Abilify Maintena (Aripiprazole) Kit [Otsuka America Pharmaceutical, Inc.]

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 oral 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 oral aripiprazole. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis . The following adverse reactions are discussed in more detail in other sections of the labeling: • Increased Mortality in Elderly Patients with Dementia - Related Psychosis Use [see Boxed Warning and Warnings and Precautions (5.1)] • Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.2)] • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)] • Tardive Dyskinesia [see Warnings and Precautions (5.4)] • Metabolic Changes [see Warnings and Precautions (5.5)] • Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (5.6)] • Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.7)] • Falls [see Warnings and Precautions (5.8)] • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.9)] • Seizures [see Warnings and Precautions (5.10)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.11)] • Body Temperature Regulation [see Warnings and Precautions (5.12)] • Dysphagia [see Warnings and Precautions (5.13)]

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.2) • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.3) • Tardive Dyskinesia: Discontinue if clinically appropriate (5.4) • Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain (5.5) • – Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with and at risk for diabetes (5.5) • – Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics (5.5) • – Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended (5.5) • Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation (5.6) • Orthostatic Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease (5.7) • Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of a clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC). Consider discontinuation if clinically significant decline in WBC/ANC in the absence of other causative factors (5.9) • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.10) • Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.11) 5.1 Increased Mortality in Elderly Patients with Dementia- Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis. 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 oral 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 oral aripiprazole. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis . 5.3 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY MAINTENA. Rare cases of NMS occurred during aripiprazole 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 pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 5.4 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 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 of symptomatic suppression on the long-term course of the syndrome is unknown. Given these considerations, ABILIFY MAINTENA 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 ABILIFY MAINTENA drug discontinuation should be considered. However, some patients may require treatment with ABILIFY MAINTENA despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia/Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1)]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes), who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug. In a short-term, placebo-controlled randomized trial in adults with schizophrenia, the mean change in fasting glucose was +9.8 mg/dL (N=88) in the ABILIFY MAINTENA-treated patients and +0.7 mg/dL (N=59) in the placebo-treated patients. Table 5 shows the proportion of ABILIFY MAINTENA-treated patients with normal and borderline fasting glucose at baseline and their changes in fasting glucose measurements. Table 5: Proportion of Patients with Potential Clinically Relevant Changes in Fasting Glucose from a 12-Week Placebo-Controlled Monotherapy Trial in Adult Patients with Schizophrenia Category Change (at least once) from Baseline Treatment Arm n/N N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift. % Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) ABILIFY MAINTENA 7/88 8.0 Placebo 0/75 0.0 Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) ABILIFY MAINTENA 1/33 3.0 Placebo 3/33 9.1 During a 52-week, open-label bipolar I disorder study in those patients who initiated ABILIFY MAINTENA treatment, 1.1% with normal baseline fasting glucose experienced a shift to high while receiving ABILIFY MAINTENA and 9.8% with borderline fasting glucose experienced a shift to high. Combined, 2.9% of these patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during this trial. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Table 6 shows the proportion of adult patients from one short-term, placebo-controlled randomized trial in adults with schizophrenia taking ABILIFY MAINTENA, with changes in total cholesterol, fasting triglycerides, fasting LDL cholesterol and HDL cholesterol. Table 6: Proportion of Patients with Potential Clinically Relevant Changes in Blood Lipid Parameters From a 12-Week Placebo-Controlled Monotherapy Trial in Adults with Schizophrenia Treatment Arm n/N N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift. % Total Cholesterol Normal to High (<200 mg/dL to ≥240 mg/dL) ABILIFY MAINTENA 3/83 3.6 Placebo 2/73 2.7 Borderline to High (200~<240 mg/dL to ≥240 mg/dL) ABILIFY MAINTENA 6/27 22.2 Placebo 2/19 10.5 Any increase (≥40 mg/dL) ABILIFY MAINTENA 15/122 12.3 Placebo 6/110 5.5 Fasting Triglycerides Normal to High (<150 mg/dL to ≥200 mg/dL) ABILIFY MAINTENA 7/98 7.1 Placebo 4/78 5.1 Borderline to High (150~<200 mg/dL to ≥200 mg/dL) ABILIFY MAINTENA 3/11 27.3 Placebo 4/15 26.7 Any increase (≥50 mg/dL) ABILIFY MAINTENA 24/122 19.7 Placebo 20/110 18.2 Fasting LDL Cholesterol Normal to High (<100 mg/dL to ≥160 mg/dL) ABILIFY MAINTENA 1/59 1.7 Placebo 1/51 2.0 Borderline to High (100~<160 mg/dL to ≥160 mg/dL) ABILIFY MAINTENA 5/52 9.6 Placebo 1/41 2.4 Any increase (≥30 mg/dL) ABILIFY MAINTENA 17/120 14.2 Placebo 9/103 8.7 HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) ABILIFY MAINTENA 14/104 13.5 Placebo 11/87 12.6 Any decrease (≥20 mg/dL) ABILIFY MAINTENA 7/122 5.7 Placebo 12/110 10.9 During a 52-week, open-label bipolar I disorder study in those patients who initiated ABILIFY MAINTENA, shifts from baseline in fasting cholesterol from normal to high were reported in 2.1% (total cholesterol) and 2.2% (LDL cholesterol) and shifts from baseline from normal to low were reported in 8.5% (HDL cholesterol). Of these patients with normal baseline triglycerides, 3.6% experienced shifts to high, and 0.0% experienced shifts to very high. Combined, 1.0% of these patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during this trial. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. In one short-term, placebo-controlled trial in adult patients with schizophrenia with ABILIFY MAINTENA, the mean change in body weight at Week 12 was +3.5 kg (N=99) in the ABILIFY MAINTENA-treated patients and +0.8 kg (N=66) in the placebo-treated patients. Table 7 shows the percentage of adult patients with schizophrenia with weight gain ≥7% of body weight in a short-term, placebo-controlled trial with ABILIFY MAINTENA. Table 7: Percentage of Patients From a 12-Week Placebo-Controlled Trial in Adult Patients with Schizophrenia with Weight Gain ≥7% of Body Weight Treatment Arm N N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. Patients n (%) Weight gain ≥7% of body weight ABILIFY MAINTENA 144 31 (21.5) Placebo 141 12 (8.5) During a 52-week, open-label bipolar I disorder study in those patients who initiated ABILIFY MAINTENA, 1.8% discontinued ABILIFY MAINTENA treatment due to weight increase. ABILIFY MAINTENA was associated with mean increase from baseline in weight of 1.0 kg at week 52. In this trial, 21.4% of these patients demonstrated ≥7% increase in body weight and 15.4% demonstrated a ≥7% decrease in body weight. 5.6 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. 5.7 Orthostatic Hypotension and Syncope ABILIFY MAINTENA may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. In the short-term, placebo-controlled trial in adults with schizophrenia, the adverse event of presyncope was reported in 1/167 (0.6%) of patients treated with ABILIFY MAINTENA, while syncope and orthostatic hypotension were each reported in 1/172 (0.6%) of patients treated with placebo. During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, orthostasis-related adverse events were reported in 4/576 (0.7%) of patients treated with ABILIFY MAINTENA, including abnormal orthostatic blood pressure (1/576, 0.2%), postural dizziness (1/576, 0.2%), presyncope (1/576, 0.2%) and orthostatic hypotension (1/576, 0.2%). In the short-term placebo-controlled trial in adults with schizophrenia, there were no patients in either treatment group with 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). During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, the incidence of significant orthostatic change in blood pressure was 0.2% (1/575). 5.8 Falls Antipsychotics, including ABILIFY MAINTENA, 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. 5.9 Leukopenia, Neutropenia, and Agranulocytosis In clinical trials and post-marketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY MAINTENA. Agranulocytosis has also been reported [see Adverse Reactions (6.1)]. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and a 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 MAINTENA 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 MAINTENA in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC counts until recovery. 5.10 Seizures As with other antipsychotic drugs, use ABILIFY MAINTENA 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. 5.11 Potential for Cognitive and Motor Impairment ABILIFY MAINTENA, like other antipsychotics, may impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that therapy with ABILIFY MAINTENA does not affect them adversely. 5.12 Body Temperature Regulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY MAINTENA for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration). 5.13 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY MAINTENA. ABILIFY MAINTENA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1)] .

• Only to be administered by intramuscular injection in the deltoid or gluteal muscle by a healthcare professional (2.1) • For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating ABILIFY MAINTENA (2.1) • Recommended dosage is 400 mg administered monthly as a single injection. Dose can be reduced to 300 mg in patients with adverse reactions (2.2) • There are two ways to initiate treatment with ABILIFY MAINTENA • 1-day initiation: Administer two separate intramuscular injections of ABILIFY MAINTENA 400 mg and a single oral dose of aripiprazole 20 mg (2.2) • 14-day initiation: In conjunction with first ABILIFY MAINTENA 400 mg dose, take 14 consecutive days of concurrent oral aripiprazole (10 mg to 20 mg) or current oral antipsychotic (2.2) • Dosage adjustments are required for missed doses (2.3) • Known CYP2D6 poor metabolizers: Recommended starting and maintenance dose is 300 mg administered monthly as a single injection (2.4) • See full prescribing information for ABILIFY MAINTENA dosage modifications due to drug interactions (2.4). • ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe (2.6), and 2) Vials (2.7). 2.1 Important Administration Information For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY MAINTENA. Due to the half-life of oral aripiprazole (i.e., 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively), it may take up to 2 weeks to fully assess tolerability. ABILIFY MAINTENA must be administered by intramuscular injection by a healthcare professional. Do not administer by any other route. For detailed preparation and administration instructions, [see Dosage and Administration (2.6, 2.7)] . 2.2 Recommended Dosage for ABILIFY MAINTENA The recommended dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection). There are two ways to initiate treatment with ABILIFY MAINTENA in patients receiving oral antipsychotics: 1-day initiation: • Administer two intramuscular injections of ABILIFY MAINTENA 400 mg in two different injection sites (in either the deltoid or gluteal muscle), and one dose of oral aripiprazole 20 mg on the first day of treatment with ABILIFY MAINTENA. • Do not administer both injections into the same muscle. 14-day initiation: • When ABILIFY MAINTENA injection is initiated in patients receiving oral aripiprazole administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to achieve therapeutic aripiprazole concentrations during initiation of therapy. • For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with the oral antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy. If there are adverse reactions with the 400 mg dosage, the dosage may be reduced to 300 mg once monthly. 2.3 Missed Doses If the second or third doses are missed: • If more than 4 weeks and less than 5 weeks have elapsed since the last injection, administer the injection as soon as possible . • If more than 5 weeks have elapsed since the last injection, restart treatment with either 1-day initiation or 14-day initiation with ABILIFY MAINTENA [see Dosage and Administration (2.2)] . If the fourth or subsequent doses are missed: • If more than 4 weeks and less than 6 weeks have elapsed since the last injection, administer the injection as soon as possible. • If more than 6 weeks have elapsed since the last injection, restart treatment with either 1-day initiation or 14-day initiation with ABILIFY MAINTENA [see Dosage and Administration (2.2)] . 2.4 Dosage Modifications for Cytochrome P450 Considerations Refer to Table 1 and Table 2 for dosage modifications for patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased to the previous dose [see Dosage and Administration (2.2)] . Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels. Dosage modifications are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days. Table 1: Dosage Modifications for ABILIFY MAINTENA (1-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days Factors Adjusted Dose No change for oral dosage required during initiation. CYP2D6 Poor Metabolizers Known CYP2D6 Poor Metabolizers 300 mg Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors Avoid use Concomitant use with CYP Inhibitors and/or Inducers Strong CYP2D6 or CYP3A4 inhibitors 300 mg CYP2D6 and CYP3A4 inhibitors Avoid use CYP3A4 inducers Avoid use Table 2: Dosage Modifications for ABILIFY MAINTENA (14-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days Factors Adjusted Dose No change for oral dosage required during initiation. CYP2D6 Poor Metabolizers Known CYP2D6 Poor Metabolizers 300 mg Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors 200 mg 200 mg and 160 mg dosage adjustment is obtained only by using the 300 mg or 400 mg strength vials. Patients Taking 400 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors 300 mg CYP2D6 and CYP3A4 inhibitors 200 mg CYP3A4 inducers Avoid use Patients Taking 300 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors 200 mg CYP2D6 and CYP3A4 inhibitors 160 mg CYP3A4 inducers Avoid use ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe [see Dosage and Administration (2.6)] , and 2) Vials [see Dosage and Administration (2.7)] . 2.5 Aripiprazole Formulations and Kits ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe available in 300 mg or 400 mg strength syringes [see Dosage and Administration (2.6)] , and 2) Single-dose vials available in 300 mg or 400 mg strength vials [see Dosage and Administration (2.7)] . The 200 mg and 160 mg dosage adjustments are obtained only by using the 300 mg or 400 mg strength vials. 2.6 Pre-filled Dual Chamber Syringe: Preparation and Administration Instructions Preparation Prior to Reconstitution For deep intramuscular deltoid or gluteal injection by healthcare professionals only. Do not administer by any other route. Inject full syringe contents immediately following reconstitution. Administer once monthly. Lay out and confirm that components listed below are provided in the kit: • One ABILIFY MAINTENA (aripiprazole) pre-filled dual chamber syringe (400 mg or 300 mg as appropriate) for extended-release injectable suspension containing lyophilized powder and Sterile Water for Injection • One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients • One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients • One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients Reconstitution of Lyophilized Powder in Pre-filled Dual Chamber Syringe Reconstitute at room temperature. • a) Push plunger rod slightly to engage threads. And then, rotate plunger rod until the rod stops rotating to release diluent. After plunger rod is at complete stop, middle stopper will be at the indicator line (see Figure 1). Figure 1 • b) Vertically shake the syringe vigorously for 20 seconds until drug is uniformly milky-white (see Figure 2). Figure 2 • c) Visually inspect the syringe for particulate matter and discoloration prior to administration. The reconstituted ABILIFY MAINTENA suspension should appear to be a uniform, homogeneous suspension that is opaque and milky-white in color. Figure 1 Figure 2 Injection Procedure Use appropriate aseptic techniques throughout injection procedure. For deep intramuscular injection only. • a) Twist and pull off Over-cap and Tip-cap (see Figure 3). Figure 3 • b) Select appropriate needle (see Figure 4). Figure 4 For deltoid administration: • 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for non-obese patients • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for obese patients For gluteal administration: • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients • 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for obese patients • c) While holding the needle cap, ensure the needle is firmly seated on the safety device with a push. Twist clockwise until SNUGLY fitted (see Figure 5). Figure 5 • d) Then PULL needle-cap straight up (see Figure 6). Figure 6 • e) Hold syringe UPRIGHT and ADVANCE PLUNGER ROD SLOWLY TO EXPEL THE AIR . Expel air until suspension fills needle base. If it's not possible to advance plunger rod to expel the air, check that plunger rod is rotated to a complete stop (see Figure 7). Figure 7 • f) Inject slowly into the deltoid or gluteal muscle. Do not massage the injection site. Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Disposal Procedure • a) Engage the needle safety device and safely discard all kit components (see Figure 8). ABILIFY MAINTENA pre-filled dual chamber syringe is for single-use only. Figure 8 • b) Rotate sites of injections between the two deltoid or gluteal muscles. Figure 8 2.7 Vial: Preparation and Administration Instructions Preparation Prior to Reconstitution For deep intramuscular injection by healthcare professionals only. Do not administer by any other route. Inject immediately after reconstitution. Administer once monthly. • a) Lay out and confirm that components listed below are provided in the kit: • Vial of ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension lyophilized powder • 2.5 mL single-dose vial of Sterile Water for Injection, USP. For drug diluent use only. Not for intravenous use. • One 3 mL, luer lock syringe with pre-attached 21-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device • One 3 mL, luer lock disposable syringe with luer lock tip • One vial adapter • One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients • One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients • One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients • b) ABILIFY MAINTENA should be suspended using the Sterile Water for Injection as supplied in the kit. • c) The Sterile Water for Injection and ABILIFY MAINTENA vials are for single-dose only. • d) Use appropriate aseptic techniques throughout reconstitution and reconstitute at room temperature. • e) Select the amount of Sterile Water for Injection needed for reconstitution (see Table 3). Table 3: Amount of Sterile Water for Injection Needed for Reconstitution 400 mg Vial 300 mg Vial Dose Sterile Water for Injection Dose Sterile Water for Injection 400 mg 1.9 mL 300 mg 1.5 mL Important: There is more Sterile Water for Injection in the vial than is needed to reconstitute ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension. The vial will have excess Sterile Water for Injection; discard any unused portion. Reconstitution of Lyophilized Powder in Vial • a) Remove the cap of the vial of Sterile Water for Injection and remove the cap of the vial containing ABILIFY MAINTENA lyophilized powder and wipe the tops with a sterile alcohol swab. • b) Using the syringe with pre-attached hypodermic safety needle, withdraw the pre-determined Sterile Water for Injection volume from the vial of Sterile Water for Injection into the syringe (see Figure 9). Residual Sterile Water for Injection will remain in the vial following withdrawal; discard any unused portion. Figure 9 • c) Slowly inject the Sterile Water for Injection into the vial containing the ABILIFY MAINTENA lyophilized powder (see Figure 10). Figure 10 • d) Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger. Subsequently, remove the needle from the vial. Engage the needle safety device by using the one-handed technique (see Figure 11). Gently press the sheath against a flat surface until the needle is firmly engaged in the needle protection sheath. Visually confirm that the needle is fully engaged into the needle protection sheath, and discard. Figure 11 • e) Shake the vial vigorously for 30 seconds until the reconstituted suspension appears uniform (see Figure 12). Figure 12 • f) Visually inspect the reconstituted suspension for particulate matter and discoloration prior to administration. The reconstituted ABILIFY MAINTENA is a uniform, homogeneous suspension that is opaque and milky-white in color. • g) If the injection is not performed immediately after reconstitution keep the vial at room temperature and shake the vial vigorously for at least 60 seconds to re-suspend prior to injection. • h) Do not store the reconstituted suspension in a syringe. Figure 9 Figure 10 Figure 11 Figure 12 Preparation Prior to Injection • a) Use appropriate aseptic techniques throughout injection of the reconstituted ABILIFY MAINTENA suspension. • b) Remove the cover from the vial adapter package (see Figure 13). Do not remove the vial adapter from the package. Figure 13 • c) Using the vial adapter package to handle the vial adapter, attach the prepackaged luer lock syringe to the vial adapter (see Figure 14). Figure 14 • d) Use the luer lock syringe to remove the vial adapter from the package and discard the vial adapter package (see Figure 15). Do not touch the spike tip of the adapter at any time . Figure 15 • e) Determine the recommended volume for injection (Table 4). Table 4: ABILIFY MAINTENA Reconstituted Suspension Volume to Inject 400 mg Vial 300 mg Vial Dose Volume to Inject Dose Volume to Inject 400 mg 2 mL --- --- 300 mg 1.5 mL 300 mg 1.5 mL 200 mg 1 mL 200 mg 1 mL 160 mg 0.8 mL 160 mg 0.8 mL • f) Wipe the top of the vial of the reconstituted ABILIFY MAINTENA suspension with a sterile alcohol swab. • g) Place and hold the vial of the reconstituted ABILIFY MAINTENA suspension on a hard surface. Attach the adapter-syringe assembly to the vial by holding the outside of the adapter and pushing the adapter's spike firmly through the rubber stopper, until the adapter snaps in place (see Figure 16). Figure 16 • h) Slowly withdraw the recommended volume from the vial into the luer lock syringe to allow for injection (see Figure 17). A small amount of excess product will remain in the vial. Figure 17 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Injection Procedure • a) Detach the luer lock syringe containing the recommended volume of reconstituted ABILIFY MAINTENA suspension from the vial. • b) Select the appropriate hypodermic safety needle and attach the needle to the luer lock syringe containing the suspension for injection. While holding the needle cap, ensure the needle is firmly seated on the safety device with a push. Twist clockwise until snugly fitted and then pull the needle cap straight away from the needle (see Figure 18). For deltoid administration: • 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for non-obese patients • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for obese patients For gluteal administration: • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients • 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for obese patients Figure 18 • (c) Slowly inject the recommended volume as a single intramuscular injection into the deltoid or gluteal muscle. Do not massage the injection site. Figure 18 Disposal Procedure • a) Engage the needle safety device as described in Section 2.6, Step (d) of Reconstitution of Lyophilized Powder in Vial and safely discard all kit components (see Figure 8). Dispose of the vials, adapter, needles, and syringe appropriately after injection. The Sterile Water for Injection and ABILIFY MAINTENA vials are for single-dose only. • b) Rotate sites of injections between the two deltoid or gluteal muscles. The recommended dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection). There are two ways to initiate treatment with ABILIFY MAINTENA in patients receiving oral antipsychotics: 1-day initiation: • Administer two intramuscular injections of ABILIFY MAINTENA 400 mg in two different injection sites (in either the deltoid or gluteal muscle), and one dose of oral aripiprazole 20 mg on the first day of treatment with ABILIFY MAINTENA. • Do not administer both injections into the same muscle. 14-day initiation: • When ABILIFY MAINTENA injection is initiated in patients receiving oral aripiprazole administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to achieve therapeutic aripiprazole concentrations during initiation of therapy. • For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with the oral antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy. If there are adverse reactions with the 400 mg dosage, the dosage may be reduced to 300 mg once monthly. Refer to Table 1 and Table 2 for dosage modifications for patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased to the previous dose [see Dosage and Administration (2.2)] . Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels. Dosage modifications are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days. Table 1: Dosage Modifications for ABILIFY MAINTENA (1-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days Factors Adjusted Dose No change for oral dosage required during initiation. CYP2D6 Poor Metabolizers Known CYP2D6 Poor Metabolizers 300 mg Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors Avoid use Concomitant use with CYP Inhibitors and/or Inducers Strong CYP2D6 or CYP3A4 inhibitors 300 mg CYP2D6 and CYP3A4 inhibitors Avoid use CYP3A4 inducers Avoid use Table 2: Dosage Modifications for ABILIFY MAINTENA (14-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days Factors Adjusted Dose No change for oral dosage required during initiation. CYP2D6 Poor Metabolizers Known CYP2D6 Poor Metabolizers 300 mg Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors 200 mg 200 mg and 160 mg dosage adjustment is obtained only by using the 300 mg or 400 mg strength vials. Patients Taking 400 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors 300 mg CYP2D6 and CYP3A4 inhibitors 200 mg CYP3A4 inducers Avoid use Patients Taking 300 mg of ABILIFY MAINTENA Strong CYP2D6 or CYP3A4 inhibitors 200 mg CYP2D6 and CYP3A4 inhibitors 160 mg CYP3A4 inducers Avoid use ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe [see Dosage and Administration (2.6)] , and 2) Vials [see Dosage and Administration (2.7)] . For extended-release injectable suspension : 300 mg and 400 mg of lyophilized powder for reconstitution in: • single-dose, pre-filled, dual chamber syringe • single-dose vial The reconstituted extended-release injectable suspension is a uniform, homogeneous suspension that is opaque and milky-white in color.

• CYP2D6 inhibitors and CYP3A4 Inhibitors : See full prescribing information for ABILIFY MAINTENA dosage modifications when used concomitantly with CYP2D6 inhibitors and/or CYP3A4 inhibitors for greater than 14 days (7.1) • CYP3A4 Inducers : Avoid concomitant use for greater than 14 days (7.1) • See full prescribing information for additional clinically significant drug interactions (7.1) 7.1 Drugs Having Clinically Important Interactions with ABILIFY MAINTENA Table 9: Clinically Important Drug Interactions with ABILIFY MAINTENA: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., ketoconazole) or strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) The concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole [see Clinical Pharmacology (12.3)]. With concomitant use of ABILIFY MAINTENA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days, reduce the ABILIFY MAINTENA dosage [see Dosage and Administration (2.4)]. Strong CYP3A4 Inducers (e.g., carbamazepine) The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole [see Clinical Pharmacology (12.3)]. Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see Dosage and Administration (2.4)] . Antihypertensive Drugs Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.7)]. Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see Warnings and Precautions (5.7)]. Monitor sedation and blood pressure. Adjust dose accordingly. 7.2 Drugs Having No Clinically Important Interactions with ABILIFY MAINTENA Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY MAINTENA is required when administered concomitantly with famotidine, valproate, lithium, lorazepam [see Clinical Pharmacology (12.3)] . 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), or CYP3A4 (e.g., dextromethorphan) when coadministered with ABILIFY MAINTENA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY MAINTENA. [See Clinical Pharmacology (12.3)] . Table 9: Clinically Important Drug Interactions with ABILIFY MAINTENA: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., ketoconazole) or strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) The concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole [see Clinical Pharmacology (12.3)]. With concomitant use of ABILIFY MAINTENA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days, reduce the ABILIFY MAINTENA dosage [see Dosage and Administration (2.4)]. Strong CYP3A4 Inducers (e.g., carbamazepine) The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole [see Clinical Pharmacology (12.3)]. Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see Dosage and Administration (2.4)] . Antihypertensive Drugs Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.7)]. Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see Warnings and Precautions (5.7)]. Monitor sedation and blood pressure. Adjust dose accordingly. Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY MAINTENA is required when administered concomitantly with famotidine, valproate, lithium, lorazepam [see Clinical Pharmacology (12.3)] . 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), or CYP3A4 (e.g., dextromethorphan) when coadministered with ABILIFY MAINTENA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY MAINTENA. [See Clinical Pharmacology (12.3)] .