ABILIFY MAINTENA

Aripiprazole is an atypical antipsychotic which is present in ABILIFY MAINTENA as its monohydrate polymorphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C 23 H 27 Cl 2 N 3 O 2 ∙H 2 O and its molecular weight is 466.40. The chemical structure is: ABILIFY MAINTENA (aripiprazole) is an extended-release injectable suspension available in 400 mg or 300 mg strength pre-filled dual chamber syringes and 400 mg or 300 mg strength vials. The labeled strengths are calculated based on the anhydrous form (aripiprazole). Inactive ingredients (per administered dose) for 400 mg and 300 mg strength products, respectively, include carboxymethyl cellulose sodium (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), sodium phosphate monobasic monohydrate (1.48 mg and 1.11 mg) and sodium hydroxide (pH adjuster). Chemical Structure

ABILIFY MAINTENA (aripiprazole) is indicated: for the treatment of schizophrenia in adults for maintenance monotherapy treatment of bipolar I disorder in adults ABILIFY MAINTENA is an atypical antipsychotic indicated: for treatment of schizophrenia in adults ( 1 ) for maintenance monotherapy treatment of bipolar I disorder in adults ( 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 or 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.

ABILIFY MAINTENA is contraindicated in patients with a known hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1 and 6.2) ] . Known hypersensitivity to aripiprazole ( 4 )

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) ] Most commonly observed adverse reactions with ABILIFY MAINTENA in patients with schizophrenia (incidence ≥5% and at least twice that for placebo) were increased weight, akathisia, injection site pain, and sedation ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Safety Database of ABILIFY MAINTENA and Oral Aripiprazole Oral aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days. ABILIFY MAINTENA has been evaluated for safety in 2,128 adult patients in clinical trials in schizophrenia, with approximately 2,633 patient-years of exposure to ABILIFY MAINTENA. A total of 1,229 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 935 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections). ABILIFY MAINTENA has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to ABILIFY MAINTENA. A total of 419 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 287 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections). The conditions and duration of treatment with ABILIFY MAINTENA included double-blind and open-label studies. The safety data presented below are derived from the 12-week double-blind placebo-controlled study of ABILIFY MAINTENA in adult patients with schizophrenia. Adverse Reactions with ABILIFY MAINTENA Most Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia Based on the placebo-controlled trial of ABILIFY MAINTENA in schizophrenia, the most commonly observed adverse reactions associated with the use of ABILIFY MAINTENA in patients (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were increased weight (16.8% vs. 7.0%), akathisia (11.4% vs. 3.5%), injection site pain (5.4% vs. 0.6%) and sedation (5.4% vs. 1.2%). Commonly Reported Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia The following findings are based on the double-blind, placebo-controlled trial that compared ABILIFY MAINTENA 400 mg or 300 mg to placebo in patients with schizophrenia. Table 8 lists the adverse reactions reported in 2% or more of ABILIFY MAINTENA-treated subjects and at a greater proportion than in the placebo group. Table 8: Adverse Reactions in ≥2% of ABILIFY MAINTENA-Treated Adult Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial This table does not include adverse reactions which had an incidence equal to or less than placebo. Percentage of Patients Reporting Reaction ABILIFY MAINTENA Placebo Preferred Term (n=167) (n=172) Gastrointestinal Disorders Constipation 10 7 Dry Mouth 4 2 Diarrhea 3 2 Vomiting 3 1 Abdominal Discomfort 2 1 General Disorders and Administration Site Conditions Injection Site Pain 5 1 Infections and Infestations Upper Respiratory Tract Infection 4 2 Investigations Increased Weight 17 7 Decreased Weight 4 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 1 Back Pain 4 2 Myalgia 4 2 Musculoskeletal Pain 3 1 Nervous System Disorders Akathisia 11 4 Sedation 5 1 Dizziness 4 2 Tremor 3 1 Respiratory, Thoracic and Mediastinal Nasal Congestion 2 1 Other Adverse Reactions Observed During the Clinical Trial Evaluation of ABILIFY MAINTENA The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients: Blood and Lymphatic System Disorders: rare - thrombocytopenia Cardiac Disorders: infrequent - tachycardia; rare - bradycardia, sinus tachycardia Endocrine Disorders: rare - hypoprolactinemia Eye Disorders: infrequent - vision blurred, oculogyric crisis Gastrointestinal Disorders: infrequent - abdominal pain upper, dyspepsia, nausea; rare -swollen tongue General Disorders and Administration Site Conditions: frequent - fatigue, injection site reactions (including erythema, induration, pruritus, injection site reaction, swelling, rash, inflammation, hemorrhage); infrequent - chest discomfort, gait disturbance; rare -irritability, pyrexia Hepatobiliary Disorders: rare - drug induced liver injury Immune System Disorders: rare - drug hypersensitivity Infections and Infestations: rare - nasopharyngitis Investigations: infrequent - blood creatine phosphokinase increased, blood pressure decreased, hepatic enzyme increased, liver function test abnormal, electrocardiogram QT-prolonged; rare - blood triglycerides decreased, blood cholesterol decreased, electrocardiogram T-wave abnormal Metabolism and Nutrition Disorders: infrequent - decreased appetite, obesity, hyperinsulinemia Musculoskeletal and Connective Tissue Disorders: infrequent - joint stiffness, muscle twitching, trismus; rare - rhabdomyolysis Nervous System Disorders: infrequent - extrapyramidal disorder, hypersomnia, lethargy; rare - bradykinesia, convulsion, dysgeusia, memory impairment, oromandibular dystonia Psychiatric Disorders: frequent - anxiety, insomnia, restlessness; infrequent - agitation, bruxism, psychotic disorder, suicidal ideation; rare - aggression, hypersexuality, panic attack Renal and Urinary Disorders : rare - glycosuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: infrequent - ejaculation delayed Vascular Disorders: infrequent - hypertension Demographic Differences An examination of population subgroups was performed across demographic subgroup categories for adverse reactions experienced by at least 5% of ABILIFY MAINTENA subjects at least twice rate of the placebo (i.e., increased weight, akathisia, injection site pain, and sedation) in the double-blind placebo-controlled trial. This analysis did not reveal evidence of differences in safety differential adverse reaction incidence on the basis of age, gender, or race alone; however, there were few subjects ≥65 years of age. Injection Site Reactions of ABILIFY MAINTENA In the data from the short-term, double-blind, placebo-controlled trial with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction (all reported as injection site pain) was 5.4% for patients treated with gluteal administered ABILIFY MAINTENA and 0.6% for placebo. The mean intensity of injection pain reported by subjects using a visual analog scale (0=no pain to 100=unbearably painful) approximately one hour after injection was 7.1 (SD 14.5) for the first injection and 4.8 (SD 12.4) at the last visit in the double-blind, placebo-controlled phase. In an open-label study comparing bioavailability of ABILIFY MAINTENA administered in the deltoid or gluteal muscle, injection site pain was observed in both groups at approximately equal rates. Extrapyramidal Symptoms (EPS) In the short-term, placebo-controlled trial of ABILIFY MAINTENA in adults with schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY MAINTENA-treated patients was 9.6% vs. 5.2% for placebo. The incidence of akathisia-related events for ABILIFY MAINTENA-treated patients was 11.5% vs. 3.5% for placebo. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. In the short-term, placebo-controlled trial of ABILIFY MAINTENA in adults with schizophrenia, the incidence of dystonia was 1.8% for ABILIFY MAINTENA vs. 0.6% for placebo. Neutropenia In the short-term, placebo-controlled trial of ABILIFY MAINTENA in adults with schizophrenia, the incidence of neutropenia (absolute neutrophil count ≤1.5 thous/mcL) for ABILIFY MAINTENA-treated patients was 5.7% vs. 2.1% for placebo. An absolute neutrophil count of <1 thous/mcL (i.e., 0.95 thous/mcL) was observed in only one patient on ABILIFY MAINTENA and resolved spontaneously without any associated adverse events [see Warnings and Precautions (5.9) ]. Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for ABILIFY MAINTENA: Cardiac Disorders: palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, angina pectoris, myocardial ischemia, atrial flutter, supraventricular tachycardia, ventricular tachycardia Eye Disorders: photophobia, diplopia, eyelid edema, photopsia Gastrointestinal Disorders: gastroesophageal reflux disease, swollen tongue, esophagitis, pancreatitis, stomach discomfort, toothache General Disorders and Administration Site Conditions: asthenia, peripheral edema, chest pain, face edema, angioedema, hypothermia, pain Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivity Injury, Poisoning, and Procedural Complications: heat stroke Investigations: blood prolactin decreased, blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, blood lactate dehydrogenase increased, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: anorexia, hyponatremia, hypoglycemia, polydipsia, diabetic ketoacidosis Musculoskeletal and Connective Tissue Disorders: muscle rigidity, muscular weakness, muscle tightness, decreased mobility, rhabdomyolysis, musculoskeletal stiffness, pain in extremity, muscle spasms Nervous System Disorders: coordination abnormal, speech disorder, hypokinesia, hypotonia, myoclonus, akinesia, bradykinesia, choreoathetosis Psychiatric Disorders: loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self-injury, completed suicide, tic, homicidal ideation, catatonia, sleepwalking Renal and Urinary Disorders: urinary retention, polyuria, nocturia Reproductive System and Breast Disorders: menstruation irregular, erectile dysfunction, amenorrhea, breast pain, gynecomastia, priapism Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea, pharyngolaryngeal pain, cough Skin and Subcutaneous Tissue Disorders: rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhidrosis, pruritus, photosensitivity reaction, alopecia, urticaria 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oral aripiprazole or ABILIFY MAINTENA. 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), pathological gambling, hiccups, blood glucose fluctuation, drug reaction with eosinophilia and systemic symptoms (DRESS), and fecal incontinence.

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) ] .

Storage Pre-filled dual chamber syringe: Store below 30°C [86°F]. Do not freeze. Protect the syringe from light by storing in the original package until time of use. Vial: Store at 25°C (77°F), excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].