---------------------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) (5.3)
`• Neuroleptic Malignant Syndrome: Manage with immediate
`
`
`discontinuation and close monitoring (5.4)
`
`
`• Tardive Dyskinesia: Discontinue if clinically appropriate (5.5)
`
`
`
`• Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus,
`
`
`
`
`dyslipidemia, and weight gain (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: Perform complete blood
`
`
`
`
`cell counts in patients with a history of a clinically significant low white
`blood cell count (WBC)/absolute neutrophil count (ANC). Consider
`
`discontinuation if clinically significant decline in WBC/ANC in the
`
`absence of other causative factors (5.10)
`
`
`• Seizures: 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)
`
`-----------------------------ADVERSE REACTIONS--------------------------­
`
`Commonly observed adverse reactions (incidence ≥5% and at least twice
`
`
`
`
`
`that for placebo) in adult patients (6.1):
`
`
`
`• Schizophrenia: akathisia
`
`
`• Bipolar mania (monotherapy): akathisia, sedation, restlessness, tremor,
`
`
`
`and extrapyramidal disorder
`
`• Bipolar mania (adjunctive therapy with lithium or valproate): akathisia,
`
`
`insomnia, and extrapyramidal disorder
`
`
`• MDD (adjunctive treatment to antidepressant therapy): akathisia,
`
`
`
`
`restlessness, insomnia, constipation, fatigue, and blurred vision
`
`
`
`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 and CYP2D6 poor metabolizers
`
`
`
`(7.1):
`
`
`
`
`
`
`
`
`
`
`
`Dosage Adjustments for
`
`
`
`Factors
`
`ABILIFY MYCITE
` Administer half recommended
`
` Known CYP2D6 Poor
`
`
`dose
`Metabolizers
`
` Known CYP2D6 Poor
`
` Administer a quarter of
`
` Metabolizers and strong CYP3A4
`
`
` recommended dose
`
`inhibitors
`Strong CYP2D6 or CYP3A4
` Administer half recommended
`
`
`
`
`
`
`dose
`inhibitors
`Strong CYP2D6 and CYP3A4
`
` Administer a quarter of
`
`
`
`
`
` recommended dose
`
`inhibitors
` Double recommended dose over 1
`
`
`Strong CYP3A4 inducers
`
`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: 12/2020
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
` ABILIFY MYCITE safely and effectively. See full prescribing
`
`
`
` information for ABILIFY MYCITE.
`
`
`
`
`ABILIFY MYCITE® (aripiprazole tablets with sensor), for oral use
`
`
`
`
`Initial U.S. Approval: 2002
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY
`
`PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and
`
`
` SUICIDAL THOUGHTS AND BEHAVIORS
`
`
` 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 MYCITE is not approved for the treatment of
`patients with dementia-related psychosis. (5.1)
`
`
`
`
`Increased risk of suicidal thoughts and behaviors in pediatric
`
`
`
`and young adult patients taking antidepressants. Closely
`
`monitor for worsening and emergence of suicidal thoughts
`
`and behaviors. (5.2)
`
` The safety and effectiveness of ABILIFY MYCITE have not
`
`
` been established in pediatric patients. (8.4)
`
`
` ---------------------------RECENT MAJOR CHANGES------------------------­
`
`
`
`
`
` 12/2020
` Dosage and Administration (2.1, 2.2)
`---------------------------INDICATIONS AND USAGE------------------------­
`
`ABILIFY MYCITE, a drug-device combination product comprised of
`
`
`
`
`
`aripiprazole tablets embedded with an Ingestible Event Marker (IEM) sensor
`
`
`
`
`intended to track drug ingestion, is indicated for the:
`
`
`• Treatment of adults with schizophrenia (1)
`
`
`
`
`
`
`• Treatment of bipolar I disorder (1)
`o Acute treatment of adults with manic and mixed episodes as
`
`
`
`
`
`
`
`monotherapy and as adjunct to lithium or valproate
`
`
`o Maintenance treatment of adults as monotherapy and as adjunct to
`
`
`
`lithium or valproate
`
`• Adjunctive treatment of adults with major depressive disorder (MDD) (1)
`
`
`
`
`
`
`
`
`Limitations of Use:
`• The ability of ABILIFY MYCITE to improve patient compliance or
`
`
`
`
`
`
`modify aripiprazole dosage has not been established. (1)
`
`
`
`• The use of ABILIFY MYCITE to track drug ingestion in “real-time” or
`
`
`
`
`
`during an emergency is not recommended because detection may be
`
`
`
`
`delayed or not occur. (1)
`
`
`------------------------DOSAGE AND ADMINISTRATION-------------------­
`
` Recommended
`
`Initial
`Maximum
`
`
`
`
`Dose
`Dose
`Dose
`
` Schizophrenia – adults
`
` 10 to 15
`
`
` 10 to 15
`
`
`30 mg/day
`
`
`
`mg/day
`(2.3)
`mg/day
`
` Bipolar mania – adults:
`
`
`
`15 mg/day
`15 mg/day
`30 mg/day
`
`monotherapy (2.4)
` Bipolar mania – adults:
`
` adjunct to lithium or
`
`
`
`valproate (2.4)
`Major Depressive
` Disorder – Adults adjunct
`
`
`
`
`to antidepressants (2.5)
`
`
`
` 10 to 15
`
`
`
`mg/day
`
` 2 to 5
`
`
`
`mg/day
`
`
`15 mg/day
`
`
`30 mg/day
`
` 5 to 10
`
`
`
`mg/day
`
`
`15 mg/day
`
`
`
`
`
`
`• Administer once daily without regard to meals (2.2)
`
`
`
`
`
`• Swallow whole; do not divide, crush, or chew (2.2)
`
`
`
`• Known CYP2D6 poor metabolizers: Administer half of the usual dose
`
`(2.6)
`-------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`Tablets with sensor: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg (3)
`---------------------------CONTRAINDICATIONS-------------------------------­
`
`Known hypersensitivity to aripiprazole tablets (4)
`
`
`
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`
`7.2 Drugs Having No Clinically Important Interactions with ABILIFY
`
`
`
`WITH DEMENTIA-RELATED PSYCHOSIS AND SUICIDAL
`
`MYCITE
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`THOUGHTS AND BEHAVIORS
`
`
`
`1 INDICATIONS AND USAGE
`8.1 Pregnancy
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`8.2 Lactation
`
`
`
`
`
`8.4 Pediatric Use
`
`2.1 Overview of the ABILIFY MYCITE System
`
`
`
`
`
`
`8.5 Geriatric Use
`
`2.2 Administration Instructions
`
`
`
`
`
`2.3 Dosage in Schizophrenia
`
`
`8.6 CYP2D6 Poor Metabolizers
`
`
`
`
`
`8.7 Hepatic and Renal Impairment
`
`2.4 Dosage in Bipolar I Disorder
`
`
`
`
`
`8.8 Other Specific Populations
`
`2.5 Dosage in Adjunctive Treatment of Major Depressive Disorder
`
`
`
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`2.6 Dosage Adjustments for Cytochrome P450 Considerations
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`9.1 Controlled Substance
`
`
`
`
`4 CONTRAINDICATIONS
`9.2 Abuse
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`9.3 Dependence
`
`
`
`10 OVERDOSAGE
`Increased Mortality in Elderly Patients with Dementia-Related
`
`5.1
`
`
`
`
`
`Psychosis
`
`10.1 Human Experience
`
`
`
`
`10.2 Management of Overdosage
`
`5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult
`
`
`
`
`11 DESCRIPTION
`Patients
`
`
`
`12 CLINICAL PHARMACOLOGY
`5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly
`
`
`
`
`
`12.1 Mechanism of Action
`
`Patients with Dementia-Related Psychosis
`
`
`
`
`
`12.2 Pharmacodynamics
`
`5.4 Neuroleptic Malignant Syndrome (NMS)
`
`
`
`
`
`5.5 Tardive Dyskinesia
`
`12.3 Pharmacokinetics
`
`
`
`
`13 NONCLINICAL TOXICOLOGY
`5.6 Metabolic Changes
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`5.7 Pathological Gambling and Other Compulsive Behaviors
`
`
`
`
`
`5.8 Orthostatic Hypotension
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`
`14 CLINICAL STUDIES
`5.9 Falls
`
`
`
`
`14.1 Overview of the Clinical Studies
`
`5.10 Leukopenia, Neutropenia, and Agranulocytosis
`
`
`
`
`
`
`14.2 Schizophrenia
`
`5.11 Seizures
`
`
`
`
`
`
`14.3 Bipolar Disorder
`
`5.12 Potential for Cognitive and Motor Impairment
`
`
`
`
`
`
`14.4 Adjunctive Treatment of Adults with Major Depressive Disorder
`
`5.13 Body Temperature Regulation
`
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`5.14 Dysphagia
`
`
`
`
`6 ADVERSE REACTIONS
`
`16.1 How Supplied
`
`
`
`
`
`16.2 Storage
`
`6.1 Clinical Trials Experience
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`7.1 Drugs Having Clinically Important Interactions with ABILIFY
`
`
`
`MYCITE
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`
`
`DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS
`
` Increased Mortality in Elderly Patients with Dementia-Related Psychosis
`
`
`
`
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs
`are at an increased risk of death. ABILIFY MYCITE is not approved for the
`
`
`
`treatment of patients with dementia-related psychosis [see Warnings and
`
`Precautions (5.1)].
`
`
`Suicidal Thoughts and Behaviors
`
`Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric
`
`
`
`and young adult patients in short-term studies. Closely monitor all antidepressant-
`
`
`
`
`
`treated patients for clinical worsening, and for emergence of suicidal thoughts and
`
`
`
`behaviors [see Warnings and Precautions (5.2)]. The safety and efficacy of
`
`
`
`
`ABILIFY MYCITE have not been established in pediatric patients [see Use in
`
`
`Specific Populations (8.4)].
`
`
`
`1
`
`
`INDICATIONS AND USAGE
`
`
`
`
`
`
` ABILIFY MYCITE, a drug-device combination product comprised of aripiprazole tablets embedded with
` an Ingestible Event Marker (IEM) sensor intended to track drug ingestion, is indicated for the:
`
`
`
`
`
` • Treatment of adults with schizophrenia.
`
`
` • Treatment of bipolar I disorder
`
` o Acute treatment of adults with manic and mixed episodes as monotherapy and as adjunct to
`
`
` lithium or valproate.
`
` o Maintenance treatment of adults as monotherapy and as adjunct to lithium or valproate.
`
`
`
`
`
` • Adjunctive treatment of adults with Major Depressive Disorder.
`
`
`
`
` Limitations of Use:
`
`• The ability of the ABILIFY MYCITE to improve patient compliance or modify aripiprazole dosage
`
`
`
`
`
`
`
`
`has not been established [see Dosage and Administration (2.1)].
`
`
`
`• The use of ABILIFY MYCITE to track drug ingestion in “real-time” or during an emergency is not
`
`
`
`
`
`
`
`recommended because detection may be delayed or not occur [see Dosage and Administration (2.1)].
`
`
`
`
`
`
`
`
`
`
`
`
` 2
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
` 2.1 Overview of the ABILIFY MYCITE System
` The ABILIFY MYCITE System is composed of the following:
`
`
`
`
`
` • Aripiprazole tablet embedded with an IEM sensor (ABILIFY MYCITE);
`
`
`
`
`
` • MYCITE® Patch (wearable sensor) that detects the signal from the IEM sensor after ingestion and
`
`
`
`
`transmits data to a smartphone (referred to as the patch);
`
`
`
` • MYCITE App - a smartphone application which is used with a compatible smartphone to display
`
`
`
`
`
`
`
`information for the patient (referred to as the app);
`
` • Web-based portal for healthcare professionals and caregivers
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`Prior to initial patient use of the ABILIFY MYCITE System, facilitate use of ABILIFY MYCITE and the
`
`
`
`patch, app, and portal; ensure the patient is capable and willing to use a smartphone and the app; and
`
`
`
`
`instruct patients to [see How Supplied/Storage and Handling (16.1)]:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Download the app,
`
`
` • Follow all the instructions in the Instructions for Use within the app and the Quick Start Guide within
`
`
`the carton, and
`
` • Ensure that the app is compatible with their specific smartphone and is paired with the patch prior to
`
`use.
`
`
`Prior to prescribing the ABILIFY MYCITE Maintenance Kit ensure the patient has access to the
`
`
`
`appropriate components of the patch [see How Supplied/Storage and Handling (16.1)].
`
`
`
`
`
`
`
`
`
`
`
`Although most ingestions will be detected within 30 minutes, it may take up to two hours for the app and
`
`
`
`
`
`
`
`
`portal to detect the ingestion of ABILIFY MYCITE; in some cases, the ingestion of the tablet with sensor
`
`
`
`
`
`may not be detected. If the tablet with sensor is not detected after ingestion, do not repeat the dose [see
`
`Adverse Reactions (6)].
`
`
`
`
`
`
`
`
`
` Administration Instructions
`2.2
`
`
` ABILIFY MYCITE
`
`
`
` Administer ABILIFY MYCITE orally with or without food [see Clinical Pharmacology (12.3)].
`
`
`
`Swallow tablets with sensor whole; do not divide, crush, or chew.
`
`
`
`
`
`MYCITE Patch
`
`
`There are two types of MYCITE Patch (referred to as patch). Each type has a corresponding Instructions
`
`
`
`
`
`for Use (IFU) within the app [see How Supplied/Storage and Handling (16.1)]:
`
`
`
`
`
`
`
`
`
`
`
`
`
`• For the 1-component patch, apply only when instructed by the app to the left side of the body just
`above the lower edge of the rib cage.
`
`• For the 2-component patch, apply only when instructed by the app to the right or left side of the
`
`
`
`
`
`body just above the lower edge of the rib cage.
`
`
`
`Additional patch instructions:
`
`
`
`
`
`
`• Do not place the patch in areas where the skin is scraped, cracked, inflamed, or irritated, or in a
`
`
`
`
`location that overlaps the area of the most recently removed patch (if there is skin irritation, instruct
`
`
`patients to remove the patch).
`
`
`
`
`
`• The app will prompt the patient to change the patch (at least weekly or sooner), and to apply and
`
`
`
`
`remove the patch correctly.
`
`
`
`• Keep the patch on when showering, swimming, or exercising.
`
`
`
`
`
`
`• For those undergoing an MRI, remove the patch and replace with a new patch as soon as possible.
`
`
`
` Dosage in Schizophrenia
` 2.3
`
`
`
` The recommended starting and target dosage for ABILIFY MYCITE in adults with schizophrenia is 10 or
`
`
`
`
`
`
` 15 mg daily. Dosage increases should generally not be made before 2 weeks [see Clinical Pharmacology
`
`(12.3)]. The maximum recommended dosage is 30 mg daily; however, doses above 15 mg daily have
`
`
`
`
`shown no additional clinically meaningful benefit.
`
`
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

` Dosage in Bipolar I Disorder
` 2.4
`
`
`
` The recommended starting dosage in adults with acute and mixed episodes associated with bipolar I
`
`
`
`
`
`
`
`
`
` disorder is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive
` treatment with lithium or valproate. The recommended target dose of ABILIFY MYCITE is 15 mg daily,
`
`
`
`
` as monotherapy or as adjunctive treatment with lithium or valproate. The dosage may be increased to
`
`
` 30 mg daily based on clinical response. The maximum recommended daily dosage is 30 mg.
`
`
`
`
`
`
`
` 2.5
`
`
`
` Dosage in Adjunctive Treatment of Major Depressive Disorder
` The recommended starting dose for ABILIFY MYCITE as adjunctive treatment of adults with MDD
`
`
`
` taking an antidepressant is 2 to 5 mg daily. The recommended dosage range is 2 to 15 mg daily. Dosage
`
`
`
`
` adjustments of up to 5 mg daily should occur gradually, at intervals of no less than 1 week. The maximum
`
`
`
` recommended daily dosage is 15 mg. Periodically reassess to determine the continued need for
`
`
`
` maintenance treatment.
`
`
`
` Dosage Adjustments for Cytochrome P450 Considerations
` 2.6
`
`
`
`
`
` 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 1). When the coadministered drug is withdrawn from the combination therapy, ABILIFY MYCITE
` dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is
`
`
` withdrawn, ABILIFY MYCITE 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 based on clinical response.
`
`
`
`
`
`
`
`
` Table 1: Dose Adjustments for ABILIFY MYCITE in Patients Who Are Known CYP2D6 Poor
`
`
`
`
`Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors,
`
` and/or CYP3A4 Inducers
`
` Factors
`
`
`
` Dosage Adjustments for ABILIFY
`
` MYCITE
` Administer half of recommended dose
`
`
`
` 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
`
`
`Strong CYP3A4 inducers (e.g.,
`
` carbamazepine, rifampin)
`
`
`
` When adjunctive ABILIFY MYCITE is administered to patients with major depressive disorder,
`
` ABILIFY MYCITE should be administered without dosage adjustment as specified in [Dosage and
`
`
`
`
`Administration (2.5)].
`
`
`
` Administer a quarter of recommended dose
`
`
`
` Administer half of recommended dose
`
`
`Administer a quarter of recommended dose
`
`
`
` Double recommended dose over 1 to 2 weeks
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`
`
` 3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
` ABILIFY MYCITE (aripiprazole tablets with sensor) is available as described in Table 2.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 2:
`
`
`
`
`
`
`
`
`
` 5 mg
`
`
`
` 10 mg
`
`
`
` 15 mg
`
`
`
` 20 mg
`
`
`
` 30 mg
`
` ABILIFY MYCITE Presentations
`
`
` Strength
` Color/Shape
`
`
` 2 mg
`
` pale green
` modified rectangle
`
` pale blue
` modified rectangle
`
`
` off-white to pale pink
` modified rectangle
`
`
` pale yellow
` round
`
`
` white to pale yellowish white
` round
`
`
` off-white to pale pink
`
` round
`
`
` Markings
`
` “DA-029”
`
` and “2”
`
` “DA-030”
`
` and “5”
`
` “DA-031”
`
` and “10”
`
` “DA-032”
`
` and “15”
`
` “DA-033”
`
` and “20”
`
` “DA-034”
`
` and “30”
`
`
`
`
`
`
`
`
`
` 4
`
`
`
` CONTRAINDICATIONS
`
`
`
`
`
` ABILIFY MYCITE 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
`
`
`
`
`
`
` Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk
` of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking
`
`
`
` atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times
` the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate
`
` of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
`
`
` Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g.,
` heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that,
`
`
` similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase
`mortality. The extent to which the findings of increased mortality in observational studies may be
`
` attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
` ABILIFY MYCITE is not approved for the treatment of patients with dementia-related psychosis [see
`
`Boxed Warning, and Warnings and Precautions (5.3)].
`
`
`
`
`
`
` Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients
`
`
`
`
`
` 5.2
`
`
`
` In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant
`
`
` classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence
`
`
`
`
`
` of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-
`
`
`
`
`
` treated patients than in placebo-treated patients. The safety and efficacy of ABILIFY MYCITE have not
`
` been established in pediatric patients [see Use in Specific Populations (8.4)]. The drug-placebo
`
`
`
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`
`
`differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are
`
`
`provided in Table 3.
`
`
`
`
`
`
`
`
`No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the
`
`
`
`
`
`number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.
`
`
`
`
`Table 3: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled
`
`Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients
`
`
`
`
`
`
`
` Drug-Placebo Difference in Number of
`Age
`
`
`
` Patients with Suicidal Thoughts or
`Range
` Behaviors per 1000 Patients Treated
`
` (years)
`
` Increases Compared to Placebo
`
`
`
` 14 additional patients
`
` <18
` 5 additional patients
`
` 18 to 24
`
`
`
` Decreases Compared to Placebo
`
`
`
`
` 1 fewer patient
`
`
`
` 25 to 64
` 6 fewer patients
`
` ≥65
`
` It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients
`
`
` extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from
` placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of
`
`
` depression.
`
`Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and
`
`
`
`behaviors, especially during the initial few months of drug therapy and at times of dosage changes.
`
`Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the
`healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing
`
`
`
`ABILIFY MYCITE, in patients whose depression is persistently worse, or who are experiencing
`
`
`emergent suicidal thoughts or behaviors.
`
`
`
`
`
` Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with
` 5.3
`
`
` Dementia-Related Psychosis
` 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 to
`
`
`
` 88 years). In the fixed-dose study, there was a statistically significant dose-response relationship for
`
`
`
` cerebrovascular adverse events in patients treated with aripiprazole. ABILIFY MYCITE is not approved
`
`
`
`for the treatment of patients with dementia-related psychosis [see Boxed Warning].
`
`
`
`
`
`
` 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 MYCITE. 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 (e.g.,
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`
`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 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, since recurrences
`
`
`of NMS have been reported.
`
` 5.5
`
`
`
` Tardive Dyskinesia
`
`
` A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients
`
`
` treated with antipsychotic drugs, including ABILIFY MYCITE. Although the prevalence of the syndrome
`
` appears to be highest among the elderly, especially elderly women, it is impossible to rely upon
`
`
`
` prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to
`
`
`
` develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive
` dyskinesia is unknown.
`
`
` The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed
`
`
` to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered
` to the patient increase. However, the syndrome can develop, although much less commonly, after
`
`
`
`
` relatively brief treatment periods at low doses.
`
`
`
`
`
`
` The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
`
` treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome
`
`
` and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has
`
` upon the long-term course of the syndrome is unknown.
`
`
`
`
`
` Given these considerations, ABILIFY MYCITE should be prescribed in a manner that is most likely to
`
`
`minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be
`
`
` reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs
`
` and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or
`
` appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of
`
` treatment producing a satisfactory clinical response should be sought. The need for continued treatment
`
`
`
` should be reassessed periodically.
`
`
`
` If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY MYCITE, drug
` discontinuation should be considered. However, some patients may require treatment with ABILIFY
`
`
`
` MYCITE despite the presence of the syndrome.
`
` 5.6 Metabolic Changes
`
`
`
` Atypical antipsychotic drugs have caused metabolic changes that include hyperglycemia, diabetes
`
`
`
`
` mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to
` produce some metabolic changes, each drug has its own specific risk profile.
`
`
`
`
`
`
`
`
`
`
`
` Hyperglycemia/Diabetes Mellitus
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`
`
`
`
`Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death,
`
`
`
`has been reported in patients treated with atypical antipsychotics. There have been reports of
`hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1, 6.2)]. Assessment of the
`
`
`
`
`relationship between atypical antipsychotic use and glucose abnormalities is complicated by the
`
`
`possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the
`
`
`
`
`increasing incidence of diabetes mellitus in the general population. Given these confounders, the
`
`
`
`relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not
`
`completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-
`related adverse reactions in patients treated with the atypical antipsychotics.
`
`
`Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics
`should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes
`
`mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics
`
`
`should undergo fasting blood glucose testing at the beginning of treatment and periodically during
`
`
`treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of
`
`
`
`hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop
`
`
`symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood
`
`glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was
`discontinued; however, some patients required continuation of anti-diabetic treatment despite
`
`discontinuation of the atypical antipsychotic drug.
`
`
`
`
`In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or
`
`
`
`bipolar disorder, the mean change in fasting glucose in aripiprazole -treated patients (+4.4 mg/dL; median
`
`
`exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL;
`
`median exposure 22 days; N=799). Table 4 shows the proportion of aripiprazole-treated patients with
`
`
`
`
`
`normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent
`
`
`
`high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).
`
`
`
`
`
`
`
`
`Table 4: Changes in Fasting Glucose in Placebo-Controlled Monotherapy Trials in Adult
`
`
`Patients (Primarily Schizophrenia and Bipolar Disorder)
`
`
`
` Category Change (at least
`
` Treatment
` once) from Baseline
`
`
`
` Arm
` Normal to High
`
`
`
`
` Aripiprazole
`(<100 mg/dL to ≥126 mg/dL)
`
`
`
` Placebo
` Borderline to High
`
`
`
`
` Aripiprazole
`
` (≥100 mg/dL and <126 mg/dL to
`
`Placebo
`
` ≥126 mg/dL)
`
`
` At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly
` different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].
`
`
`
`
`
` Fasting
`
`Glucose
`
`
`
` n/N
`
`
` 31/822
`
` 22/605
`
` 31/176
`13/142
`
`
`
` %
`
` 3.8
`
` 3.6
`
` 17.6
`9.2
`
`
`
`
` The mean change in fasting glucose in adjunctive aripiprazole-treated patients with major depressive
`
`
`
`
`
` disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-
` treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 5 shows the proportion of adult
`
`
`
`
`
`
` patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median
`
`
` exposure 42 days) in patients with major depressive disorder.
`
`
`
` Table 5: Changes in Fasting Glucose from Placebo-Controlled Adjunctive Trials in Adult
`
`
` Patients with Major Depressive Disorder
`
`
`
`
`
`Reference ID: 4720059
`
`
`
`

`

`
`
` Category Change (