ARISTADA INITIO

ARISTADA INITIO contains aripiprazole lauroxil, an atypical antipsychotic. The chemical name of aripiprazole lauroxil is 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate. The empirical formula is C 36 H 51 Cl 2 N 3 O 4 and its molecular weight is 660.7 g/mol. The chemical structure is: ARISTADA INITIO is available as a white to off-white sterile aqueous extended-release injectable suspension for intramuscular injection in the following strength of aripiprazole lauroxil (and deliverable volume from a single-dose pre-filled syringe): 675 mg (2.4 mL). This product's specific extended-release and dosing characteristics are derived from aripiprazole lauroxil's submicron particle size distribution. The inactive ingredients include polysorbate 20 (16.2 mg/mL), sodium chloride (3.3 mg/mL), sodium citrate dihydrate (8.1 mg/mL), sodium phosphate dibasic anhydrous (0.74 mg/mL), sodium phosphate monobasic dihydrate (0.84 mg/mL) and water for injection. Figure

ARISTADA INITIO, in combination with oral aripiprazole, is indicated for the initiation of ARISTADA when used for the treatment of schizophrenia in adults. ARISTADA INITIO, in combination with oral aripiprazole, is indicated for the initiation of ARISTADA ® when used for the treatment of schizophrenia in adults ( 1 ).

Administer one 675 mg injection of ARISTADA INITIO and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection ( 2.1 ). ARISTADA INITIO is only to be used as a single dose and is not for repeated dosing ( 2.1 ). Administer ARISTADA INITIO by intramuscular injection in either the deltoid or gluteal muscle by a healthcare professional ( 2.1 ). For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA INITIO ( 2.1 ). See Dosage and Administration for detailed preparation and administration instructions ( 2.4 ). Avoid use in known CYP2D6 poor metabolizers ( 2.3 , 7.1 ). Avoid use with strong CYP2D6 or CYP 3A4 inhibitors and strong CYP3A4 inducers ( 2.3 , 7.1 ). ARISTADA INITIO is not interchangeable with ARISTADA ( 2.1 , 5.3 ). 2.1 Recommended Dosage ARISTADA INITIO is only to be used as a single dose to initiate ARISTADA treatment or as a single dose to re-initiate ARISTADA treatment following a missed dose of ARISTADA. ARISTADA INITIO is not for repeated dosing. ARISTADA INITIO is not interchangeable with ARISTADA due to differing pharmacokinetic profiles [see Warnings and Precautions ( 5.3 )] . ARISTADA INITIO is to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA INITIO. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation. After establishing tolerability with oral aripiprazole, administer the first ARISTADA intramuscular injection (441 mg, 662 mg, 882 mg, or 1064 mg) in conjunction with both: One 675 mg injection of ARISTADA INITIO in the deltoid or gluteal muscle (which corresponds to 459 mg of aripiprazole) [see Clinical Pharmacology ( 12.3 )]; and One 30 mg dose of oral aripiprazole. The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA prescribing information for additional information regarding dosage and administration of ARISTADA. Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle. 2.2 Missed Doses of ARISTADA ARISTADA INITIO may be used to re-initiate treatment with ARISTADA following a missed dose of ARISTADA. When a dose of ARISTADA is missed, administer the next injection of ARISTADA as soon as possible. Depending on the time elapsed since the last ARISTADA injection, supplement the next ARISTADA injection as recommended in Table 1 below. Table 1: Recommendation for Concomitant Supplementation Following Missed Doses of ARISTADA Dose of Patient's Last ARISTADA Injection Length of Time Since Last Injection 441 mg ≤ 6 weeks > 6 and ≤ 7 weeks > 7 weeks 662 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks 882 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks 1064 mg ≤ 10 weeks > 10 and ≤ 12 weeks > 12 weeks Dosage and Administration for Re-initiation of ARISTADA No Supplementation Required Supplement with a Single Dose of ARISTADA INITIO Re-initiate with a Single Dose of ARISTADA INITIO and a Single Dose of Oral Aripiprazole 30 mg 2.3 Dose Adjustments for CYP450 Considerations ARISTADA INITIO is only available at a single strength as a single-dose pre-filled syringe, so dosage adjustments are not possible. Therefore, avoid use in patients who are known CYP2D6 poor metabolizers or taking strong CYP3A4 inhibitors, strong CYP2D6 inhibitors, or strong CYP3A4 inducers. 2.4 Important Administration Instructions The kit contains a syringe containing ARISTADA INITIO sterile aqueous extended-release injectable suspension and 3 safety needles (a 2-inch 20 gauge needle with yellow needle hub, a 1 ½-inch 20 gauge needle with yellow needle hub, and a 1-inch 21 gauge needle with green needle hub) for intramuscular injection. Store all materials at room temperature. A | 5 mL syringe containing 675 mg/2.4 mL ARISTADA INITIO sterile aqueous extended-release injectable suspension B | 20 gauge needle, 2-inch with yellow needle hub C | 20 gauge needle, 1½-inch with yellow needle hub D | 21 gauge needle, 1-inch with green needle hub 1. TAP and vigorously SHAKE the syringe. 1a. Tap the syringe at least 10 times to dislodge any material which may have settled. 1b. Shake the syringe vigorously for a minimum of 30 seconds to ensure a uniform suspension. If the syringe is not used within 15 minutes, shake again for 30 seconds. 2. SELECT the injection needle. 2a. Select injection site. 2b. Select needle length based on injection site. For patients with a larger amount of subcutaneous tissue overlaying the injection site muscle, use the longer of the needles provided. Table 2: ARISTADA INITIO Injection Site and Associated Needle Length Injection Site Needle Length 675 mg dose Deltoid 21 gauge, 1-inch or 20 gauge, 1½-inch Gluteal 20 gauge, 1½-inch or 20 gauge, 2-inch 3. ATTACH the injection needle. Attach the appropriate needle securely with a clockwise twisting motion. Do NOT overtighten. Overtightening could lead to needle hub cracking. 4. PRIME the syringe to remove air. 4a. Bring the syringe into upright position and tap the syringe to bring air to the top. 4b. Depress the plunger rod to remove air until a few drops are released. It is normal to see small air bubbles remaining in the syringe. 5. Inject in a RAPID and CONTINUOUS manner. Product requires a RAPID injection. Do not hesitate. Administer the entire content intramuscularly. Do not inject by any other route. 6. DISPOSE of the needle. Cover the needle by pressing the safety device. Dispose of used and unused items in a proper waste container. Figure Figure Figure Figure Figure Figure Figure Figure

ARISTADA INITIO is contraindicated in patients with a known hypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions ( 6 )]. Known hypersensitivity to aripiprazole ( 4 ).

The following are discussed in more details in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-related Psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke [see Boxed Warning , Warnings and Precautions ( 5.2 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.4 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.5 )] Metabolic Changes [see Warnings and Precautions ( 5.6 )] Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions ( 5.7 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.8 )] Falls [see Warnings and Precautions ( 5.9 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.12 )] Body Temperature Regulation [see Warnings and Precautions ( 5.13 )] Dysphagia [see Warnings and Precautions ( 5.14 )] Most commonly observed adverse reaction (incidence ≥5% and at least twice that for placebo) was akathisia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Alkermes, Inc. at 1-866-274-7823 or FDA at 1-800-FDA-1088 or WWW.FDA.GOV/MEDWATCH. 6.1 Clinical Studies 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 ARISTADA INITIO, in combination with oral aripiprazole, for the initiation of ARISTADA when used for the treatment of schizophrenia in adults has been established and is based on clinical trials of ARISTADA (aripiprazole lauroxil) including 1019 adult patients with schizophrenia. Patient Exposure ARISTADA INITIO has been evaluated for safety in 170 adult patients in clinical trials in schizophrenia. In pharmacokinetic studies, the safety profile of ARISTADA INITIO was generally consistent with that observed for ARISTADA. ARISTADA (Aripiprazole Lauroxil) Trials in Adults with Schizophrenia Commonly Observed Adverse Reactions with Aripiprazole Lauroxil The most common adverse reaction (incidence ≥5% and at least twice the rate of placebo in patients treated with aripiprazole lauroxil) was akathisia. Adverse Reactions Occurring at an Incidence of 2% or More in Aripiprazole Lauroxil-Treated Patients Adverse reactions associated with the use of aripiprazole lauroxil (incidence of 2% or greater, rounded to the nearest percent and aripiprazole lauroxil incidence greater than placebo) that occurred were: injection site pain, increased weight, increased blood creatinine phosphokinase, akathisia, headache, insomnia, and restlessness. Injection Site Reactions ARISTADA INITIO In pharmacokinetic studies evaluating ARISTADA INITIO, the incidences of injection site reactions with ARISTADA INITIO were similar to the incidence observed with aripiprazole lauroxil. ARISTADA (Aripiprazole Lauroxil) Injection site reactions were reported by 4% of patients treated with 441 mg aripiprazole lauroxil and 5% of patients treated with 882 mg aripiprazole lauroxil compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg aripiprazole lauroxil, 882 mg aripiprazole lauroxil and placebo groups, respectively). Other injection site reactions (induration, swelling and redness) occurred at less than 1%. Extrapyramidal Symptoms In a schizophrenia efficacy study in aripiprazole lauroxil-treated patients, the incidence of other EPS-related events, excluding akathisia and restlessness, was 5% and 7% for patients on 441 mg and 882 mg, respectively, versus 4% for placebo-treated patients. 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. Other Adverse Reactions Observed in Clinical Studies with Aripiprazole Lauroxil 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. Cardiac – angina pectoris, tachycardia, palpitations Gastrointestinal disorders – constipation, dry mouth General disorders – asthenia Musculoskeletal – muscular weakness Nervous system disorders – dizziness Psychiatric disorders – anxiety, suicide 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 ARISTADA INITIO or aripiprazole lauroxil. Blood and Lymphatic System Disorders: thrombocytopenia Cardiac Disorders: bradycardia, atrial flutter, cardiorespiratory arrest, atrioventricular block, atrial fibrillation, myocardial ischemia, myocardial infarction, cardiopulmonary failure Eye Disorders: photophobia, diplopia Gastrointestinal Disorders: gastroesophageal reflux disease General Disorders and Administration Site Conditions: peripheral edema, chest pain, face edema Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivity Injury, Poisoning, and Procedural Complications: fall, heat stroke Investigations: blood prolactin decreased, weight decreased, hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased, blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: anorexia, hypokalemia, hyponatremia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: muscle tightness, rhabdomyolysis, mobility decreased Nervous System Disorders: memory impairment, cogwheel rigidity, hypokinesia, bradykinesia, akinesia, myoclonus, coordination abnormal, speech disorder, choreoathetosis Psychiatric Disorders: aggression, loss of libido, delirium, libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking Renal and Urinary Disorders: urinary retention, nocturia Reproductive System and Breast Disorders: erectile dysfunction, gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia, urticaria Vascular Disorders: hypotension, hypertension 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to 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, oculogyric crisis, drug reaction with eosinophilia and systemic symptoms (DRESS), and fecal incontinence.

7.1 Drugs Having Clinically Important Interactions with ARISTADA INITIO Table 4: Clinically Important Drug Interactions with ARISTADA INITIO Strong CYP3A4 Inhibitors and CYP2D6 Inhibitors Clinical Impact: Concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of ARISTADA INITIO with strong CYP3A4 or strong CYP2D6 inhibitors because the dosage of ARISTADA INITIO cannot be modified [see Dosage and Administration ( 2.3 )]. Examples: itraconazole, clarithromycin, quinidine, fluoxetine, paroxetine Strong CYP3A4 Inducers Clinical Impact: Concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of oral aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. Intervention: Avoid concomitant use of ARISTADA INITIO with strong CYP3A4 inducers because the dosage of ARISTADA INITIO cannot be modified [see Dosage and Administration ( 2.3 )]. Examples: carbamazepine, rifampin Antihypertensive Drugs Clinical Impact: Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Intervention: Avoid concomitant use of ARISTADA INITIO with antihypertensive drugs because the dosage of ARISTADA INITIO cannot be modified [see Warnings and Precautions ( 5.8 )]. Examples: carvedilol, lisinopril, prazosin Benzodiazepines Clinical Impact: 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 ( 5.8 )]. Intervention: Avoid concomitant use of ARISTADA INITIO with benzodiazepines because the dosage of ARISTADA INITIO cannot be modified [see Warnings and Precautions ( 5.8 )]. Example: lorazepam 7.2 Drugs Having No Clinically Important Interactions with ARISTADA INITIO Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ARISTADA INITIO is required when administered concomitantly with famotidine, valproate, or lithium [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, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with ARISTADA INITIO. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, or sertraline when co-administered with ARISTADA INITIO [see Clinical Pharmacology ( 12.3 )] .

16.2 Storage Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (between 59°F and 86°F). Do not freeze.