`• 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):
`
`
`Factors
`
`Known CYP2D6 Poor
`Metabolizers
`Known CYP2D6 Poor
`Metabolizers and strong CYP3A4
`inhibitors
`Strong CYP2D6 or CYP3A4
`inhibitors
`Strong CYP2D6 and CYP3A4
`inhibitors
`Strong CYP3A4 inducers
`
`Dosage Adjustments for
`ABILIFY MYCITE
`Administer half recommended
`dose
`
`Administer a quarter of
`recommended dose
`
`Administer half recommended
`dose
`Administer a quarter of
`recommended dose
`Double recommended 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: 11/2017
`
`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)
`---------------------------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--------------------
`Initial
`Recommended
`Maximum
`
`Dose
`Dose
`Dose
`Schizophrenia – adults
`10-15
`10-15 mg/day
`30 mg/day
`mg/day
`(2.3)
`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)
`
` •
`
` 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)
`
`---------------------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)
`
`
`
`Reference ID: 4180759
`
`
`
`10-15
`mg/day
`
`2-5
`mg/day
`
`15 mg/day
`
`30 mg/day
`
`5-10 mg/day
`
`15 mg/day
`
`
`
`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS AND SUICIDAL
`THOUGHTS AND BEHAVIORS
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Overview of the ABILIFY MYCITE System
`2.2 Administration Instructions
`2.3 Dosage in Schizophrenia
`2.4 Dosage in Bipolar I Disorder
`2.5 Dosage in Adjunctive Treatment of Major Depressive Disorder
`2.6 Dosage Adjustments for Cytochrome P450 Considerations
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Mortality in Elderly Patients with Dementia-Related
`Psychosis
`5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult
`Patients
`5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly
`Patients with Dementia-Related Psychosis
`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
`5.12 Potential for Cognitive and Motor Impairment
`5.13 Body Temperature Regulation
`5.14 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
`MYCITE
`7.2 Drugs Having No Clinically Important Interactions with ABILIFY
`MYCITE
`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
`10.2 Management of Overdosage
`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
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Schizophrenia
`14.2 Bipolar Disorder
`14.3 Adjunctive Treatment of Adults with Major Depressive Disorder
`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: 4180759
`
`
`
`
`
`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 [see Clinical Studies (14.1)]
`• Treatment of bipolar I disorder
`o Acute treatment of adults with manic and mixed episodes as monotherapy and as adjunct to
`lithium or valproate [see Clinical Studies (14.2)]
`o Maintenance treatment of adults as monotherapy and as adjunct to lithium or valproate [see
`Clinical Studies (14.2)]
`• Adjunctive treatment of adults with Major Depressive Disorder [see Clinical Studies (14.3)]
`
`
`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)].
`
`
`
`Reference ID: 4180759
`
`3
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Overview of the ABILIFY MYCITE System
`The ABILIFY MYCITE System is composed of the following components:
`
`
`• 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;
`• MYCITE APP - a smartphone application (app) which is used with a compatible smartphone to
`display information for the patient;
`• Web-based portal for healthcare professionals and caregivers
`
`Prior to initial patient use of the ABILIFY MYCITE System, facilitate use of the combination product
`and its components (patch, app, portal) and ensure the patient is capable and willing to use smartphones
`and apps. Before using any component of the ABILIFY MYCITE System, instruct patients to:
`
`• Download the MYCITE APP and follow all the Instructions for Use.
`• Ensure that the app is compatible with their specific smartphone
`
`Although most ingestions will be detected within 30 minutes, it may take up to two hours for the
`smartphone app and web portal to detect the ingestion of ABILIFY MYCITE; in some cases, the
`ingestion of the tablet may not be detected. If the tablet is not detected after ingestion, do not repeat the
`dose [see Adverse Reactions (6)].
`
`The status of the MYCITE Patch is indicated by a status icon in the app to inform the user that the patch
`is properly adhered and fully functioning. Instruct patients to ensure that the app is paired with the patch
`prior to use. Refer to the information provided in the product packaging and electronic Instructions for
`Use within the MYCITE APP.
`
`2.2 Administration Instructions
`ABILIFY MYCITE
`Administer ABILIFY MYCITE orally with or without food [see Clinical Pharmacology (12.3)].
`Swallow tablets whole; do not divide, crush, or chew.
`
`MYCITE Patch
`Apply the MYCITE Patch only when instructed by the app to the left side of the body just above the
`lower edge of the rib cage. Do not place the MYCITE 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. Instruct
`patients to keep the patch on when showering, swimming, or exercising. The MYCITE Patch should be
`changed weekly or sooner as needed. The app will prompt patient to change the patch and will direct
`patient to apply and remove the patch correctly. Patients undergoing an MRI need to remove their patch
`and replace with a new one as soon as possible. If there is skin irritation, instruct patients to remove the
`patch.
`
`
`
`Reference ID: 4180759
`
`4
`
`
`
`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.
`
`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.
`
`Dosage in Adjunctive Treatment of Major Depressive Disorder
`2.5
`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 co-administered drug is withdrawn from the combination therapy, ABILIFY
`MYCITE dosage should then be adjusted to its original level. When the co-administered 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
`
`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)
`
`Dosage Adjustments for ABILIFY
`MYCITE
`Administer half of recommended dose
`
`Administer a quarter of recommended dose
`
`Administer half of recommended dose
`
`
`
`Reference ID: 4180759
`
`5
`
`
`
`Administer a quarter of recommended dose
`
`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)].
`
`Double recommended dose over 1 to 2 weeks
`
`3 DOSAGE FORMS AND STRENGTHS
`
`ABILIFY MYCITE (aripiprazole tablets with sensor) is available as described in Table 2.
`
`Table 2:
`
`ABILIFY MYCITE Presentations
`
`Tablet
`Strength
`2 mg
`
`5 mg
`
`10 mg
`
`15 mg
`
`20 mg
`
`30 mg
`
`Tablet
`Color/Shape
`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
`
`Tablet
`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
`
`Increased Mortality in Elderly Patients with Dementia-Related Psychosis
`5.1
`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,
`
`
`
`Reference ID: 4180759
`
`6
`
`
`
`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, 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
`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
`
`
`
`Age
`Range
`(years)
`
`<18
`18-24
`
`25-64
`≥65
`
`Drug-Placebo Difference in Number of
`Patients of Suicidal Thoughts or Behaviors
`per 1000 Patients Treated
`Increases Compared to Placebo
`14 additional patients
`5 additional patients
`Decreases Compared to Placebo
`1 fewer patient
`6 fewer patients
`
`
`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.
`
`
`
`Reference ID: 4180759
`
`7
`
`
`
`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: 78-88
`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].
`
`Neuroleptic Malignant Syndrome (NMS)
`5.4
`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.,
`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.
`
`Tardive Dyskinesia
`5.5
`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.
`
`
`
`Reference ID: 4180759
`
`8
`
`
`
`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
`
`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.
`
`
`
`Reference ID: 4180759
`
`9
`
`
`
`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)
`
`Fasting
`Glucose
`
`Treatment
`Arm
`Aripiprazole
`Placebo
`Aripiprazole
`Placebo
`
`Category Change (at least
`once) from Baseline
`Normal to High
`(<100 mg/dL to ≥126 mg/dL)
`Borderline to High
`(≥100 mg/dL and <126 mg/dL to
`≥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].
`
`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
`
`Category Change (at least
`once) from Baseline
`Normal to High
`(<100 mg/dL to ≥126 mg/dL)
`Borderline to High
`(≥100 mg/dL and <126 mg/dL to
`≥126 mg/dL)
`
`Treatment
`Arm
`Aripiprazole
`Placebo
`Aripiprazole
`Placebo
`
`n/N
`2/201
`2/204
`4/34
`3/37
`
`%
`1.0
`1.0
`11.8
`8.1
`
`Fasting
`Glucose
`
`
`
`Dyslipidemia
`
`Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
`
`Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.
`Table 6 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder
`monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median
`exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting
`LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated
`patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24
`days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days).
`
`
`
`Reference ID: 4180759
`
`10
`
`
`
`Table 6:
`
`Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy
`Trials in Adults (Primarily Schizophrenia and Bipolar Disorder)
`
`
`
`Total Cholesterol
`Normal to High
`(<200 mg/dL to ≥240 mg/dL)
`Fasting Triglycerides
`Normal to High
`(<150 mg/dL to ≥200 mg/dL)
`Fasting LDL Cholesterol
`Normal to High
`(<100 mg/dL to ≥160 mg/dL)
`HDL Cholesterol
`Normal to Low
`(≥40 mg/dL to <40 mg/dL)
`
`Treatment Arm
`Aripiprazole
`
`Placebo
`
`Aripiprazole
`
`Placebo
`
`Aripiprazole
`
`Placebo
`
`Aripiprazole
`
`Placebo
`
`n/N
`34/1357
`
`27/973
`
`40/539
`
`30/431
`
`2/332
`
`2/268
`
`121/1066
`
`99/794
`
`%
`2.5
`
`2.8
`
`7.4
`
`7.0
`
`0.6
`
`0.7
`
`11.4
`
`12.5
`
`In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from
`Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol
`were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol
`(fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%);
`Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol
`(fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%);
`Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.
`
`Table 7 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting
`triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials
`in adult patients with major depressive disorder (median exposure 42 days).
`
`Table 7:
`
`Changes in Blood Lipid Parameters From Placebo-Controlled Adjunctive
`Trials in Adult Patients with Major Depressive Disorder
`
`
`
`Total Ch