These Highlights Do Not Include All The Information Needed To Use Abilify Safely And Effectively. See Full Prescribing Information For Abilify.

Adults

The recommended starting and target dose for ABILIFY is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.1)].

Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either ABILIFY 15 mg/day or placebo and observed for relapse [see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F)[see USP Controlled Room Temperature].

Antipsychotics, including ABILIFY, 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.

ABILIFY 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 misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and major depressive disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ABILIFY should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see Adverse Reactions (6.1, 6.2)].

MedDRA terminology has been used to classify the adverse reactions.

Aripiprazole is an atypical antipsychotic drug that is available as ABILIFY^® (aripiprazole) Tablets. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C₂₃H₂₇Cl₂N₃O₂ and its molecular weight is 448.38. The chemical structure is:

ABILIFY Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. ABILIFY and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

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.

Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (12.3)].

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

Of the 13,543 patients treated with oral ABILIFY in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of ABILIFY 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.

ABILIFY is not approved for the treatment of patients with psychosis associated with Alzheimer's disease [see Boxed Warning and Warnings and Precautions (5.1)].

Efficacy of ABILIFY was established in the following adequate and well-controlled trials:

• Four short-term trials and one maintenance trial in adult patients and one short-term trial in adolescents (ages 13 to 17 years) with schizophrenia [see Clinical Studies (14.1)]
• Four short-term monotherapy trials and one 6-week adjunctive trial in adult patients and one short-term monotherapy trial in pediatric patients (ages 10 to 17 years) with manic or mixed episodes [see Clinical Studies (14.2)]
• One maintenance monotherapy trial and one maintenance adjunctive trial in adult patients with bipolar I disorder [see Clinical Studies (14.2)]
• Two short-term trials in adult patients with MDD who had an inadequate response to antidepressant therapy during the current episode [see Clinical Studies (14.3)]
• Two short-term trials in pediatric patients (ages 6 to 17 years) for the treatment of irritability associated with autistic disorder [see Clinical Studies (14.4)]
• Two short-term trials in pediatric patients (ages 6 to 18 years) with Tourette's Disorder [see Clinical Studies (14.5)]

ABILIFY is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6.2)].

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Cerebrovascular Adverse Events, Including Stroke [see Warnings and Precautions (5.2)]
• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.3)]
• Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)]
• Tardive Dyskinesia [see Warnings and Precautions (5.5)]
• Metabolic Changes [see Warnings and Precautions (5.6)]
• Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (5.7)]
• Orthostatic Hypotension [see Warnings and Precautions (5.8)]
• Falls [see Warnings and Precautions (5.9)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.10)]
• Seizures/Convulsions [see Warnings and Precautions (5.11)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
• Body Temperature Regulation [see Warnings and Precautions (5.13)]
• Suicide [see Warnings and Precautions (5.14)]
• Dysphagia [see Warnings and Precautions (5.15)]

Dosage adjustment due to drug interactions (7.1):

Aripiprazole exhibits high affinity for dopamine D₂ and D₃, serotonin 5-HT_1A and 5-HT_2A receptors (K_i values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D₄, serotonin 5-HT_2C and 5-HT₇, alpha₁-adrenergic and histamine H₁ receptors (K_i values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K_i=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC₅₀>1000 nM).

ABILIFY 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.

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. 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.

Tardive dyskinesia 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 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, drug discontinuation should be considered. However, some patients may require treatment with ABILIFY despite the presence of the syndrome.

ABILIFY (aripiprazole) Tablets are indicated for the treatment of:

• Schizophrenia
• Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder
• Adjunctive Treatment of Major Depressive Disorder
• Irritability Associated with Autistic Disorder
• Treatment of Tourette's Disorder

The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D₂ and 5-HT_1A receptors and antagonist activity at 5-HT_2A receptors.

ABILIFY is not a controlled substance.

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 ABILIFY and in 0.1% (1/732) of pediatric patients (6 to 18 years).

As with other antipsychotic drugs, ABILIFY 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.

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.1, 5.2)
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4)
• Tardive Dyskinesia: Discontinue if clinically appropriate (5.5)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain (5.6)
  • Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes (5.6)
  • Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics (5.6)
  • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Monitor weight (5.6)
• Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation (5.7)
• Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.8)
• Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics including ABILIFY. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.10)
• Seizures/Convulsions: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.11)
• Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.12)
• Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients (5.14)

• Administer once daily without regard to meals (2)

• Known CYP2D6 poor metabolizers: Half of the usual dose (2.6)

ABILIFY may cause orthostatic hypotension, perhaps due to its alpha₁-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral ABILIFY (n=2,467) included (ABILIFY incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on oral ABILIFY included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%) [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 ABILIFY was not meaningfully different from placebo (ABILIFY incidence, placebo incidence): in adult oral ABILIFY-treated patients (4%, 2%), or in pediatric oral ABILIFY-treated patients aged 6 to 18 years (0.4%, 1%).

ABILIFY 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)].

ABILIFY^® (aripiprazole) Tablets are available as described in Table 2.

The following adverse reactions have been identified during postapproval use of ABILIFY. 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.

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)].

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1)

Lactation: Monitor the breastfed infant for dehydration and lack of appropriate weight gain (8.2)

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

The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

ABILIFY has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and who had approximately 7,619 patient-years of exposure to oral ABILIFY and 749 patients with exposure to aripiprazole injection. A total of 3,390 patients were treated with oral ABILIFY for at least 180 days and 1,933 patients treated with oral ABILIFY had at least one year of exposure.

ABILIFY has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's Disorder and who had approximately 1,342 patient-years of exposure to oral ABILIFY. A total of 959 pediatric patients were treated with oral ABILIFY for at least 180 days and 556 pediatric patients treated with oral ABILIFY had at least one year of exposure.

The conditions and duration of treatment with ABILIFY (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.

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

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY 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) [see Adverse Reactions (6.2)].

No dosage adjustment for ABILIFY is required on the basis of a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide) .

30 Tablets NDC 59148-006-13

ABILIFY®

(aripiprazole)

TABLETS

2 mg

DISPENSE WITH MEDICATION GUIDE

Rx only

Otsuka America Pharmaceutical, Inc.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY. Rare cases of NMS occurred during ABILIFY treatment in the worldwide clinical database. Clinical manifestations of NMS are 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 (CNS) 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.

Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg/day and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg/day which are 13 and 19 times the MRHD of 30 mg/day based on mg/m² body surface area. 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.

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY. 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 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 in patients with severe neutropenia (absolute neutrophil count <1,000/mm³) and follow their WBC counts until recovery.

ABILIFY, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (ABILIFY incidence, placebo incidence): in adult patients (n=2,467) treated with oral ABILIFY (11%, 6%) and in pediatric patients ages 6 to 17 years (n=611; 24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral ABILIFY in short-term, placebo-controlled trials.

Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY does not affect them adversely.

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in ABILIFY-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with ABILIFY. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

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 aripiprazole. 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.

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 dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.

When adjunctive ABILIFY is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment as specified in Dosage and Administration (2.3) .

Based on pharmacokinetic studies, no dosage adjustment of ABILIFY is required when administered concomitantly with famotidine, valproate, lithium, and 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 coadministered with ABILIFY. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY [see Clinical Pharmacology (12.3)].

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24 years) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 3.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ABILIFY should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24 years; there was a reduction in risk with antidepressant use in patients aged 65 years and older [see Warnings and Precautions (5.3)].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.3)].

Adults

The recommended starting and target dose for ABILIFY is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.1)].

Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either ABILIFY 15 mg/day or placebo and observed for relapse [see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F)[see USP Controlled Room Temperature].

Antipsychotics, including ABILIFY, 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.

ABILIFY 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 misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and major depressive disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ABILIFY should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see Adverse Reactions (6.1, 6.2)].

MedDRA terminology has been used to classify the adverse reactions.

Aripiprazole is an atypical antipsychotic drug that is available as ABILIFY^® (aripiprazole) Tablets. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C₂₃H₂₇Cl₂N₃O₂ and its molecular weight is 448.38. The chemical structure is:

ABILIFY Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. ABILIFY and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

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.

Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (12.3)].

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

Of the 13,543 patients treated with oral ABILIFY in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of ABILIFY 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.

ABILIFY is not approved for the treatment of patients with psychosis associated with Alzheimer's disease [see Boxed Warning and Warnings and Precautions (5.1)].

Efficacy of ABILIFY was established in the following adequate and well-controlled trials:

• Four short-term trials and one maintenance trial in adult patients and one short-term trial in adolescents (ages 13 to 17 years) with schizophrenia [see Clinical Studies (14.1)]
• Four short-term monotherapy trials and one 6-week adjunctive trial in adult patients and one short-term monotherapy trial in pediatric patients (ages 10 to 17 years) with manic or mixed episodes [see Clinical Studies (14.2)]
• One maintenance monotherapy trial and one maintenance adjunctive trial in adult patients with bipolar I disorder [see Clinical Studies (14.2)]
• Two short-term trials in adult patients with MDD who had an inadequate response to antidepressant therapy during the current episode [see Clinical Studies (14.3)]
• Two short-term trials in pediatric patients (ages 6 to 17 years) for the treatment of irritability associated with autistic disorder [see Clinical Studies (14.4)]
• Two short-term trials in pediatric patients (ages 6 to 18 years) with Tourette's Disorder [see Clinical Studies (14.5)]

ABILIFY is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6.2)].

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Cerebrovascular Adverse Events, Including Stroke [see Warnings and Precautions (5.2)]
• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.3)]
• Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)]
• Tardive Dyskinesia [see Warnings and Precautions (5.5)]
• Metabolic Changes [see Warnings and Precautions (5.6)]
• Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (5.7)]
• Orthostatic Hypotension [see Warnings and Precautions (5.8)]
• Falls [see Warnings and Precautions (5.9)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.10)]
• Seizures/Convulsions [see Warnings and Precautions (5.11)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
• Body Temperature Regulation [see Warnings and Precautions (5.13)]
• Suicide [see Warnings and Precautions (5.14)]
• Dysphagia [see Warnings and Precautions (5.15)]

Dosage adjustment due to drug interactions (7.1):

Aripiprazole exhibits high affinity for dopamine D₂ and D₃, serotonin 5-HT_1A and 5-HT_2A receptors (K_i values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D₄, serotonin 5-HT_2C and 5-HT₇, alpha₁-adrenergic and histamine H₁ receptors (K_i values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K_i=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC₅₀>1000 nM).

ABILIFY 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.

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. 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.

Tardive dyskinesia 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 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, drug discontinuation should be considered. However, some patients may require treatment with ABILIFY despite the presence of the syndrome.

ABILIFY (aripiprazole) Tablets are indicated for the treatment of:

• Schizophrenia
• Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder
• Adjunctive Treatment of Major Depressive Disorder
• Irritability Associated with Autistic Disorder
• Treatment of Tourette's Disorder

The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D₂ and 5-HT_1A receptors and antagonist activity at 5-HT_2A receptors.

ABILIFY is not a controlled substance.

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 ABILIFY and in 0.1% (1/732) of pediatric patients (6 to 18 years).

As with other antipsychotic drugs, ABILIFY 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.

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.1, 5.2)
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4)
• Tardive Dyskinesia: Discontinue if clinically appropriate (5.5)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain (5.6)
  • Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes (5.6)
  • Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics (5.6)
  • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Monitor weight (5.6)
• Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation (5.7)
• Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.8)
• Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics including ABILIFY. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.10)
• Seizures/Convulsions: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.11)
• Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.12)
• Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients (5.14)

• Administer once daily without regard to meals (2)

• Known CYP2D6 poor metabolizers: Half of the usual dose (2.6)

ABILIFY may cause orthostatic hypotension, perhaps due to its alpha₁-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral ABILIFY (n=2,467) included (ABILIFY incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on oral ABILIFY included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%) [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 ABILIFY was not meaningfully different from placebo (ABILIFY incidence, placebo incidence): in adult oral ABILIFY-treated patients (4%, 2%), or in pediatric oral ABILIFY-treated patients aged 6 to 18 years (0.4%, 1%).

ABILIFY 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)].

ABILIFY^® (aripiprazole) Tablets are available as described in Table 2.

The following adverse reactions have been identified during postapproval use of ABILIFY. 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.

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)].

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1)

Lactation: Monitor the breastfed infant for dehydration and lack of appropriate weight gain (8.2)

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

The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

ABILIFY has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and who had approximately 7,619 patient-years of exposure to oral ABILIFY and 749 patients with exposure to aripiprazole injection. A total of 3,390 patients were treated with oral ABILIFY for at least 180 days and 1,933 patients treated with oral ABILIFY had at least one year of exposure.

ABILIFY has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's Disorder and who had approximately 1,342 patient-years of exposure to oral ABILIFY. A total of 959 pediatric patients were treated with oral ABILIFY for at least 180 days and 556 pediatric patients treated with oral ABILIFY had at least one year of exposure.

The conditions and duration of treatment with ABILIFY (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.

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

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY 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) [see Adverse Reactions (6.2)].

No dosage adjustment for ABILIFY is required on the basis of a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide) .

30 Tablets NDC 59148-006-13

ABILIFY®

(aripiprazole)

TABLETS

2 mg

DISPENSE WITH MEDICATION GUIDE

Rx only

Otsuka America Pharmaceutical, Inc.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY. Rare cases of NMS occurred during ABILIFY treatment in the worldwide clinical database. Clinical manifestations of NMS are 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 (CNS) 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.

Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg/day and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg/day which are 13 and 19 times the MRHD of 30 mg/day based on mg/m² body surface area. 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.

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY. 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 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 in patients with severe neutropenia (absolute neutrophil count <1,000/mm³) and follow their WBC counts until recovery.

ABILIFY, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (ABILIFY incidence, placebo incidence): in adult patients (n=2,467) treated with oral ABILIFY (11%, 6%) and in pediatric patients ages 6 to 17 years (n=611; 24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral ABILIFY in short-term, placebo-controlled trials.

Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY does not affect them adversely.

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in ABILIFY-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with ABILIFY. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

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 aripiprazole. 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.

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 dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.

When adjunctive ABILIFY is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment as specified in Dosage and Administration (2.3) .

Based on pharmacokinetic studies, no dosage adjustment of ABILIFY is required when administered concomitantly with famotidine, valproate, lithium, and 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 coadministered with ABILIFY. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY [see Clinical Pharmacology (12.3)].

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24 years) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 3.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ABILIFY should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24 years; there was a reduction in risk with antidepressant use in patients aged 65 years and older [see Warnings and Precautions (5.3)].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.3)].