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)
`
`05/2008
`05/2008
`
`05/2008
`11/2007
`
`05/2008
`05/2008
`05/2008
`
`05/2008
`11/2007
`11/2007
`
`---------------------------RECENT MAJOR CHANGES---------------------------
`Boxed Warning, Suicidality and Antidepressant Drugs
`11/2007
`Boxed Warning, Increased Mortality in Elderly Patients
`xx/2008
`
` with Dementia-Related Psychosis
`Indications and Usage,
` Adolescent (13 to 17 years) Schizophrenia (1.1)
` Adjunctive Therapy (Lithium or Valproate) in Adult and
`
`Pediatric (10 to 17 years) Patients with Bipolar Mania (1.2)
` Pediatric (10 to 17 years) Bipolar Mania (1.2)
` Adjunctive Treatment in Adults with MDD (1.3)
`Dosage and Administration,
` Adolescent Schizophrenia (2.1)
` 15 mg starting dose in Bipolar Mania (2.2)
` Adjunctive Therapy (Lithium or Valproate) in Adult and
`
`Pediatric Patients with Bipolar Mania (2.2)
` Pediatric Bipolar Mania (2.2)
` Adjunctive Treatment in Adults with MDD (2.3)
`Warnings and Precautions, Clinical Worsening of Depression
` and Suicide Risk (5.2)
`---------------------------INDICATIONS AND USAGE----------------------------
`ABILIFY is an atypical antipsychotic indicated
`
`as oral formulations for:
`• Treatment of Schizophrenia in adults and adolescents aged 13 to 17 years
`(1.1)
`• Treatment of manic or mixed episodes associated with Bipolar I Disorder as
`monotherapy or adjunctive to lithium or valproate in adults and pediatric
`
`patients aged 10 t o 17 years (1.2)
`
`• Adjunctive treatment of Major Depressive Disorder in adults (1.3)
`
`as an injection for:
`
`• Treatment of adults with agitation associated with Schizophrenia or Bipolar I
`Disorder, manic or mixed episodes (1.4)
`------------------------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
`
`Schizophrenia – adults (2.1)
`
`Schizophrenia – adolescents
`(2.1)
`Bipolar Mania – adults
`monotherapy or as an
`adjunct to lithium or
`valproate (2.2)
`Bipolar Mania - pediatric
`patients
`monotherapy or as an
`adjunct to lithium or
`valproate (2.2)
`
`
`2-5 mg
`/day
`
`5-10 mg
`/day
`
`15 mg
`/day
`
`
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`As an adjunct to
`antidepressants for the
`treatment of Major
`Depressive Disorder (2.3)
`30 mg/day
`9.75 mg /1.3
`Agitation associated with
`injected
`mL injected
`Schizophrenia or Bipolar
`IM
`IM
`Mania – adults (2.4)
`•
`Oral formulations: Administer once daily without regard to meals (2)
`•
`IM injection: Wait at least 2 hours between doses. Maximum daily dose 30
`mg (2.4)
`----------------------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 i schemic 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)
`Seizures/Convulsions: Use cautiously in patients with a history of seizures
`or with conditions that lower the seizure threshold (5.7)
`Potential for Cognitive and Motor Impairment: Use caution when
`operating machinery (5.8)
`Suicide: The possibility of a suicide attempt is inherent in Schizophrenia
`and Bipolar Disorder. Closely supervise high-risk patients (5.10)
`-------------------------------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: a kathisia, 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
`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-----------------------------
`•
`Strong CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, fluoxetine) inhibitors
`will increase ABILIFY drug concentrations; reduce ABILIFY dose by one-
`half when used concomitantly (2.5, 7.1), except w hen used as adjunctive
`treatment with antidepressants (2.5)
`CYP3A4 inducers (eg, carbamazepine) will decrease ABILIFY drug
`concentrations; double ABILIFY dose when used concomitantly (2.5, 7.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`2 mg
`/day
`
`10 mg
`/day
`
`30 mg
`/day
`
`Revised: XX/2008
`
`
`
` Approved 1.0
`
`
`
`Page 1 of 72
`
` Item 2 proposed.pdf
`
`
`
`
`
`

`

` 8
`
`
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`8.2
`Labor and Delivery
`
`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
`9.1
`Controlled Substance
`
`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 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`CLINICAL STUDIES
`14.1 Schizophrenia
`
`14.2 Bipolar Disorder
`
`14.3 Adjunctive Treatment of Major Depressive Disorder
`
`14.4 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
`
`17.2 Medication Guide
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`9
`
`10
`
`11
`12
`
`13
`
`14
`
`16
`
`17
`
`1
`
`2
`
`3
`4
`5
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS AND SUICIDALITY
`AND ANTIDEPRESSANT DRUGS
`INDICATIONS AND USAGE
`1.1
`Schizophrenia
`
`1.2
`Bipolar Disorder
`
`1.3
`Adjunctive Treatment of Major Depressive Disorder
`
`1.4
`Agitation Associated with Schizophrenia or Bipolar Mania
`
`DOSAGE AND ADMINISTRATION
`2.1
`Schizophrenia
`
`2.2
`Bipolar Disorder
`
`2.3
`Adjunctive Treatment of Major Depressive Disorder
`
`2.4
`Agitation Associated with Schizophrenia or Bipolar Mania
`
`(Intramuscular Injection)
`
`2.5
`Dosage Adjustment
`
`Dosing of Oral Solution
`
`2.6
`2.7
`Dosing of Orally Disintegrating Tablets
`
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Use in Elderly Patients with Dementia-Related Psychosis
`
`5.2
`Clinical Worsening of Depression and Suicide Risk
`
`5.3
`Neuroleptic Malignant Syndrome (NMS)
`
`5.4
`Tardive Dyskinesia
`
`5.5
`Hyperglycemia and Diabetes Mellitus
`
`5.6
`Orthostatic Hypotension
`
`5.7
`Seizures/Convulsions
`
`5.8
`Potential for Cognitive and Motor Impairment
`
`5.9
`Body Temperature Regulation
`
`5.10 Suicide
`
`5.11 Dysphagia
`
`5.12 Use in Patients with Concomitant Illness
`
`ADVERSE REACTIONS
`6.1
`Overall Adverse Reactions Profile
`
`6.2
`Clinical Studies Experience
`
`6.3
`Postmarketing Experience
`
`DRUG INTERACTIONS
`7.1
`Potential for Other Drugs to Affect ABILIFY
`
`7.2
`Potential for ABILIFY to Affect Other Drugs
`
`7.3
`Drugs Having No Clinically Important Interactions with
`
`ABILIFY
`
`
`6
`
`7
`
`
`
` Approved 1.0
`
`
`
`2
`
` Item 2 proposed.pdf
`
`
`
`
`
`

`

`
`
`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)].
`
`
`
`
` Approved 1.0
`
`
`
`3
`
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`
`
`
`
`
`

`

`
`
`1
`
`INDICATIONS AND USAGE
`
`1.1 Schizophrenia
`
` ABILIFY is indicated for acute and maintenance treatment of Schizophrenia in adults
`and in adolescents 13 to 17 years of age [see CLINICAL STUDIES (14.1)].
`
`1.2 Bipolar Disorder
`
`Monotherapy
`
`ABILIFY is indicated for acute and maintenance treatment of manic and mixed episodes
`associated with Bipolar I Disorder with or without psychotic features in adults and in
`pediatric patients 10 to 17 years of age [see CLINICAL STUDIES (14.2)].
`
` Adjunctive Therapy
`
`ABILIFY is indicated as an adjunctive therapy to either lithium or valproate for the acute
`treatment of manic and mixed episodes associated with Bipolar I Disorder with or
`without psychotic features in adults and in pediatric patients 10 to 17 years of age [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 acute
`treatment of Major Depressive Disorder in adults [see CLINICAL STUDIES (14.3)].
`
`1.4 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 in adults. "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 [see CLINICAL STUDIES
`(14.4)].
`
`
`
` Approved 1.0
`
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`
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`
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`
`
`
`

`

`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Schizophrenia
`
`Usual Dose for Acute Treatment
`
`Adults
`
` 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 not be made before 2 weeks, the time needed to achieve steady-state
`[see CLINICAL STUDIES (14.1)].
`
`
`
` Adolescents
`
` The recommended target dose of ABILIFY is 10 mg/day. Aripiprazole was studied in
`
`
`
` pediatric 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 Therapy
`
`
`Adults
`
`While there is no body of evidence available to answer the question of how long a patient
`
`
`treated with aripiprazole should remain on it, systematic evaluation of patients with
`
`Schizophrenia who had been symptomatically stable on other antipsychotic medications
`
`for periods of 3 months or longer, were discontinued from those medications, and were
`
`
`then administered ABILIFY 15 mg/day and observed for relapse during a period of up to
`
`26 weeks, has demonstrated a benefit of such maintenance treatment [see CLINICAL
`
`
`STUDIES (14.1)]. Patients should be periodically reassessed to determine the need for
`
`
`maintenance treatment.
`
`
`
` Approved 1.0
`
`
`
`5
`
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`
`
`
`
`
`

`

`
`
`
`
` Adolescents
`
` The efficacy of ABILIFY for the maintenance treatment of Schizophrenia in the pediatric
`
`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, 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
`for some patients with
`treatment may be acceptable
`previous antipsychotic
`
`
`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 Disorder
`
`Usual Dose for Acute Treatment
`
`Adults
`
`
`
`The recommended starting and target dose is 15 mg as monotherapy or as adjunctive
`
`therapy with lithium or valproate given once a day, without regard to meals. The dose can
`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 [see CLINICAL STUDIES (14.2)].
`
`
`
`Pediatric Patients
`
`The efficacy of aripiprazole has been established in the treatment of pediatric patients 10
`
`
`to 17 years of age with Bipolar I Disorder at doses of 10 mg/day or 30 mg/day. The
`
`recommended target dose of ABILIFY is 10 mg/day, as monotherapy or as adjunctive
`
`
`
`
`therapy with lithium or valproate. The starting daily dose of the tablet formulation in
`
`these patients was 2 mg/day, which was titrated to 5 mg/day after 2 days and to the target
`dose of 10 mg/day after 2 additional days. Subsequent dose increases should be
`
`
`
` Approved 1.0
`
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`
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`
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`
`
`
`

`

`
`
` administered in 5 mg/day increments. ABILIFY can be administered without regard to
`
`
` meals. [See CLINICAL STUDIES (14.2).]
`
`
`
`
`
` Maintenance Therapy
`
`Adults
`
`While there is no body of evidence available to answer the question of how long a patient
`
`
`treated with aripiprazole should remain on it, whether used as monotherapy or as
`
`adjunctive therapy, adult patients with Bipolar I Disorder who had been symptomatically
`
`
`stable on ABILIFY Tablets (15 mg/day or 30 mg/day as monotherapy with a starting
`
`dose of 30 mg/day) for at least 6 consecutive weeks and then randomized to ABILIFY
`
`Tablets (15 mg/day or 30 mg/day) or placebo and monitored for relapse, demonstrated a
`benefit of such maintenance treatment [see CLINICAL STUDIES (14.2)]. While it is
`
`generally agreed that pharmacological treatment beyond an acute response in Mania is
`desirable, both for maintenance of the initial response and for prevention of new manic
`episodes, there are no systematically obtained data to support the use of aripiprazole in
`
`such longer-term treatment (beyond 6 weeks). Physicians who elect to use ABILIFY for
`extended periods, that is, longer than 6 weeks, should periodically re-evaluate the long-
`term usefulness of the drug for the individual.
`
`Pediatric Patients
`
`
`The efficacy of ABILIFY for the maintenance treatment of Bipolar I Disorder in the
`
`pediatric population has not been evaluated. While there is no body of evidence available
`
`
`to answer the question of how long the pediatric patient treated with ABILIFY should be
`
`maintained, 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.
`
`
`
`
` Approved 1.0
`
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`

`
`
`2.3
`
`Adjunctive Treatment of Major Depressive Disorder
`
`Usual Dose for Acute Treatment
`
`Adults
`
`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)].
`
`
`
`
`Pediatric Patients
`
`
`The efficacy of ABILIFY for the adjunctive treatment of Major Depressive Disorder in
`
`the pediatric population has not been evaluated.
`
`Maintenance Therapy
`
`
`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 need for maintenance treatment.
`
`2.4 Agitation Associated with Schizophrenia or Bipolar Mania
`(Intramuscular Injection)
`
`Usual Dose
`
`Adults
`
`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
`
`
`
`
`
` Approved 1.0
`
`
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`8
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`
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`
`
`
`

`

`
`
` injections given more frequently than every 2 hours have not been adequately evaluated
`
`
` in clinical trials [see CLINICAL STUDIES (14.4)].
`
`
`
`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.
`
`Pediatric Patients
`
`ABILIFY Intramuscular Injection has not been evaluated in pediatric patients.
`
`2.5
`
`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 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)].
`
`
`
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` 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).
`
`
`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)].
`
`
`2.6
`
`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)].
`
`2.7
`
`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, and 2.3)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`ABILIFY® (aripiprazole) Tablets are available as described in Table 2.
`
`Table 2:
`
`ABILIFY Tablet Presentations
`
` Tablet
`
`Strength
`
`2 mg
`
`
`5 mg
`
`
`
`
` Approved 1.0
`
`
`
` Tablet
`
`Color/Shape
`green
`
`modified rectangle
`
`blue
`modified rectangle
`
`10
`
` Tablet
`
`
` Markings
`"A-006"
`
`and "2"
`
`"A-007"
`and "5"
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`Table 2:
`
`ABILIFY Tablet Presentations
`
`
`Tablet
`Strength
`
`10 mg
`
`
`15 mg
`
`20 mg
`
`30 mg
`
`
`Tablet
`Color/Shape
`pink
`modified rectangle
`
`yellow
`
`round
`white
`
`round
`pink
`
`round
`
`
`Tablet
`
`Markings
`"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 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
`
`reaction
`Known hypersensitivity
`to ABILIFY. Reactions have
`pruritus/urticaria to anaphylaxis [see ADVERSE REACTIONS (6.3)].
`
`
`ranged
`
`from
`
`
`
` Approved 1.0
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`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 incidence of cerebrovascular adverse
`events (eg, stroke, transient ischemic attack), including fatalities, in aripiprazole-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 aripiprazole. Aripiprazole is not approved for the treatment of
`
`patients with dementia-related psychosis [see also BOXED WARNING].
`
`Safety Experience in Elderly Patients with Psychosis Associated with
`
`
`Alzheimer’s Disease
`
`In three, 10-week, placebo-controlled studies of aripiprazole in elderly patients with psychosis
` associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56-99 years), the
`
`
`
` treatment-emergent adverse events that were reported at an incidence of ≥3% and aripiprazole
` incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%],
`
`
` somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily,
`
` urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation [placebo 0%,
`
`aripiprazole 4%], and lightheadedness [placebo 1%, aripiprazole 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, vigilance should be exercised, particularly for the emergence of
` difficulty swallowing or excessive somnolence, which could predispose to accidental
`
`
` injury or aspiration [see also BOXED WARNING].
`
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`5.2
`
`Clinical Worsening of Depression and Suicide Risk
`
`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 Major
`
`Depressive Disorder (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 indicatio