`
`
`
` 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
`
`
`
`
`
`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)
`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
` Schizophrenia – adults (2.1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
` 10-15
`
`
` mg/day
` 2 mg/day
`
`
`
`
`
`
` 10 mg/day
`
`
`
` 15 mg/day
`
` 10-15
`
`
` mg/day
` 2 mg/day
`
`
`
`
` 15 mg/day
`
`
`
` 15 mg/day
`
`
`
` 10 mg/day
`
`
`
` 2-5 mg/day
`
`
`
` 5-10 mg/day
`
`
`
` 2 mg/day
`
`
`
` 5-10 mg/day
`
`
`
` 2 mg/day
`
`
`
` 5 mg/day
`
`
`
` 2 mg/day
`
`
`
` 10 mg/day
`
` 15
`
`
` mg/day
`
` 15
`
` mg/day
`
` 10
`
` mg/day
`
` 20
`
` mg/day
`
` 30
`mg/day
`injected
`
`
` IM
`
`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 ---------------------
`
`
`
`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
`
`
`
`
`
`
`
`-------------------------- RECENT MAJOR CHANGES ------------------------
`patients with known cardiovascular or cerebrovascular disease, and risk
`
`
`
`
`
`Warnings and Precautions, Pathological Gambling and Other Compulsive
`of dehydration or syncope (5.8)
`
`
`
`
`
`
`
`
`Behaviors (5.7)
`08/2016
`Leukopenia, Neutropenia, and Agranulocytosis: have been reported with
`
`•
`
`
`
`Warnings and Precautions, Falls (5.9)
`02/2017
`
`
`
`
`
`
`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 Bristol-
`Myers Squibb at 1-800-721-5072 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
`
`--------------------------- 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
` 10-15 mg/day
`
` 30
`
` mg/day
`
` 30
`
` mg/day
`
` 30
`
` mg/day
`
` 30
`
` mg/day
`
` 30
` 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
`
`
`
` 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 (2.5)
`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)
`
`•
`
`Reference ID: 4059985
`
`
`
` 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
`
`
`
`
` Strong CYP2D6 and CYP3A4
`
`
`
` Administer a quarter of usual dose
`
`
` inhibitors
` Double usual dose over 1 to 2
`
` Strong CYP3A4 inducers
`
`
` weeks
`----------------------- USE IN SPECIFIC POPULATIONS ---------------------
`
`
`
`
`Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in
`
`
`
`
`•
`neonates with third trimester exposure (8.1)
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
` Nursing Mothers: Discontinue drug or nursing, taking into consideration
`
`
`
` importance of drug to the mother (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`Revised: 02/2017
`
`
`
`
`
`
`Labor and Delivery
`8.2
`
`
`Nursing Mothers
`8.3
`
`
`Pediatric Use
`8.4
`
`
`Geriatric Use
`8.5
`
`
`
`CYP2D6 Poor Metabolizers
`8.6
`
`
`Hepatic and Renal Impairment
`8.7
`
`
`
`Other Specific Populations
`8.8
`
`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
`
`
`
`Animal Toxicology and/or Pharmacology
`13.2
`
`
`14 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
`
`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
`
`Clinical Worsening of Depression and Suicide Risk
`
`
`Pathological Gambling and Other Compulsive Behaviors
`
`Use of Orally Disintegrating Tablet
`
`
`Interference with Cognitive and Motor Performance
`
`
`Nursing
`
`Concomitant Medication
`
`Heat Exposure and Dehydration
`
`Sugar Content
`
`Phenylketonurics
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`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
`
`Suicidal Thoughts and Behaviors in Children, Adolescents, and
`5.3
`
`
`
`
`Young Adults
`
`
`5.4
`Neuroleptic Malignant Syndrome (NMS)
`
`
`Tardive Dyskinesia
`5.5
`
`
`5.6
`Metabolic Changes
`
`
`5.7
`Pathological Gambling and Other Compulsive Behaviors
`
`5.8
`Orthostatic Hypotension
`
`
`5.9
`Falls
`
`
`Leukopenia, Neutropenia, and Agranulocytosis
`5.10
`
`
`
`
`5.11
`Seizures/Convulsions
`
`
`5.12
`Potential for Cognitive and Motor Impairment
`
`
`
`5.13
`Body Temperature Regulation
`
`
`5.14
`Suicide
`
`
`5.15 Dysphagia
`
`ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`
`
`Postmarketing Experience
`6.2
`
`7 DRUG INTERACTIONS
`
`
`7.1
`Drugs Having Clinically Important Interactions with ABILIFY
`
`
`
`Drugs Having No Clinically Important Interactions with
`7.2
`
`
`
`
`ABILIFY
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`8.1
`
`
`6
`
`
`
`Reference ID: 4059985
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: INCREASED MORTALITY IN ELDERLY
`
` PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and
`
`
` SUICIDAL THOUGHTS AND BEHAVIORS WITH
`
`
` ANTIDEPRESSANT DRUGS
`
`
`
` treated with
`Elderly patients with dementia-related psychosis
`
` 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
`
`
` [see WARNINGS AND
`and communication with
`the prescriber
`
`
` 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:
`
`
`
`Reference ID: 4059985
`
`
`
`
` • Agitation associated with schizophrenia or bipolar mania [see
`
` CLINICAL STUDIES (14.6)]
`
`
`
`
`
`
`
`
`
` 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
`
`Reference ID: 4059985
`
`
`
`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.
`
`
`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.
`
`
`Reference ID: 4059985
`
`
`
` 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 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.
`
`
`Reference ID: 4059985
`
`
`
`
`
` 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.
`
`for Cytochrome
`
`
`
` P450
`
`
` 2.7 Dosage Adjustments
`
`
` 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.
`
`
`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
`
`
`
`Table 2:
`
`
` 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
`
`
`
`
`
` Administer a quarter of usual dose
`
`
`
` Administer half of usual dose
`
`
`Administer a quarter of usual dose
`
`Reference ID: 4059985
`
`
`
`Strong CYP3A4 inducers (e.g.,
` Double usual dose over 1 to 2 weeks
`
`
` carbamazepine, rifampin)
`
` 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)].
`
`
`
` 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:
`
` Tablet
`
`
` Strength
`2 mg
`
`
`
`
` 5 mg
`
`
`
` 10 mg
`
`
`
` 15 mg
`
`
`
` 20 mg
`
`
`
` 30 mg
`
`
`
` ABILIFY Tablet Presentations
`
`
`
` 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”
`
`
` ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets are
` available as described in Table 4.
`
`
`
`
`
`Reference ID: 4059985
`
`
`
`
`
` Table 4:
`
`
`
` ABILIFY DISCMELT Orally Disintegrating Tablet
`
` Presentations
`
` Tablet
`
`
` Strength
`10 mg
`
`
`
`
` 15 mg
`
` Tablet
`
` Markings
`
`“A” and “640”
`
`
`
` “10”
`“A” and “641”
`
`
`“15”
`
`
`
`
` Tablet
`
` Color/Shape
`
`pink (with scattered specks)
`
`
` round
` yellow (with scattered
`
` specks)
`
` round
` 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
`
`
`
` 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
`
`
`Reference ID: 4059985
`
`
`
`
`
` 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
`
`
` 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].
`
`
`
`
` in Children,
`
`
`
`
` 5.3 Suicidal Thoughts and Behaviors
`
`
`
`
` 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
`
`Reference ID: 4059985
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`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