazepine, rifampin)
`
`
`
` Administer a quarter of usual dose
`
`
`
` Administer half of usual dose
`
`
`Administer a quarter of usual dose
`
`
`
` Double usual dose over 1 to 2 weeks
`
`
` 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).
`
`
` 2.8 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)].
`
`
`Reference ID: 4556968
`
`

`

` 2.9 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 3.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3: ABILIFY Tablet Presentations
`
` Tablet
`
` Tablet
`
`
` Strength
`
` Color/Shape
`2 mg
`
`
` green
` modified rectangle
`
`
` blue
` modified rectangle
`
`
` pink
`
` modified rectangle
`
` yellow
`
` round
`
` white
`
` round
`
` pink
` round
`
`
`
`
` 5 mg
`
`
`
` 10 mg
`
`
`
` 15 mg
`
`
`
` 20 mg
`
`
`
` 30 mg
`
` 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”
`
`
`
` ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets are available as described in
`
`
` Table 4.
`
`
`
`
`
`
`
`
`
`
`
` Table 4: ABILIFY DISCMELT Orally Disintegrating Tablet Presentations
` Tablet
`
` Tablet
`
` Tablet
`
`
` Strength
` Color/Shape
` Markings
`
`
`10 mg
`
`“A” and “640”
`pink (with scattered specks)
`
`
`
`
`
` round
` “10”
` “A” and “641”
`
` yellow (with scattered specks)
`
`
` round
` “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.
`
`
`
` 15 mg
`
`
`
`
`
` 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.
`
`
`
`
`
`
`Reference ID: 4556968
`
`

`

` 4 CONTRAINDICATIONS
`
` ABILIFY is contraindicated in patients with a history of a hypersensitivity reaction to
`
`
` aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse
`
`
`Reactions (6.2)].
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Increased Mortality 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].
`
`
`
`Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s Disease
`
`
`In three, 10-week, placebo-controlled studies of ABILIFY in elderly patients with psychosis
`
`associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the
`
`adverse reactions that were reported at an incidence of ≥3% and ABILIFY incidence at least
`
`
`
`
`
`
`twice that for placebo were lethargy [placebo 2%, ABILIFY 5%], somnolence (including
`
`sedation) [placebo 3%, ABILIFY 8%], and incontinence (primarily, urinary incontinence)
`
`
`[placebo 1%, ABILIFY 5%], excessive salivation [placebo 0%, ABILIFY 4%], and
`
`lightheadedness [placebo 1%, ABILIFY 4%].
`
`
`The safety and efficacy of ABILIFY in the treatment of patients with psychosis associated with
`
`
`dementia have not been established. If the prescriber elects to treat such patients with ABILIFY,
`
`
`
`
`assess for the emergence of difficulty swallowing or excessive somnolence, which could
`
`
`
`
`predispose to accidental injury or aspiration [see Boxed Warning].
`
`
`
`
`
`
`
` 5.2 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 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). In the fixed-dose study, there was a statistically significant dose
`
`
`
`
`
`
`
` response relationship for cerebrovascular adverse events in patients treated with ABILIFY.
`
`
` ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see
`
`
`
`
` Boxed Warning].
`
`
`
`Reference ID: 4556968
`
`

`

`
`
`
`
`
`
`
` 5.3 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. There has been a long-standing concern, however, that
`
`
` antidepressants may have a role in inducing worsening of depression and the emergence of
`
`
` suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term,
`
` placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
`
`increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and
`
` young adults (ages 18-24) with MDD and other psychiatric disorders. 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 with antidepressants compared to placebo in adults aged 65
`and older.
`
`
`The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
`
`Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24
`
`
`short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-
`
`controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
`
`term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
`There was considerable variation in risk of suicidality among drugs, but a tendency toward an
`
`
`
`increase in the younger patients for almost all drugs studied. There were differences in absolute
`
`
`
`risk of suicidality across the different indications, with the highest incidence in MDD. The risk
`
`differences (drug vs. placebo), however, were relatively stable within age strata and across
`
`
`
`indications. These risk differences (drug-placebo difference in the number of cases of suicidality
`
`
`
`per 1000 patients treated) are provided in Table 5.
`
`
`Table 5:
`
` Age Range
`
`
`Drug-Placebo Difference in Number of Cases of
`
` Suicidality per 1000 Patients Treated
`
`
` Increases Compared to Placebo
`
`
` 14 additional cases
` <18
`
`
` 5 additional cases
` 18-24
`
` Decreases Compared to Placebo
`
`
`
` 1 fewer case
`
` 25-64
` 6 fewer cases
`
`
` ≥65
` No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
`
`
`
` number was not sufficient to reach any conclusion about drug effect on suicide.
`
`
`
`
`
`Reference ID: 4556968
`
`

`

`It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
`
`
`months. However, there is substantial evidence from placebo-controlled maintenance trials in
`
`
`adults with depression that the use of antidepressants can delay the recurrence of depression.
`
`
`
`All patients being treated with antidepressants for any indication should be monitored
`appropriately and observed closely for clinical worsening, suicidality, and unusual changes
`
`
`
`in behavior, especially during the initial few months of a course of drug therapy, or at times
`
`
`of dose changes, either increases or decreases.
`
`
`The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
`
`aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
`
`
`
`been reported in adult and pediatric patients being treated with antidepressants for MDD as well
`
`
`as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the
`
`
`emergence of such symptoms and either the worsening of depression and/or the emergence of
`
`suicidal impulses has not been established, there is concern that such symptoms may represent
`
`
`precursors to emerging suicidality.
`
`
`Consideration should be given to changing the therapeutic regimen, including possibly
`
`
`discontinuing the medication, in patients whose depression is persistently worse, or who are
`
`
`experiencing emergent suicidality or symptoms that might be precursors to worsening depression
`
`or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
`
`patient’s presenting symptoms.
`
`
`Families and caregivers of patients being treated with antidepressants for major depre