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)].

2.1 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

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)].

2.2 Administration Instructions

2.3 Dosage in Schizophrenia

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.

2.4 Dosage in Bipolar I Disorder

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 one week. The maximum recommended daily dosage is 15 mg. Periodically reassess to determine the continued need for maintenance treatment.

2.6 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 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.

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)].

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)].

5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

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.

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.

5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with 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., 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.

5.7 Pathological Gambling and Other Compulsive Behaviors

Postmarketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with ABILIFY MYCITE. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

5.8 Orthostatic Hypotension

ABILIFY MYCITE may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%) [see Adverse Reactions (6.1)].

The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence) in adult oral aripiprazole-treated patients (4%, 2%).

ABILIFY MYCITE should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see Drug Interactions (7.1)].

5.9 Falls

Antipsychotics, including ABILIFY MYCITE, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.10 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY MYCITE at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY MYCITE in patients with severe neutropenia (absolute neutrophil count <1,000/mm3) and follow their WBC counts until recovery.

5.11 Seizures

In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2,467) of undiagnosed adult patients treated with oral aripiprazole.

As with other antipsychotic drugs, ABILIFY MYCITE should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.12 Potential for Cognitive and Motor Impairment

ABILIFY MYCITE, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In short-term, placebo-controlled trials, somnolence (including sedation) was reported in 11% of aripiprazole-treated patients compared with 6% of placebo-treated patients. Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients on oral aripiprazole in short-term, placebo-controlled trials.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY MYCITE does not affect them adversely.

5.13 Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY MYCITE for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

5.14 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. ABILIFY MYCITE and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ABILIFY MYCITE for the treatment of adults with schizophrenia, treatment of adults with manic and mixed episodes associated with bipolar I disorder, and adjunctive treatment of adults with major depressive disorder (MDD) has been established and is based on trials of aripiprazole including 13,543 adult patients who participated in multiple-dose clinical trials in schizophrenia, bipolar disorder, major depressive disorder, and other disorders, and who had approximately 7,619 patient-years of exposure to oral aripiprazole. A total of 3,390 patients were treated with oral aripiprazole for at least 180 days and 1,933 patients treated with oral aripiprazole had at least one year of exposure.

The conditions and duration of treatment with aripiprazole (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure.

The most common adverse reactions of aripiprazole in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hiccups, oculogyric crisis, pathological gambling, and fecal incontinence.

7.1 Drugs Having Clinically Important Interactions with ABILIFY MYCITE

Table 13 below includes clinically important drug interactions with ABILIFY MYCITE.

7.2 Drugs Having No Clinically Important Interactions with ABILIFY MYCITE

Based on pharmacokinetic studies, no dosage adjustment of ABILIFY MYCITE is required when administered concomitantly with famotidine, valproate, lithium, lorazepam.

In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with ABILIFY MYCITE. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with ABILIFY MYCITE [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of ABILIFY MYCITE in pediatric patients have not been established.

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning,and Warnings and Precautions (5.2)].

8.5 Geriatric Use

No dosage adjustment of ABILIFY MYCITE is recommended for elderly patients for the approved indications [see Boxed Warning, Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Elderly patients treated with antipsychotic drugs with dementia-related psychosis had a greater incidence of stroke and transient ischemic attack. ABILIFY MYCITE is not approved for the treatment of elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1, 5.3)].

8.6 CYP2D6 Poor Metabolizers

ABILIFY MYCITE dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

8.7 Hepatic and Renal Impairment

8.8 Other Specific Populations

No dosage adjustment for ABILIFY MYCITE is required on the basis of a patient's sex, race, or smoking status [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

ABILIFY MYCITE is not a controlled substance.

9.2 Abuse

ABILIFY MYCITE has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY MYCITE misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

9.3 Dependence

In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.

10.1 Human Experience

In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

10.2 Management of Overdosage

No specific information is available on the treatment of overdose with ABILIFY MYCITE. If over-exposure occurs call your poison control center at 1-800-222-1222. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.

12.1 Mechanism of Action

The mechanism of action of aripiprazole in the treatment of schizophrenia, bipolar I disorder, or adjunctive treatment of major depressive disorder is unknown. However, the efficacy of aripiprazole could be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

12.2 Pharmacodynamics

Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50>1,000 nM). Actions at receptors other than D2, 5-HT1A, and 5-HT2A may explain some of the adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

12.3 Pharmacokinetics

Aripiprazole activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D2 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma. The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. Aripiprazole accumulation is predictable from single-dose pharmacokinetics. At steady-state, the pharmacokinetics of aripiprazole is dose-proportional. Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg. The 40 and 60 mg/kg/day doses are 13 and 19 times the maximum recommended human dose (MRHD) based on mg/m2 and 7 to 14 times human exposure at MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

14.1 Overview of the Clinical Studies

The safety and efficacy of aripiprazole tablets for the treatment of adults with schizophrenia, acute treatment of adults with manic and mixed episodes associated with Bipolar I disorder, and adjunctive treatment of adults with major depressive disorder (MDD) has been established and is based on the following adequate and well-controlled trials of aripiprazole tablets:

• Four short-term trials and one maintenance trial in adult patients with schizophrenia [see Clinical Studies (14.2)]
• Four short-term monotherapy trials and one 6-week adjunctive trial in adult patients with manic or mixed episodes [see Clinical Studies (14.3)]
• One maintenance monotherapy trial and in one maintenance adjunctive trial in adult patients with bipolar I disorder [see Clinical Studies (14.3)]
• Two short-term trials in adult patients with MDD who had an inadequate response to antidepressant therapy during the current episode [see Clinical Studies (14.4)]

14.2 Schizophrenia

The efficacy of aripiprazole tablets in the treatment of schizophrenia was evaluated in five short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish aripiprazole tablets from placebo, but one study, the smallest, did not. Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole tablets and the active comparators.

In the four positive trials for aripiprazole tablets, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

In a 4-week trial (n=414) comparing two fixed doses of aripiprazole tablets (15 or 30 mg/day) to placebo, both doses of aripiprazole tablets were superior to placebo in the PANSS total score (Study 1 in Table 14), PANSS positive subscale, and CGI-severity score. In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale.

In a 4-week trial (n=404) comparing two fixed doses of aripiprazole tablets (20 or 30 mg/day) to placebo, both doses of aripiprazole tablets were superior to placebo in the PANSS total score (Study 2 in Table 14), PANSS positive subscale, PANSS negative subscale, and CGI-severity score.

In a 6-week trial (n=420) comparing three fixed doses of aripiprazole tablets (10, 15, or 20 mg/day) to placebo, all three doses of aripiprazole tablets were superior to placebo in the PANSS total score (Study 3 in Table 14), PANSS positive subscale, and the PANSS negative subscale.

In a 6-week trial (n=367) comparing three fixed doses of aripiprazole tablets (2, 5, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole tablets was superior to placebo in the PANSS total score (Study 4 in Table 14), the primary outcome measure of the study. The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure.

Thus, the efficacy of 10, 15, 20, and 30 mg daily doses was established in two studies for each dose. Among these doses, there was no evidence that the higher dose groups offered any advantage over the lowest dose group of these studies.

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.

A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from their antipsychotic medications and randomized to aripiprazole tablets 15 mg/day or placebo for up to 26 weeks of observation for relapse. Relapse during the double-blind phase was defined as CGI-Improvement score of ≥5 (minimally worse), scores ≥5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or ≥20% increase in the PANSS total score. Patients receiving aripiprazole tablets 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6).

Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

14.3 Bipolar Disorder

Maintenance Treatment of Bipolar I Disorder

Monotherapy Maintenance Therapy

A maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label aripiprazole tablets and who had maintained a clinical response for at least 6 weeks. The first phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label aripiprazole tablets (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one outpatients were then randomized in a double-blind fashion to either the same dose of aripiprazole tablets they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse. During the randomization phase, aripiprazole tablets were superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study (Study 7 in Figure 7). A total of 55 mood events were observed during the double-blind treatment phase. Nineteen were from the aripiprazole tablets group and 36 were from the placebo group. The number of observed manic episodes in the aripiprazole tablets group (6) were fewer than that in the placebo group (19), while the number of depressive episodes in the aripiprazole tablets group (9) was similar to that in the placebo group (11).

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences.

Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7)

Adjunctive Maintenance Therapy

An adjunctive maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode. Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 mcg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤35% improvement on the Y-MRS total score) to lithium or valproate received aripiprazole tablets with a starting dose of 15 mg/day with the option to increase to 30 mg or reduce to 10 mg as early as Day 4, as adjunctive therapy with open-label lithium or valproate. Prior to randomization, patients on the combination of single-blind aripiprazole tablets and lithium or valproate were required to maintain stability (Y-MRS and MADRS total scores ≤12) for 12 consecutive weeks. Three hundred thirty-seven patients were then randomized in a double-blind fashion, to either the same dose of aripiprazole tablets they were on at the end of the stabilization period or placebo plus lithium or valproate and were then monitored for manic, mixed, or depressive relapse for a maximum of 52 weeks. Aripiprazole tablets were superior to placebo on the primary endpoint, time from randomization to relapse to any mood event (Study 8 in Figure 8). A mood event was defined as hospitalization for a manic, mixed, or depressive episode, study discontinuation due to lack of efficacy accompanied by Y-MRS score >16 and/or a MADRS >16, or an SAE of worsening disease accompanied by Y-MRS score >16 and/or a MADRS >16. A total of 68 mood events were observed during the double-blind treatment phase. Twenty-five were from the aripiprazole group and 43 were from the placebo group. The number of observed manic episodes in the aripiprazole group (7) were fewer than that in the placebo group (19), while the number of depressive episodes in the aripiprazole group (14) was similar to that in the placebo group (18). The Kaplan-Meier curves of the time from randomization to relapse to any mood event during the 52-week double-blind treatment phase for aripiprazole tablets and placebo groups are shown in Figure 8.

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences.

Figure 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse to Any Mood Event (Bipolar Study 8)

14.4 Adjunctive Treatment of Adults with Major Depressive Disorder

The efficacy of aripiprazole tablets in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine extended-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). Inadequate response for prospective treatment was defined as less than 50% improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose.

The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme).

In the two trials (n=381, n=362), aripiprazole tablets were superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 16). In one study, aripiprazole tablets were also superior to placebo in reducing the mean SDS score.

In both trials, patients received aripiprazole tablets adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4 mg/day.

An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regards to gender, a smaller mean reduction on the MADRS total score was seen in males than in females.

16.1 How Supplied

The ABILIFY MYCITE kit contains aripiprazole tablets embedded with an Ingestible Event Marker (IEM) sensor co-packaged with MYCITE Patches (wearable sensors) (referred to as the patch). The patch is available as a:

• 2-component patch, comprised of a removable electronics module (referred to as the "pod") and an adhesive "strip" (see Table 18 and Figure 9). The pod contains electronic components to record drug ingestion information and transfer the data to a compatible smartphone. The 30 Day Starter kits contain (a) aripiprazole tablets with sensor, (b) strips, and (c) one pod; whereas, the Maintenance kits contain (a) aripiprazole tablets with sensor and (b) strips [see Dosage and Administration (2.2)].

The patch has a corresponding IFU within the app. The status of the patch is indicated by a status icon in the app to inform the user that the patch is properly adhered and fully functioning.

Figure 9: MYCITE Patch (2-component)

Assembled

ABILIFY MYCITE Kits (2-component patch)

ABILIFY MYCITE kits are available in the following strengths and packages:

16.2 Storage

General Instructions for Use

Instruct patients to:

• Refer to the app store to ensure compatibility with their specific smartphone.
• First download the MYCITE App and follow instructions provided by the app.

Advise patients that:

• The initial use should be facilitated by the healthcare provider [see Dosage and Administration (2.1)].
• They need a functioning pod before using the Maintenance Kit [see How Supplied/Storage and Handling (16.1)].

Advise patients that most ingestions will be detected within 30 minutes; however, in some cases it can take over 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, the dose should not be repeated.

Managing Lost or Disabled Smartphone

Advise patients that if their smartphone is lost, impaired or otherwise rendered unusable, some information collected by the system (synced) may be lost. Advise patients to change their MYCITE Patch immediately and connect to a new smartphone using their current account information. Information previously synced to the patients account will be available.

Using the MYCITE Patch in Different Environments

The MYCITE Patch will communicate with a paired device when it is within 9-foot proximity. The MYCITE Patch should remain on an individual whether they are showering, swimming, or exercising as it is intended to tolerate water or perspiration. Patients undergoing an MRI, however, need to remove their patch and replace with a new one as soon as possible. In order for the MYCITE Patch to communicate with a smartphone, the device must be powered on and Bluetooth®-enabled.

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, Warnings and Precautions (5.2)].

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal adverse reaction referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS [see Warnings and Precautions (5.4)].

Tardive Dyskinesia

Advise patients that abnormal involuntary movements have been associated with the administration of antipsychotic drugs. Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Pathological Gambling and Other Compulsive Behaviors

Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, increased urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.7)].

Orthostatic Hypotension and Syncope

Educate patients about the risk of orthostatic hypotension and syncope especially early in treatment, when re-initiating treatment, or when increasing the dosage [see Warnings and Precautions (5.8)].

Leukopenia, Neutropenia and Agranulocytosis

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while taking ABILIFY MYCITE [see Warnings and Precautions (5.10)].

Interference with Cognitive and Motor Performance

Because ABILIFY MYCITE may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ABILIFY MYCITE therapy does not affect them adversely [see Warnings and Precautions (5.12)].

Heat Exposure and Dehydration

Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)].

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ABILIFY MYCITE. Advise patients that ABILIFY MYCITE may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder). Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ABILIFY MYCITE during pregnancy [see Use In Specific Populations (8.1)].

Lactation

ABILIFY MYCITE use during pregnancy may affect milk supply. Advise the lactating patient to discuss any plans for breastfeeding with their healthcare provider, and to monitor the breastfed infant for dehydration and lack of appropriate weight gain [see Use in Specific Populations (8.2)].