`
`These highlights do not include all the information needed to use ABILIFY
`
`
`safely and effectively. See full prescribing information for ABILIFY.
`
`
`ABILIFY® (aripiprazole) Tablets
`ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets
`
`
`ABILIFY® (aripiprazole) Oral Solution
`
`ABILIFY® (aripiprazole) Injection FOR INTRAMUSCULAR USE ONLY
`
`Initial U.S. Approval: 2002
`
`
`
`
`
`
`
`
`
`
`
`Schizophrenia – adults (2.1)
`
`–
`
`adults:
`
`Schizophrenia – adolescents
`(2.1)
`mania
`Bipolar
`
`monotherapy (2.2)
`Bipolar mania – adults: adjunct to
`
`
`lithium or valproate (2.2)
`Bipolar mania – pediatric patients:
`monotherapy or as an adjunct to
`
`
`lithium or valproate (2.2)
`Major Depressive Disorder – Adults
`
`
`adjunct to antidepressants (2.3)
` Irritability associated with autistic
`
` disorder – pediatric patients (2.4)
`Patients < 50 kg
`Tourette’s
`
`disorder
`(2.5)
`
`
`
`
`
`15
`mg/day
`15
`mg/day
`10
`mg/day
`
`20
`mg/day
`
`30
`mg/day
`
`injected
`IM
`
`
`10-15
`mg/day
`
`2 mg/day
`
`10 mg/day
`
`15 mg/day
`
`15 mg/day
`
`10-15
`mg/day
`
`2 mg/day
`
`15 mg/day
`
`10 mg/day
`
`2-5 mg/day
`
`5-10 mg/day
`
`2 mg/day
`
`5-10 mg/day
`
`2 mg/day
`
`5 mg/day
`
`2 mg/day
`
`10 mg/day
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL
`
`THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT
`DRUGS
`See full prescribing information for complete boxed warning.
`
`Elderly patients with dementia-related psychosis treated with
`antipsychotic drugs are at an increased risk of death. ABILIFY is
`
`not approved for the treatment of patients with dementia-related
`
`
`psychosis. (5.1)
`Increased risk of suicidal thinking and behavior in children,
`
`adolescents, and young adults taking antidepressants. Monitor for
`
`worsening and emergence of suicidal thoughts and behaviors. (5.3)
`
`--------------------------- RECENT MAJOR CHANGES --------------------------
`
`
`Warnings and Precautions (5.5)
`08/2019
`
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`
`
`ABILIFY is an atypical antipsychotic. The oral formulations are indicated for:
`
`
`Schizophrenia (14.1)
`
`
`
`Acute Treatment of Manic and Mixed Episodes associated with Bipolar I
`
`
`(14.2)
`
`Adjunctive Treatment of Major Depressive Disorder (14.3)
`
`
`Irritability Associated with Autistic Disorder (14.4)
`
`
`
`Treatment of Tourette’s disorder (14.5)
`
`The injection is indicated for:
`
`
`Agitation associated with schizophrenia or bipolar mania (14.6)
`
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------
`
`
`Initial Dose Recommended
`Maximum
`Dose
`Dose
`10-15 mg/day
`30
`mg/day
`30
`mg/day
`30
`mg/day
`
`30
`mg/day
`30
`mg/day
`
`
`
`
`–
`
`Patients ≥ 50 kg
`
`Agitation
`with
`associated
`schizophrenia or bipolar mania –
`
`
`
`adults (2.6)
`
`9.75 mg
`
`/1.3 mL
`
`injected IM
`
`
`
`
`
`
`
`
`
`Oral formulations: Administer once daily without regard to meals (2)
`
`IM injection: Wait at least 2 hours between doses. Maximum daily dose
`30 mg (2.6)
`
`
`Known CYP2D6 poor metabolizers: Half of the usual dose (2.7)
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`
`
`
`Tablets: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg (3)
`
`
`
`
`Orally Disintegrating Tablets: 10 mg and 15 mg (3)
`
`
`
`
`
`Oral Solution: 1 mg/mL (3)
`
`
`
`
`
`Injection: 9.75 mg/1.3 mL single-dose vial (3)
`
`
`
`
`
`Reference ID: 4472992
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------
`
`Known hypersensitivity to ABILIFY (4)
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`
`Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-
`
`
`Related Psychosis: Increased incidence of cerebrovascular adverse
`reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.2)
`Neuroleptic Malignant Syndrome: Manage with immediate
`discontinuation and close monitoring (5.4)
`
`Tardive Dyskinesia: Discontinue if clinically appropriate (5.5)
`
`
` Metabolic Changes: Atypical antipsychotic drugs have been associated
`with metabolic changes that include hyperglycemia/diabetes mellitus,
`dyslipidemia, and body weight gain (5.6)
`
`o Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in
`
`patients with and at risk for diabetes (5.6)
`o Dyslipidemia: Undesirable alterations in lipid levels have been
`
`observed in patients treated with atypical antipsychotics (5.6)
`o Weight Gain: Weight gain has been observed with atypical
`
`
`antipsychotic use. Monitor weight (5.6)
`Pathological Gambling and Other Compulsive Behaviors: Consider dose
`
`reduction or discontinuation (5.7)
`Orthostatic Hypotension: Monitor heart rate and blood pressure and warn
`
`patients with known cardiovascular or cerebrovascular disease, and risk of
`dehydration or syncope (5.8)
`Leukopenia, Neutropenia, and Agranulocytosis: have been reported with
`antipsychotics including ABILIFY. Patients with a history of a clinically
`significant low white blood cell count (WBC) or a drug-induced
`leukopenia/neutropenia should have their complete blood count (CBC)
`
`monitored frequently during the first few months of therapy and
`discontinuation of ABILIFY should be considered at the first sign of a
`clinically significant decline in WBC in the absence of other causative
`factors (5.10)
`Seizures/Convulsions: Use cautiously in patients with a history of seizures
`or with conditions that lower the seizure threshold (5.11)
`Potential for Cognitive and Motor Impairment: Use caution when
`operating machinery (5.12)
`Suicide: The possibility of a suicide attempt is inherent in schizophrenia
`
`and bipolar disorder. Closely supervise high-risk patients (5.14)
`------------------------------ ADVERSE REACTIONS -----------------------------
`
`
`
`Commonly observed adverse reactions (incidence ≥5% and at least twice
`that for placebo) were (6.1):
`
`
`Adult patients with schizophrenia: akathisia
`
`
`Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal
`
`disorder, somnolence, and tremor
`Adult patients (monotherapy) with bipolar mania: akathisia, sedation,
`
`
`restlessness, tremor, and extrapyramidal disorder
`Adult patients (adjunctive therapy with lithium or valproate) with bipolar
`mania: akathisia, insomnia, and extrapyramidal disorder
`
`Pediatric patients (10 to 17 years) with bipolar mania: somnolence,
`
`extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary
`
`hypersecretion, and dizziness
`Adult patients with major depressive disorder (adjunctive treatment to
`
`antidepressant therapy): akathisia, restlessness, insomnia, constipation,
`fatigue, and blurred vision
`
`Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue,
`vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite,
`
`salivary hypersecretion, extrapyramidal disorder, and lethargy
`Pediatric patients (6 to 18 years) with Tourette’s disorder: sedation,
`
`
`somnolence, nausea, headache, nasopharyngitis, fatigue, increased appetite
`
`Adult patients with agitation associated with schizophrenia or bipolar
`mania: nausea
`
`To report SUSPECTED ADVERSE REACTIONS, contact Otsuka
`
`America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800
`FDA-1088 or www.fda.gov/medwatch.
`------------------------------ DRUG INTERACTIONS -----------------------------
`
`
`Dosage adjustment due to drug interactions (7.1):
`
`
`Factors
`
`Known CYP2D6 Poor Metabolizers
`
`Known CYP2D6 Poor Metabolizers
`and strong CYP3A4 inhibitors
`
`Dosage Adjustments for
`ABILIFY
`
`Administer half of usual dose
`
`Administer a quarter of usual dose
`
`
`
`
`Strong CYP2D6 or CYP3A4
`
`inhibitors
`Strong CYP2D6 and CYP3A4
`inhibitors
`
`Strong CYP3A4 inducers
`
`
`Administer half of usual dose
`
`Administer a quarter of usual dose
`
`Double usual dose over 1 to 2
`weeks
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`
`
`
`Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates
`with third trimester exposure (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`Revised: 08/2019
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`
`WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL
`
`THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Schizophrenia
`
`
`2.2 Bipolar I Disorder
`
`
`2.3 Adjunctive Treatment of Major Depressive Disorder
`
`
`2.4
`Irritability Associated with Autistic Disorder
`
`
`2.5 Tourette’s Disorder
`
`2.6 Agitation Associated with Schizophrenia or Bipolar Mania
`
`
`
`(Intramuscular Injection)
`
`
`
`2.7 Dosage Adjustments for Cytochrome P450 Considerations
`
`
`
`2.8 Dosing of Oral Solution
`
`
`2.9 Dosing of Orally Disintegrating Tablets
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`Increased Mortality in Elderly Patients with Dementia-Related
`
`5.1
`
`Psychosis
`
`
`
`5.2 Cerebrovascular Adverse Events, Including Stroke
`
`5.3 Suicidal Thoughts and Behaviors in Children, Adolescents, and
`
`
`Young Adults
`
`
`
`5.4 Neuroleptic Malignant Syndrome (NMS)
`
`
`5.5 Tardive Dyskinesia
`
`
`5.6 Metabolic Changes
`
`
`5.7 Pathological Gambling and Other Compulsive Behaviors
`
`
`5.8 Orthostatic Hypotension
`
`
`5.9 Falls
`
`
`5.10
` Leukopenia, Neutropenia, and Agranulocytosis
`
`
`5.11 Seizures/Convulsions
`
`
`5.12
` Potential for Cognitive and Motor Impairment
`
`
`5.13 Body Temperature Regulation
`
`
`5.14
` Suicide
`
`
`5.15 Dysphagia
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`7.1 Drugs Having Clinically Important Interactions with ABILIFY
`
`
`
`7.2 Drugs Having No Clinically Important Interactions with ABILIFY
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 CYP2D6 Poor Metabolizers
`
`
`8.7 Hepatic and Renal Impairment
`
`
`8.8 Other Specific Populations
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`
`9.1 Controlled Substance
`
`
`9.2 Abuse
`
`
`9.3 Dependence
`
`10 OVERDOSAGE
`
`
`10.1
` Human Experience
`
`
` Management of Overdosage
`10.2
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2
` Pharmacodynamics
`
`
`12.3
` Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1
` Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
` Animal Toxicology and/or Pharmacology
`13.2
`
`14 CLINICAL STUDIES
`
`
`14.1
` Schizophrenia
`
`
`14.2
` Bipolar Disorder
`
`
`14.3
` Adjunctive Treatment of Major Depressive Disorder
`
`
`14.4
` Irritability Associated with Autistic Disorder
`
`
`14.5
` Tourette’s Disorder
`
`
`14.6
` Agitation Associated with Schizophrenia or Bipolar Mania
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1
` How Supplied
`
`
`16.2
` Storage
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`Reference ID: 4472992
`
`
`
`FULL PRESCRIBING INFORMATION
`
` WARNING: INCREASED MORTALITY IN ELDERLY
`PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
`and SUICIDAL THOUGHTS AND BEHAVIORS WITH
`ANTIDEPRESSANT DRUGS
`
`treated with
`Elderly patients with dementia-related psychosis
`
` antipsychotic drugs are at an increased risk of death. ABILIFY is not
`approved for the treatment of patients with dementia-related psychosis
`[see Warnings and Precautions (5.1)].
`Antidepressants increased the risk of suicidal thoughts and behavior in
`
` children, adolescents, and young adults in short-term studies. These
`studies did not show an increase in the risk of suicidal thoughts and
`behavior with antidepressant use in patients over age 24; there was a
`reduction in risk with antidepressant use in patients aged 65 and older
`[see Warnings and Precautions (5.3)].
`In patients of all ages who are started on antidepressant therapy, monitor
`closely for worsening, and for emergence of suicidal thoughts and
`behaviors. Advise families and caregivers of the need for close
`observation and communication with the prescriber [see Warnings and
`
`Precautions (5.3)].
`
`
`
`
`1 INDICATIONS AND USAGE
`
`ABILIFY Oral Tablets, Orally-Disintegrating Tablets, and Oral Solution are
`indicated for the treatment of:
`
`
` Schizophrenia [see Clinical Studies (14.1)]
`
`
` Acute Treatment of Manic and Mixed Episodes associated with Bipolar I
`
`Disorder [see Clinical Studies (14.2)]
`
`
`
` Adjunctive Treatment of Major Depressive Disorder [see Clinical Studies
`(14.3)]
`
`
`Irritability Associated with Autistic Disorder [see Clinical Studies (14.4)]
`
`
`
`
` Treatment of Tourette’s Disorder [see Clinical Studies (14.5)]
`
`
`
`ABILIFY Injection is indicated for the treatment of:
`
`
`
` Agitation associated with schizophrenia or bipolar mania [see Clinical
`
`Studies (14.6)]
`
`
`Reference ID: 4472992
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Schizophrenia
`Adults
`The recommended starting and target dose for ABILIFY is 10 or 15 mg/day
`administered on a once-a-day schedule without regard to meals. ABILIFY has
`been systematically evaluated and shown to be effective in a dose range of 10 to
`30 mg/day, when administered as the tablet formulation; however, doses higher
`than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage
`
`increases should generally not be made before 2 weeks, the time needed to
`
`achieve steady-state [see Clinical Studies (14.1)].
`
`Maintenance Treatment: Maintenance of efficacy in schizophrenia was
`demonstrated in a trial involving patients with schizophrenia who had been
`symptomatically stable on other antipsychotic medications for periods of 3
`months or longer. These patients were discontinued from those medications and
`randomized to either ABILIFY 15 mg/day or placebo, and observed for relapse
`[see Clinical Studies (14.1)]. Patients should be periodically reassessed to
`determine the continued need for maintenance treatment.
`
`Adolescents
`The recommended target dose of ABILIFY is 10 mg/day. Aripiprazole was
`studied in adolescent patients 13 to 17 years of age with schizophrenia at daily
`doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in
`these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target
`dose of 10 mg after 2 additional days. Subsequent dose increases should be
`administered in 5 mg increments. The 30 mg/day dose was not shown to be more
`efficacious than the 10 mg/day dose. ABILIFY can be administered without
`regard to meals [see Clinical Studies (14.1)]. Patients should be periodically
`
`reassessed to determine the need for maintenance treatment.
`
`Switching from Other Antipsychotics
`There are no systematically collected data to specifically address switching
`
`patients with schizophrenia from other antipsychotics to ABILIFY or concerning
`immediate
`concomitant administration with other antipsychotics. While
`
`discontinuation of the previous antipsychotic treatment may be acceptable for
`some patients with schizophrenia, more gradual discontinuation may be most
`appropriate for others. In all cases, the period of overlapping antipsychotic
`administration should be minimized.
`
`Reference ID: 4472992
`
`
`
`2.2 Bipolar I Disorder
`Acute Treatment of Manic and Mixed Episodes
`Adults: The recommended starting dose in adults is 15 mg given once daily as
`monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with
`lithium or valproate. ABILIFY can be given without regard to meals. The
`recommended target dose of ABILIFY is 15 mg/day, as monotherapy or as
`
` adjunctive therapy with lithium or valproate. The dose may be increased to
`30 mg/day based on clinical response. The safety of doses above 30 mg/day has
`not been evaluated in clinical trials.
`
`Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years)
`as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a target
`dose of 10 mg/day after 2 additional days. Recommended dosing as adjunctive
`therapy to lithium or valproate is the same. Subsequent dose increases, if needed,
`should be administered in 5 mg/day increments. ABILIFY can be given without
`regard to meals [see Clinical Studies (14.2)].
`2.3 Adjunctive Treatment of Major Depressive Disorder
`Adults
`The recommended starting dose for ABILIFY as adjunctive treatment for patients
`
` already taking an antidepressant is 2 to 5 mg/day. The recommended dosage
`range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur
`gradually, at intervals of no less than 1 week [see Clinical Studies (14.3)].
`Patients should be periodically reassessed to determine the continued need for
`
`maintenance treatment.
`
` 2.4 Irritability Associated with Autistic Disorder
`Pediatric Patients (6 to 17 years)
`The recommended dosage range for the treatment of pediatric patients with
`irritability associated with autistic disorder is 5 to 15 mg/day.
`
`Dosing should be initiated at 2 mg/day. The dose should be increased to
`
` 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose
`adjustments of up to 5 mg/day should occur gradually, at intervals of no less than
`1 week [see Clinical Studies (14.4)]. Patients should be periodically reassessed
`to determine the continued need for maintenance treatment.
`
`Reference ID: 4472992
`
`
`
`2.5 Tourette’s Disorder
`Pediatric Patients (6 to 18 years)
`The recommended dosage range for Tourette’s Disorder is 5 to 20 mg/day.
`
`For patients weighing less than 50 kg, dosing should be initiated at
`2 mg/day with a target dose of 5 mg/day after 2 days. The dose can be
`
`
` increased to 10 mg/day in patients who do not achieve optimal control of
`tics. Dosage adjustments should occur gradually at intervals of no less
`
` than 1 week.
`
`For patients weighing 50 kg or more, dosing should be initiated at
`2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a
`target dose of 10 mg/day on day 8. The dose can be increased up to
`20 mg/day for patients who do not achieve optimal control of tics. Dosage
`adjustments should occur gradually in increments of 5 mg/day at intervals
`of no less than 1 week. [See Clinical Studies (14.5)].
`
`
`
`
` Patients should be periodically reassessed to determine the continued need for
`maintenance treatment.
`2.6 Agitation Associated with Schizophrenia or Bipolar
`Mania (Intramuscular Injection)
`Adults
`The recommended dose in these patients is 9.75 mg. The recommended dosage
`range is 5.25 to 15 mg. No additional benefit was demonstrated for 15 mg
`compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical
`factors warrant. If agitation warranting a second dose persists following the initial
`dose, cumulative doses up to a total of 30 mg/day may be given. However, the
`
`efficacy of repeated doses of ABILIFY injection in agitated patients has not been
`
`systematically evaluated in controlled clinical trials. The safety of total daily
`
`doses greater than 30 mg or injections given more frequently than every 2 hours
`have not been adequately evaluated in clinical trials [see Clinical Studies (14.6)].
`
`If ongoing ABILIFY therapy is clinically indicated, oral ABILIFY in a range of
`10 to 30 mg/day should replace ABILIFY injection as soon as possible [see
`
`Dosage and Administration (2.1 and 2.2)].
`
`Administration of ABILIFY Injection
`To administer ABILIFY Injection, draw up the required volume of solution into
`the syringe as shown in Table 1. Discard any unused portion.
`
`Reference ID: 4472992
`
`
`
`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.
`2.7 Dosage
` Adjustments
`for Cytochrome
`P450
`Considerations
`
`Dosage adjustments are recommended in patients who are known CYP2D6 poor
`metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6
`inhibitors or strong CYP3A4 inducers (see Table 2). When the coadministered
`drug is withdrawn from the combination therapy, ABILIFY dosage should then
`be adjusted to its original level. When the coadministered CYP3A4 inducer is
`withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2
`
`weeks. Patients who may be receiving a combination of strong, moderate, and
`weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and
`a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate
`CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual
`dose initially and then adjusted to achieve a favorable clinical response.
`
`Table 2:
`
`Dose Adjustments for ABILIFY in Patients who are
`known CYP2D6 Poor Metabolizers and Patients
`Taking Concomitant CYP2D6 Inhibitors, 3A4
`Inhibitors, and/or CYP3A4 Inducers
`Dosage Adjustments for ABILIFY
`
` Administer half of usual dose
`
`Factors
`Known CYP2D6 Poor Metabolizers
`Known CYP2D6 Poor Metabolizers
`taking concomitant strong CYP3A4
`inhibitors (e.g., itraconazole,
`clarithromycin)
`Strong CYP2D6 (e.g., quinidine,
`fluoxetine, paroxetine) or CYP3A4
`inhibitors (e.g., itraconazole,
`clarithromycin)
`Strong CYP2D6 and CYP3A4
`
`inhibitors
`
`
`Administer a quarter of usual dose
`
`
`Administer half of usual dose
`
`
`Administer a quarter of usual dose
`
`Reference ID: 4472992
`
`
`
`Strong CYP3A4 inducers (e.g.,
`
`Double usual dose over 1 to 2 weeks
`
`carbamazepine, rifampin)
` When adjunctive ABILIFY is administered to patients with major depressive
`
`disorder, ABILIFY should be administered without dosage adjustment as
`specified in Dosage and Administration (2.3).
`2.8 Dosing of Oral Solution
`
`The oral solution can be substituted for tablets on a mg-per-mg basis up to the
`25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the
`
` solution [see Clinical Pharmacology (12.3)].
`2.9 Dosing of Orally Disintegrating Tablets
`
`The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral
`tablets [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`ABILIFY® (aripiprazole) Tablets are available as described in Table 3.
`
`Table 3:
`
`
`
` ABILIFY Tablet Presentations
`
`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 4.
`
`Reference ID: 4472992
`
`
`
`Table 4:
`
`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
`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.
`
`Tablet
`Markings
`“A” and “640”
`“10”
`
`“A” and “641”
`“15”
`
`ABILIFY® (aripiprazole) Injection for Intramuscular Use is a clear, colorless
`
`solution available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in
`clear, Type 1 glass vials.
`
`4 CONTRAINDICATIONS
`
`ABILIFY is contraindicated in patients with a history of a hypersensitivity
`reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to
`anaphylaxis [see Adverse Reactions (6.2)].
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Increased Mortality in Elderly Patients with Dementia-
`Related Psychosis
`
`
`
` Increased Mortality
`
`Elderly patients with dementia-related psychosis treated with antipsychotic
`drugs are at an increased risk of death. ABILIFY (aripiprazole) is not
`approved for the treatment of patients with dementia-related psychosis [see
`Boxed Warning].
`
`Safety Experience in Elderly Patients with Psychosis Associated with
`Alzheimer’s Disease
`
`In three, 10-week, placebo-controlled studies of ABILIFY in elderly patients with
`psychosis associated with Alzheimer’s disease (n=938; mean age: 82.4 years;
`range: 56-99 years), the adverse reactions that were reported at an incidence of
`≥3% and ABILIFY incidence at least twice that for placebo were lethargy
`
`Reference ID: 4472992
`
`
`
`[placebo 2%, ABILIFY 5%], somnolence (including sedation) [placebo 3%,
`ABILIFY 8%], and incontinence (primarily, urinary incontinence) [placebo 1%,
`
` ABILIFY 5%], excessive salivation [placebo 0%, ABILIFY 4%], and
`lightheadedness [placebo 1%, ABILIFY 4%].
`
`The safety and efficacy of ABILIFY in the treatment of patients with psychosis
`
` associated with dementia have not been established. If the prescriber elects to
`
` treat such patients with ABILIFY, assess for the emergence of difficulty
`swallowing or excessive somnolence, which could predispose to accidental injury
`or aspiration [see Boxed Warning].
`5.2 Cerebrovascular Adverse Events, Including Stroke
`
`In placebo-controlled clinical studies (two flexible dose and one fixed dose study)
`
`of dementia-related psychosis,
`there was an
`increased
` incidence of
`cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including
`fatalities, in ABILIFY-treated patients (mean age: 84 years; range: 78-88 years).
`In the fixed-dose study, there was a statistically significant dose response
`relationship for cerebrovascular adverse events in patients treated with ABILIFY.
`ABILIFY is not approved for the treatment of patients with dementia-related
`
`psychosis [see Boxed Warning].
`5.3 Suicidal
` Thoughts and Behaviors
`Adolescents, and Young Adults
`
`in Children,
`
`Patients with major depressive disorder (MDD), both adult and pediatric, may
`experience worsening of their depression and/or the emergence of suicidal
`ideation and behavior (suicidality) or unusual changes in behavior, whether or not
`they are taking antidepressant medications, and this risk may persist until
`significant remission occurs. Suicide is a known risk of depression and certain
`other psychiatric disorders, and these disorders themselves are the strongest
`predictors of suicide. There has been a long-standing concern, however, that
`antidepressants may have a role in inducing worsening of depression and the
`
`emergence of suicidality in certain patients during the early phases of treatment.
`Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs
`(SSRIs and others) showed that these drugs increase the risk of suicidal thinking
`
`and behavior (suicidality) in children, adolescents, and young adults (ages 18-24)
`with MDD and other psychiatric disorders. Short-term studies did not show an
`increase in the risk of suicidality with antidepressants compared to placebo in
`adults beyond age 24; there was a reduction with antidepressants compared to
`
`placebo in adults aged 65 and older.
`
`Reference ID: 4472992
`
`
`
`The pooled analyses of placebo-controlled trials in children and adolescents with
`MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders
`included a total of 24 short-term trials of 9 antidepressant drugs in over 4400
`patients. The pooled analyses of placebo-controlled trials in adults with MDD or
`other psychiatric disorders included a total of 295 short-term trials (median
`duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There
`was considerable variation in risk of suicidality among drugs, but a tendency
`toward an increase in the younger patients for almost all drugs studied. There
`were differences in absolute risk of suicidality across the different indications,
`with the highest incidence in MDD. The risk differences (drug vs. placebo),
`however, were relatively stable within age strata and across indications. These
`
`risk differences (drug-placebo difference in the number of cases of suicidality per
`1000 patients treated) are provided in Table 5.
`
`Table 5:
`Age Range
`
`Drug-Placebo Difference in Number of
`Cases of Suicidality per 1000 Patients
`Treated
`
`Increases Compared to Placebo
`
`14 additional cases
`<18
`
`5 additional cases
`18-24
`Decreases Compared to Placebo
`
`
`1 fewer case
`25-64
`6 fewer cases
`≥65
`No suicides occurred in any of the pediatric trials. There were suicides in the adult
`trials, but the number was not sufficient to reach any conclusion about drug effect
`on suicide.
`
`
`It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
`several months. However, there is substantial evidence from placebo-controlled
`maintenance trials in adults with depression that the use of antidepressants can
`delay the recurrence of depression.
`
`All patients being treated with antidepressants for any indication should be
`monitored appropriately and observed closely for clinical worsening,
`suicidality, and unusual changes in behavior, especially during the initial few
`
`months of a course of drug therapy, or at times of dose changes, either
`increases or decreases.
`
`
`The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability,
`hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
`hypomania, and mania, have been reported in adult and pediatric patients being
`treated with antidepressants for MDD as well as for other indications, both
`
`Reference ID: 4472992
`
`
`
`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 healthcare 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.
`5.4 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 ABILIFY. Rare cases of NMS occurred during ABILIFY
`
`treatment in the worldwide clinical database. Clinical manifestations of NMS are
`
`Reference ID: