2.1 Schizophrenia in Patients 13 Years and Older

2.2 Adjunctive Treatment of Major Depressive Disorder in Adults

The recommended starting dosage for OPIPZA as adjunctive treatment of MDD in adults already taking an antidepressant is 2 mg to 5 mg once daily. The recommended dosage range is 2 mg to 15 mg once daily. Dosage adjustments of up to 5 mg per day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.3)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

2.3 Irritability Associated with Autistic Disorder in Pediatric Patients 6 years and Older

The recommended dosage range for the treatment of pediatric patients 6 to 17 years with irritability associated with autistic disorder is 5 mg to 15 mg once daily.

Dosing should be initiated at 2 mg once daily. The dose should be increased to 5 mg per day, with subsequent increases to 10 mg or 15 mg per day if needed. Dose adjustments of up to 5 mg per day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.4)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

2.4 Tourette's Disorder in Pediatric Patients 6 years and Older

The recommended dosage range for treatment of Tourette's disorder in pediatric patients 6 years and older is 5 mg to 20 mg once daily.

For patients weighing less than 50 kg, dosage should be initiated at 2 mg once daily with a target dosage of 5 mg once daily after 2 days. The dosage can be increased to 10 mg once daily in patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually at intervals of no less than one week.

For patients weighing 50 kg or more, dosing should be initiated at 2 mg once daily for 2 days, and then increased to 5 mg once daily for 5 days, with a target dosage of 10 mg once daily on Day 8. The dosage can be increased up to 20 mg once daily for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg per day at intervals of no less than one week [see Clinical Studies (14.5)].

Patients should be periodically reassessed to determine the continued need for maintenance treatment.

2.5 Important Administration Information

Instruct patients and/or caregivers to read the "Instruction for Use" carefully for complete directions on how to properly dose and administer OPIPZA.

Administer OPIPZA orally with or without food [see Clinical Pharmacology (12.3)].

Apply OPIPZA on top of the tongue where it dissolves in saliva and can be swallowed in a normal manner without the need for water or other liquids.

The patient should refrain from chewing the film and should not swallow an undissolved film. Do not cut or split OPIPZA.

Administer only one oral film at a time. If an additional film is needed to complete the dosage, administer after the previous film has completely dissolved.

2.6 Dosage Recommendations and Modifications for Cytochrome P450 Considerations

Dosage recommendations and modifications for patients who are known CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers are described in Table 1.

When the coadministered drug is withdrawn from the combination therapy, Aripiprazole Oral Film dosage should be adjusted to its previous dose. When the coadministered CYP3A4 inducer is withdrawn, Aripiprazole Oral Film dosage should be reduced to the previous dose over 1 to 2 weeks. Patients 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 recommended dose initially and then adjusted to achieve clinical response [see Dosage and Administration (2.5)].

When adjunctive OPIPZA is administered to patients with major depressive disorder, OPIPZA should be administered without dosage adjustment as specified in Dosage and Administration (2.2).

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.

OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)]

5.2 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 reactions (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 reactions in patients treated with aripiprazole. OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

5.3 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2.

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults 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 and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication 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 OPIPZA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. It should be noted that OPIPZA is not approved for use in treating depression in the pediatric population.

5.4 Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex has been reported with antipsychotic drugs, including aripiprazole. Rare cases of NMS have been reported during aripiprazole treatment in the global 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.

If NMS is suspected, immediately discontinue OPIPZA and provide symptomatic treatment and monitoring.

5.5 Tardive Dyskinesia

Tardive dyskinesia, 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 predict which patients will 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 appear to increase as the duration of treatment and the total cumulative dose increases. However, the syndrome can develop after relatively brief treatment periods at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself may suppress (or partially suppress) the signs and symptoms of the syndrome and 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, OPIPZA 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 treated with OPIPZA, drug discontinuation should be considered. However, some patients may require treatment with OPIPZA despite the presence of the syndrome.

5.6 Metabolic Changes

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.

5.7 Pathological Gambling and Other Compulsive Behaviors

Post-marketing 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.

5.8 Orthostatic Hypotension and Syncope

OPIPZA 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 treated with another oral aripiprazole product (n=2,467) included (aripiprazole 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 another oral aripiprazole product 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 another oral aripiprazole product was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adults treated with another oral aripiprazole product (4%, 2%), in pediatric patients treated with another oral aripiprazole-product aged 6 to 18 years (0.4%, 1%).

Use OPIPZA 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)]. Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

5.9 Falls

Antipsychotics, including OPIPZA, 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 OPIPZA 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 OPIPZA 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 and in 0.1% (1/732) of pediatric patients (6 to 18 years) treated with another oral aripiprazole product.

As with other antipsychotic drugs, use OPIPZA 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

OPIPZA, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials of another oral aripiprazole product, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2,467) treated with oral aripiprazole (11%, 6%), 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 aripiprazole in short-term, placebo-controlled trials.

Patients should be cautioned about operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that therapy with OPIPZA 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 OPIPZA 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)].

5.14 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. OPIPZA 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)].

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 OPIPZA for the treatment of adults with schizophrenia in patients 13 years and older, adjunctive treatment of adults with MDD, treatment of irritability associated with autistic disorder in pediatric patients 6 years and older, and treatment of Tourette's disorder in pediatric patients 6 years and older is based on adequate and well-controlled studies of another oral aripiprazole product. Below is a display of adverse reactions of oral aripiprazole (referred to as "aripiprazole" in this section) from those adequate and well-controlled studies.

Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, major depressive disorder, and other indications, 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.

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

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

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, and pathological gambling.

7.1 Drugs Having Clinically Important Interactions with OPIPZA

Table 18 includes clinically important drug interactions with OPIPZA.

7.2 Drugs Having No Clinically Important Interactions with OPIPZA

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

In addition, no dosage adjustment is necessary for substrates of CYP2D6, CYP2C9, CYP2C19, or CYP3A4 when coadministered with OPIPZA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with OPIPZA [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of OPIPZA in pediatric patients with major depressive disorder 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)].

8.5 Geriatric Use

No dosage adjustment of OPIPZA is recommended for geriatric patients [see 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, major depressive disorder, or another indication 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. OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

8.6 CYP2D6 Poor Metabolizers

OPIPZA 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 Renal Impairment

No dosage adjustment for OPIPZA is required on the basis of a patient's renal function (glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment

No dosage adjustment for OPIPZA is required on the basis of a patient's hepatic function (Child-Pugh scores between 5 and 15) [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

OPIPZA contains aripiprazole, which is not a controlled substance.

9.2 Abuse

Aripiprazole 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 aripiprazole 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.

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. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in patients age 12 years and younger involving oral aripiprazole ingestions up to 195 mg (6.5 times the maximum recommended daily dose) with no fatalities.

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.

Management of Overdosage

Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

No specific information is available on the treatment of overdose with OPIPZA. 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 listed indications, 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-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>1000 nM).

12.3 Pharmacokinetics

Aripiprazole oral film 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.

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/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.

14.1 Overview of the Clinical Studies

The efficacy of OPIPZA for the treatment of schizophrenia in patients ages 13 to 17 years, adjunctive treatment of adults with MDD, treatment of irritability associated with autistic disorder in pediatric patients 6 years and older, and treatment of Tourette's disorder in pediatric patients 6 years and older is based on the following adequate and well-controlled studies of another oral aripiprazole product (referred to as "aripiprazole" in this section):

• Four short-term trials and one maintenance trial in adult patients and one short-term trial in pediatric patients ages 13 to 17 years with schizophrenia [see Clinical Studies (14.1)]
• 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)]

14.2 Schizophrenia

14.3 Adjunctive Treatment of Adults with Major Depressive Disorder

The efficacy of aripiprazole 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 controlled-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 was superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 28). In one study, aripiprazole was also superior to placebo in reducing the mean SDS score.

In both trials, patients received aripiprazole 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 regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females.

14.4 Irritability Associated with Autistic Disorder

14.5 Tourette's Disorder

How Supplied

OPIPZA is available in the strengths and packages listed in Table 23.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, and Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome

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

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care 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, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking OPIPZA . 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, and also at times of re-initiating treatment or increases in dosage [see Warnings and Precautions (5.8)].

Leukopenia/Neutropenia

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

Potential for Cognitive and Motor Impairment

Inform patients that OPIPZA has the potential to impair judgment, thinking, or motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle until they are reasonably certain that OPIPZA therapy does not affect them adversely [see Warnings and Precautions (5.12)].

Concomitant Medication

Advise patients to inform their healthcare providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drug Interactions (7.1)].

Heat Exposure and Dehydration

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

Pregnancy

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

Administration Information

Advise the patient of the following [see Dosage and Administration (2.5)]:

• Administer OPIPZA with or without food.
• Apply OPIPZA on top of the tongue where it dissolves in saliva and can be swallowed in a normal manner without the need for water or other liquids.
• Refrain from chewing the film or swallowing an undissolved film. Do not cut or split OPIPZA.
• Administer only one oral film at a time. If an additional film is needed to complete the dosage, administer after the previous film has completely dissolved.