`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`21-436/S-019, S-020, S-022
`21-713/S-014, S-015, S-017
`21-729/S-006, S-007, S-009
`21-866/S-006, S-007, S-009
`Trade Name:
`Abilify
`
`
`Aripiprazole
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`Otsuka Pharmaceutical
`
`May 6, 2008
`
` As oral formulations for the treatment of
`Schizophrenia in adults and adolescents aged 13 to 17
`years. The treatment of acute manic or mixed
`episodes associated with Bipolar I Disorder in adults
`and pediatric patients aged 10 to 17 years. Adjunctive
`treatment of Major Depressive Disorder in adults.
`As an injection for the treatment of adults with
`agitation associated with Schizophrenia or Bipolar I
`Disorder, manic or mixed.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-436/S-019, S-020, S-022
`21-713/S-014, S-015, S-017
`21-729/S-006, S-007, S-009
`21-866/S-006, S-007, S-009
`
`CONTENTS
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Approvable Letter
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`X
`
`
`X
`X
`X
`
`
`X
`
`
`
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`21-436/S-019, S-020, S-022
`21-436/S-019, 8-020, 8-022
`21-713/S-014, S-015, S-017
`21-713/S-014, 8-015, 8-017
`21-729/S-006, S-007, S-009
`21-729/S-006, 8-007, 8-009
`21-866/S-006, S-007, S-009
`21-866/S-006, 8-007, 8-009
`APPROVAL LETTER
`
`APPLICA TION NUMBER:
`
`
`
`APPROVAL LETTER
`
`

`

`
`
` DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`
`
` Food and Drug Administration
`Rockville, MD 20857
`
`
`
`
`
`
`NDA 21-436 S-019, S-020, S-022
`NDA 21-713 S-014, S-015, S-017
`NDA 21-729 S-006, S-007, S-009
`NDA 21-866 S-006, S-007, S-009
`
`
`Otsuka Pharmaceutical Development & Commercialization, Inc.
`Attn: Kusuma Mallikaarjun, Ph.D.
`Senior Director, Regulatory Affairs
`2440 Research Boulevard
`Rockville, MD 20850
`
`Dear Dr. Mallikaarjun:
`
`Please refer to your supplemental new drug applications [sNDAs] submitted and received on
`July 11, 2007 [NDA 21-436 S-019, S-020] under section 505(b) of the Federal Food, Drug, and
`
`Cosmetic Act for Abilify (aripiprazole) Tablets.
`
`Please also refer to your supplemental new drug applications [sNDAs] submitted August 28,
`2007 and received on August 29, 2007 [NDA 21-713 S-014, S-015; NDA 21-729 S-006, S-007;
`and NDA 21-866 S-006, S-007] under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act for Abilify (aripiprazole) Oral Solution, Orally Disintegrating Tablet, and Injection for
`Intramuscular Use, respectively.
`
`Please also refer to your labeling supplements NDA 21-436 S-022, NDA 21-713 S-017, NDA
`21-729 S-009, and NDA 21-866 S-009, submitted December 27, 2007 and received December
`28, 2007.
`
`
`Please also refer to your amendments to NDA 21-436 S-019 and S-020, NDA 21-713 S-014 and
`S-015; NDA 21-729 S-006 and S-007; and NDA 21-866 S-006 and S-007, submitted on
`September 4, 2007, September 6, 2007, October 18, 2007, January 18, 2008, and March 19,
`2008.
`
`Your supplemental NDAs 21-436 S-019, 21-713 S-014, 21-729 S-006, and 21-866 S-006
`provide for the use of Abilify as monotherapy in the acute treatment of bipolar disorder, manic or
`mixed, at a starting dose of 15 mg/day.
`
`Your supplemental NDAs 21-436 S-020, 21-713 S-015, 21-729 S-007, and 21-866 S-007
`provide for the use of Abilify as adjunctive therapy added to lithium or valproate in the short-
`term treatment of bipolar disorder, manic or mixed, again at a starting dose of 15 mg/day.
`
`Your labeling supplements NDA 21-436 S-022, NDA 21-713 S-017, NDA 21-729 S-009, and
`NDA 21-866 S-009 provide for revision of the "Drug Interactions" section of labeling to state
`that aripiprazole has no clinically meaningful effect on the pharmacokinetics of lamotrigine.
`
`

`

`
`
`2
`
`NDA 21-436 S-019, S-020, S-022
`NDA 21-713 S-014, S-015, S-017
`NDA 21-729 S-006, S-007, S-009
`NDA 21-866 S-006, S-007, S-009
`
`We have completed our review of these applications as amended. They are approved, effective
`on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`Content of Labeling: Structured Product Labeling [SPL]. the final printed labeling (FPL) must
`be identical to the enclosed labeling [package insert], and must be formatted in accordance with
`the requirements of 21 CFR 201.66.
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured Product Labeling (SPL) format, as described
`at http://www.fda.gov/oc/datacouncil/spl.html , that is identical to the enclosed agreed-upon
`labeling text. Upon receipt, we will transmit that version to the National Library of Medicine for
`public dissemination. For administrative purposes, please designate this submission "SPL for
`approved NDA labeling under NDA 21-436 S-019, NDA 21-436 S-020, NDA 21-713 S-014,
`NDA 21-713 S-015, NDA 21-729 S-006, NDA 21-729 S-007, NDA 21-866 S-006, and NDA 21-
`866 S-007".
`
`Pediatric Research Equity Act (PREA) Requirements: Phase 4 Commitments.
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`With reference to NDA 21-436 S-019, NDA 21-713 S-014, NDA 21-729 S-006, and NDA 21-
`866 S-006, we are waiving the requirement for pediatric studies in all age groups, because:
`A) necessary studies are impossible or highly impracticable. The pediatric starting dose
`of aripiprazole is 2 mg/day; this is titrated to 5 mg/day after 2 days and 10 mg/day after 2
`more days. The target dose for pediatric patients is 10 mg/day. Therefore, study of a 15
`mg starting dose in pediatric patients is not feasible.
`
`
`With reference to NDA 21-436 S-020, NDA 21-713 S-015, NDA 21-729 S-007, and NDA 21-
`866 S-007, this product is now appropriately labeled for use in all relevant pediatric populations.
`Therefore, no additional pediatric studies are needed at this time.
`
`There are no other Phase 4 commitments or Phase 4 requirements for any of these submissions.
`
`"Dear Healthcare Professional" Letters.
`If you issue a letter communicating important information about this product (i.e., a “Dear
`Health Care Professional” letter), we request that you submit a copy of the letter to all four
`NDAs referenced above, with a copy to the following address:
`
`
`
`
`
`
`
`MEDWATCH, HFD-410
`Food and Drug Administration
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`
`

`

`
`
`NDA 21-436 S-019, S-020, S-022
`NDA 21-713 S-014, S-015, S-017
`NDA 21-729 S-006, S-007, S-009
`NDA 21-866 S-006, S-007, S-009
`
`Introductory Promotional Materials.
`In addition, submit three copies of the introductory promotional materials that you propose to use
`for these products. Submit all proposed materials in draft or mock-up form, not final print. Send
`one copy to this Division and two copies of both the promotional materials and the package
`insert directly to:
`
`
`3
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Reporting Requirements. We remind you that you must comply with reporting requirements for
`an approved NDA (21 CFR 314.80 and 314.81).
`
`If you have any questions, please call Doris J. Bates, Ph.D., Regulatory Project Manager, at 301-
`796-1040.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Thomas P. Laughren, M.D.
`Director
`
`Division of Psychiatry Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`
`Enclosure: agreed-upon labeling.
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`/s/
`
`---------------------
`Thomas Laughren
`
`5/6/2008 10:47:15 AM
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`21-436/S-019, S-020, S-022
`21-436/S-019, 8-020, 8-022
`21-713/S-014, S-015, S-017
`21-713/S-014, 8-015, 8-017
`21-729/S-006, S-007, S-009
`21-729/S-006, 8-007, 8-009
`21-866/S-006, S-007, S-009
`21-866/S-006, 8-007, 8-009
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`

`

`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 atypical
`antipsychotic drugs are at an increased risk of death compared to
`placebo. 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
`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 to 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 mg
`/day
`
`10 mg
`/day
`
`30 mg
`/day
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`
`
`Page 1 of 72
`
`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 ischemic attack,
`including fatalities) (5.1)
`Suicidality and Antidepressants Increased risk of suicidality in children,
`adolescents, and young adults with Major Depressive Disorder (5 2)
`Neuroleptic Malignant Syndrome Manage with immediate discontinuation
`and close monitoring (5.3)
`Tardive Dyskinesia Discontinue if clinically appropriate (5.4)
`Hyperglycemia and Diabetes Mellitus Monitor glucose regularly in
`patients with and at risk for diabetes (5.5)
`Orthostatic Hypotension Use with caution in patients with known
`cardiovascular or cerebrovascular disease (5.6)
`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,
`tremor, restlessness, 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
`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 when 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
`
`2-5 mg
`/day
`
`5-10 mg
`/day
`
`15 mg
`/day
`
`
`
`Revised: 05/2008
`
`

`

`Final Agreed Upon Labeling
`
`
`
`8
`
`11
`12
`
`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 prescr bing information
`are not listed
`
`9
`
`10
`
`13
`
`14
`
`16
`
`17
`
`1
`
`2
`
`3
`4
`5
`
`6
`
`7
`
`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
`
`2
`
`

`

`Final Agreed Upon Labeling
`
`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 atypical antipsychotic
`drugs are at an increased risk of death compared to placebo. Analyses of seventeen
`placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a
`risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen 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. 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)].
`
`3
`
`

`

`Final Agreed Upon Labeling
`
`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)].
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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.
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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
`previous antipsychotic
`treatment may be acceptable
`for some patients with
`Schizophrenia, more gradual discontinuation may be most appropriate for others. In all
`cases, the period of overlapping antipsychotic administration should be minimized.
`
`2.2 Bipolar 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
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`Final Agreed Upon Labeling
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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.
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`Final Agreed Upon Labeling
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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
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`Final Agreed Upon Labeling
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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 adjust