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
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`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)
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`
`See full prescribing information for complete boxed warning.
`Children, adolescents, and young adults taking antidepressants for
`Major Depressive Disorder and other psychiatric disorders are at
`increased risk of suicidal thinking and behavior. (5.2)
`---------------------------RECENT MAJOR CHANGES---------------------------
`Boxed Warning, Suicidality and Antidepressant Drugs
` 11/2007
`Indications and Usage, Pediatric (13 to 17 yrs) Schizophrenia (1.1) 10/2007
`Dosage and Administration, Pediatric Schizophrenia (2.1) 10/2007
`Indications and Usage, Adjunctive Treatment in Adults with
` 11/2007
` Major Depressive Disorder (1.3)
`Dosage and Administration, Adjunctive Treatment in Adults with
` Major Depressive Disorder (2.3)
` 11/2007
`Warnings and Precautions, Clinical Worsening and Suicide Risk (5.2) 11/2007
`
`---------------------------INDICATIONS AND USAGE----------------------------
`ABILIFY is an atypical antipsychotic indicated
` as oral formulations for:
`• Treatment of Schizophrenia in adults and adolescents aged 13-17 years (1.1)
`• Treatment of acute manic or mixed episodes associated with Bipolar I
`Disorder in adults (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 (1.4)
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`Recommended Dose Maximum
`
`Initial Dose
`Dose
`30 mg /day
`
`10-15 mg
`/day
`2 mg
`/day
`
`15-30 mg
`/day
`
`2-5 mg
`/day
`
` 10-15 mg /day
`
`10 mg
`/day
`
` 15-30 mg
`/day
`
`5-10 mg
`/day
`
`9.75 mg /1.3
`mL injected
`IM
`
`
`
`30 mg /day
`
`30 mg /day
`
`15 mg/day
`
`30 mg /day
`injected IM
`
`•
`
`•
`
`ABILIFY oral formulations: Administer once daily without regard to meals
`(2)
`ABILIFY 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: 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 yrs) with Schizophrenia: extrapyramidal
`disorder, somnolence, and tremor
`Adult patients with Bipolar Mania: constipation, akathisia, sedation,
`tremor, restlessness, and extrapyramidal disorder
`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 (e.g., ketoconazole) or CYP2D6 (e.g., 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 (e.g., 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
`
`Revised: 11/2007
`
`
`
`
`
`
`
`
`
`
`
`
`Page 1 of 65
`
`Schizophrenia-
`adults (2.1)
`Schizophrenia –
`adolescents
`(2.1)
`Bipolar Mania–
`adults (2.2)
`
`As an adjunct to
`antidepressants for
`the treatment of
`Major Depressive
`Disorder (2.4)
`Agitation
`associated with
`Schizophrenia or
`Bipolar Mania–
`adults (2.4)
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`8
`
`7.3
`Drugs Having No Clinically Important Interactions with
`ABILIFY
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`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
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`11
`12
`
`9
`
`10
`
`13
`
`14
`
`16
`
`2
`
`3
`4
`5
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`INDICATIONS AND USAGE
`1
`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 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
`
`6
`
`7
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`
`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)].
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`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
`
`

`

`
`
`1
`
`INDICATIONS AND USAGE
`
`1.1 Schizophrenia
`
`Adults
`
`ABILIFY is indicated for acute and maintenance treatment of Schizophrenia [see
`CLINICAL STUDIES (14.1)].
`
`Adolescents
`
`ABILIFY is indicated for the treatment of Schizophrenia in adolescents 13 to 17 years of
`age [see CLINICAL STUDIES (14.1)].
`
`1.2 Bipolar Disorder
`
`Adults
`
`ABILIFY is indicated for acute and maintenance treatment of manic and mixed episodes
`associated with Bipolar I Disorder with or without psychotic features [see CLINICAL
`STUDIES (14.2)].
`
`1.3
`
`Adjunctive Treatment of Major Depressive Disorder
`
`Adults
`
`ABILIFY is indicated for use as an adjunctive treatment to antidepressants for Major
`Depressive Disorder [see CLINICAL STUDIES (14.3)].
`
`1.4 Agitation Associated with Schizophrenia or Bipolar Mania
`
`Adults
`
`ABILIFY Injection is indicated for the treatment of agitation associated with
`Schizophrenia or Bipolar Disorder, manic or mixed. "Psychomotor agitation" is defined
`in DSM-IV as "excessive motor activity associated with a feeling of inner tension."
`Patients experiencing agitation often manifest behaviors that interfere with their diagnosis
`and care (e.g., threatening behaviors, escalating or urgently distressing behavior, or self-
`exhausting behavior), leading clinicians to the use of intramuscular antipsychotic
`
`4
`
`

`

`
`
`medications to achieve immediate control of the agitation [see CLINICAL STUDIES
`(14.4)].
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Schizophrenia
`
`Usual Dose
`
`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
`
`5
`
`

`

`
`
`STUDIES (14.1)]. Patients should be periodically reassessed to determine the need for
`maintenance treatment.
`
`Pediatric Patients
`
`The efficacy of ABILIFY for the maintenance treatment of Schizophrenia in the pediatric
`population has not been evaluated.
`
`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
`
`Adults
`
`In clinical trials, the starting dose was 30 mg given once a day, without regard to meals.
`A dose of 30 mg/day was found to be effective when administered as the tablet
`formulation. Approximately 15% of patients had their dose decreased to 15 mg based on
`assessment of tolerability. The safety of doses above 30 mg/day has not been evaluated in
`clinical trials [see CLINICAL STUDIES (14.2)].
`
`Pediatric Patients
`
`ABILIFY has not been evaluated in pediatric patients with Bipolar Disorder.
`
`Maintenance Therapy
`
`While there is no body of evidence available to answer the question of how long a patient
`treated with aripiprazole should remain on it, adult patients with Bipolar I Disorder who
`had been symptomatically stable on ABILIFY Tablets (15 mg/day or 30 mg/day 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,
`
`6
`
`

`

`
`
`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.
`
`2.3 Adjunctive Treatment of Major Depressive Disorder
`
`Usual Dose
`
`Adults
`
`The recommended starting dose for ABILIFY as adjunctive treatment for patients already
`taking an antidepressant is 2mg/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. The long-term efficacy of ABILIFY for the adjunctive
`treatment of Major Depressive Disorder has not been established [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.
`
`
`
`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
`
`7
`
`

`

`
`
`factors warrant. If agitation warranting a second dose persists following the initial dose,
`cumulative doses up to a total of 30 mg/day may be given. However, the efficacy of
`repeated doses of aripiprazole injection in agitated patients has not been systematically
`evaluated in controlled clinical trials. The safety of total daily doses greater than 30 mg
`or injections given more frequently than every 2 hours have not been adequately
`evaluated in clinical trials [see CLINICAL STUDIES (14.4)].
`
`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
`
`Required Volume of Solution
`Single-Dose
`0.7 mL
`5.25 mg
`1.3 mL
`9.75 mg
`2 mL
`15 mg
`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 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
`
`8
`
`

`

`
`
`CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole
`dose should then be increased [see DRUG INTERACTIONS (7.1)].
`
`Dosage adjustment for patients taking aripiprazole concomitantly with potential
`CYP2D6 inhibitors: When concomitant administration of potential CYP2D6
`inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs,
`aripiprazole dose should be reduced at least to one-half of its normal dose. When
`the CYP2D6 inhibitor is withdrawn from the combination therapy, the
`aripiprazole dose should then be increased [see DRUG INTERACTIONS (7.1)].
`
`When adjunctive ABILIFY is administered to patients with Major Depressive
`Disorder, ABILIFY should be administered without dosage adjustment as
`specified in DOSAGE AND ADMINISTRATION (2.3).
`
`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
`
`9
`
`

`

`
`
`
`
`Tablet
`Strength
`
`2 mg
`
`5 mg
`
`10 mg
`
`15 mg
`
`20 mg
`
`30 mg
`
`Tablet
`Color/Shape
`green
`modified rectangle
`blue
`modified rectangle
`pink
`modified rectangle
`yellow
`round
`white
`round
`pink
`round
`
`Tablet
`Markings
`"A-006"
`and "2"
`"A-007"
`and "5"
`"A-008"
`and "10"
`"A-009"
`and "15"
`"A-010"
`and "20"
`"A-011"
`and "30"
`
`ABILIFY® DISCMELT™ (aripiprazole) Orally Disintegrating Tablets are available as
`described in Table 3.
`
`10 mg
`
`Table 3: ABILIFY DISCMELT Orally Disintegrating Tablet Presentations
`Tablet
`Tablet Color
`Tablet
`Strength
`/ Shape
`Markings
`pink (with scattered specks)
`"A" and "640"
`round
`"10"
`yellow (with scattered specks)
`"A" and "641"
`round
`"15"
`ABILIFY® (aripiprazole) Oral Solution (1 mg/mL) is a clear, colorless to light yellow
`solution, supplied in child-resistant bottles along with a calibrated oral dosing cup.
`
`15 mg
`
`ABILIFY® (aripiprazole) Injection for Intramuscular Use is a clear, colorless solution
`available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass
`vials.
`
`4 CONTRAINDICATIONS
`
` Reactions have ranged from
`to ABILIFY.
`Known hypersensitivity reaction
`pruritus/urticaria to anaphylaxis [see ADVERSE REACTIONS (6.3)].
`
`10
`
`

`

`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Use in Elderly Patients with Dementia-Related Psychosis
`
`Increased Mortality
`
`Elderly patients with dementia-related psychosis treated with atypical antipsychotic
`drugs are at an increased risk of death compared to placebo. 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 (e.g., 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 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 indications. These risk differences (drug-
`placebo difference in the number of cases of suicidality per 1000 patients treated) are
`provided in Table 4.
`
`
`Table 4
`Age Range
`
`
`<18
`
`Drug-Placebo Difference in Number of
`Cases of Suicidality per 1000 Patients
`Treated
`Increases Compared to Placebo
`14 additional cases
`
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`
`
`18-24
`
`25-64
`≥65
`
`5 additional cases
`Decreases Compared to Placebo
`1 fewer case
`6 fewer cases
`
`
`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
`Major Depressive Disorder as well as for other indications, both psychiatric and
`nonpsychiatric. Although a causal link between the emergence of such symptoms and
`either the worsening of depression and/or the emergence of suicidal impulses has not
`been established, there is concern that such symptoms may represent precursors to
`emerging suicidality.
`
`Consideration should be given to changing the therapeutic regimen, including possibly
`discontinuing the medication, in patients whose depression is persistently worse, or who
`are experiencing emergent suicidality or symptoms that might be precursors to worsening
`depression or suicidality, especially if these symptoms are severe, abrupt in onset, or
`were not part of the patient's presenting symptoms.
`
`Families and caregivers of patients being treated with antidepressants for Major
`Depressive Disorder or other indications, both psychiatric and nonpsychiatric,
`should be alerted about the need to monitor patients for the emergence of agitation,
`irritability, unusual changes in behavior, and the other symptoms described above,
`as well as the emergence of suicidality, and to report such symptoms immediately to
`
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`
`health care providers. Such monitoring should include daily observation by families
`and caregivers. Prescriptions for ABILIFY should be written for the smallest quantity of
`tablets consistent with good patient management, in order to reduce the risk of overdose.
`
`Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
`presentation of Bipolar Disorder. It is generally believed (though not established in
`controlled trials) that treating such an episode with an antidepressant alone may increase
`the likelihood of precipitation of a mixed/manic episode in patients at risk for Bipolar
`Disorder. Whether any of the symptoms described above represent such a conversion is
`unknown. However, prior to initiating treatment with an antidepressant, patients with
`depressive symptoms should be adequately screened to determine if they are at risk for
`bipolar disorder; such screening should include a detailed psychiatric history, including a
`family history of suicide, Bipolar Disorder, and depression.
`
`It should be noted that ABILIFY is not approved for use in treating depression in the
`pediatric population.
`
`
`5.3 Neuroleptic Malignant Syndrome (NMS)
`
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
`Syndrome (NMS) may occur with administration of antipsychotic drugs, including
`aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide
`clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity,
`altered mental status, and evidence of autonomic instability (irregular pulse or blood
`pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may
`include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute
`renal failure.
`
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
`diagnosis, it is important to exclude cases where the clinical presentation includes both
`serious medical illness (eg, pneumonia, systemic infection) and untreated or inadequately
`treated extrapyramidal signs and symptoms (EPS). Other important considerations in the
`differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and
`primary central nervous system pathology.
`
`The management of NMS should include: 1) immediate discontinuation of antipsychotic
`drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic
`treatment and medical monitoring; and 3) treatment of any concomitant serious medical
`
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`problems for which specific treatments are available. There is no general agreement
`about specific pharmacological treatment regimens for uncomplicated NMS.
`
`If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
`reintroduction of drug therapy should be carefully considered. The patient should be
`carefully monitored, sin