DRUG INTERACTIONS

7.1. Drugs Having Clinically Important Interactions with ARISTADA Table 10: Clinically Important Drug Interactions with ARISTADA Concomitant Drug Name or Drug Class Clinical Rationale

Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The 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)].

With concomitant use of ARISTADA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 2 weeks reduce the ARISTADA dose [see Dosage and Administration

(2.4)]. Strong CYP3A4 The concomitant use of oral With concomitant use of ARISTADA Inducer (e.g., aripiprazole and carbamazepine with a strong CYP3A4 inducer for carbamazepine, decreased the exposure of aripiprazole more than 2 weeks consider rifampin) compared to the use of oral aripiprazole alone [see Clinical Pharmacology

(12.3)]. increasing the ARISTADA dose [see Dosage and Administration (2.4)]. Antihypertensive Drugs Due 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 (5.6)]. Benzodiazepines The intensity of sedation was greater Monitor sedation and blood pressure. (e.g., lorazepam) 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 (5.6)]. Adjust dose accordingly.

7.2. Drugs Having No Clinically Important Interactions with ARISTADA Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ARISTADA is required when administered concomitantly with famotidine, valproate, 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.

Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, or sertraline when co-administered with ARISTADA [see Clinical Pharmacology (12.3)]. 18 Reference ID: 3829516

8. USE IN SPECIFIC POPULATIONS 8.1. Pregnanc

28/15    TRESIBA

Name of the Drug-   ARISTADA

Active Ingredient-      Aripiprazole Lauroxil

Indication-                  To treat adults with schizophrenia                                                                            

Date                              10/5/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use ARISTADA™ safely and effectively.

See full prescribing information for ARISTADA™ . ARISTADA™ (aripiprazole lauroxil) extended-release injectable suspension, for intramuscular use

Initial U.S. Approval: 2015

WARNING:

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS-

See full prescribing information for complete boxed warning.

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. (5.1) • ARISTADA is not approved for the treatment of patients with dementia-related psychosis. (5.1) __________________

INDICATIONS AND USAGE -

ARISTADA is an atypical antipsychotic indicated for the treatment of schizophrenia (1).

 DOSAGE AND ADMINISTRATION

? To be administered by intramuscular injection in the deltoid (441 mg dose only) or gluteal (441 mg, 662 mg or 882 mg) muscle by a healthcare professional (

2.1). ? For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA

(2.1). ? ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly or 882 mg dose every 6 weeks

(2.1). ? In conjunction with the first ARISTADA injection, administer treatment with oral aripiprazole for 21 consecutive days

(2.1). ? Dosing regimen adjustments may be required for missed doses (2.2). ? Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than 2 weeks (2.4).

______________ _____________ DO

ADVERSE REACTIONS-

 Most commonly observed adverse reaction with ARISTADA (incidence =5% and at least twice that for placebo) was akathisia

 CONTRAINDICATIONS-

 Known hypersensitivity to aripiprazole

 WARNINGS AND PRECAUTIONS

 Cerebrovascular Adverse Reactions in Elderly Patients with Dementia Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemia 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: Monitor for hyperglycemia, dyslipidemia, and weight gain

(5.5). ? Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope

(5.6). ? Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors

(5.7). ? Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold

(5.8). ? Potential for Cognitive and Motor Impairment: Use caution when operating machinery

PATIENT COUNSELING INFORMATION -

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

Neuroleptic Malignant Syndrome Counsel patients about a potentially fatal adverse reaction referred to as NMS that has been reported in association with administration of antipsychotic drugs.

Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS [see Warnings and Precautions (5.3)].

Tardive Dyskinesia Advise patients that abnormal involuntary movements have been associated with administration of antipsychotic drugs

. Counsel patients to notify their healthcare provider if they notice any movements which they cannot control in their face, tongue, or other body part [see Warnings and Precautions

(5.4)]. Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)].

Orthostatic Hypotension Educate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing), particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.6)].

Leukopenia/ Neutropenia Advise patients with a pre-existing low WBC count or a history of drug-induced leucopenia/neutropenia that they should have their CBC monitored while receiving ARISTADA [see Warnings and Precautions (5.7)].

Interference with Cognitive and Motor Performance Because ARISTADA may have the potential to impair judgment, thinking or motor skills, instruct patients to be cautious about operating hazardous machinery, including automobiles, until they are reasonably certain that ARISTADA therapy does not affect them adversely [see Warnings and

Precautions (5.9)]. 31 Reference ID: 3829516 Heat Exposure and Dehydration Advise patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.10)].

Concomitant Medication Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)].

Pregnancy Advise patients that ARISTADA may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA during pregnancy [see Use in

Specific Populations (8.1)]. For additional information, visit www.ARISTADA.com or call 1-866-274-7823

Manufactured and marketed by: Alkermes, Inc. 852 Winter Street Waltham, MA 02451-1420 ©2015 Alkermes, Inc. All rights r

CLINICAL PHARMACOLOGY

Mechanism of Action ARISTADA is a prodrug of aripiprazole. Following intramuscular injection, ARISTADA is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole, which is then hydrolyzed to aripiprazole. The mechanism of action of aripiprazole in the body is unknown.

However, efficacy could be mediated through a combination of partial agonist activity D2 and 5 HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5 HT1A, and 5-HT2A could explain some of the adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

12.2. Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors (Ki values 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Ki values 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki =98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000 nM). Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.

12.3. Pharmacokinetics ARISTADA is a prodrug of aripiprazole and its activity in the body is primarily due to aripiprazole, and to a lesser extent dehydro-aripiprazole (major metabolite of aripiprazole), which has been shown to have affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma.

Absorption and Distribution After single intramuscular injection the appearance of aripiprazole in the systemic circulation starts from 5 to 6 days and continues to be released for an additional 36 days. Aripiprazole 22 Reference ID: 3829516 concentrations increase with consecutive doses of ARISTADA and reach steady-state following the fourth monthly injection.

The concentration-time course of dehydro-aripiprazole followed that of aripiprazole. With the addition of oral aripiprazole supplementation for 21 days at the time of the first ARISTADA dose, aripiprazole concentrations reach therapeutic levels within 4 days. Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of ARISTADA was 268 L, indicating extensive extravascular distribution following absorption. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 mg/day to 30 mg/day oral aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans. Aripiprazole exposure was similar for deltoid and gluteal intramuscular injections of 441 mg ARISTADA, thus are interchangeable. Administration of 882 mg every 6 weeks results in plasma aripiprazole concentrations that are within the established therapeutic range for 441 to 882 mg monthly

. Metabolism and Elimination The biotransformation of ARISTADA likely involves enzyme-mediated hydrolysis to form N-hydroxymethyl-aripiprazole, which subsequently undergoes water mediated hydrolysis to aripiprazole. Elimination of aripiprazole is mainly through hepatic metabolism involving CYP3A4 and CYP2D6

. Dosage adjustments are recommended in CYP2D6 poor metabolizers due to high aripiprazole concentrations [see Dosage and Administration (2.4)]. The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of ARISTADA 441, 662 and 882 mg. The significantly longer aripiprazole apparent half-life compared to oral aripiprazole (mean 75 hours) is attributed to the dissolution and formation rate-limited elimination of aripiprazole following ARISTADA administration.

Drug Interaction Studies No specific drug interaction studies have been performed with ARISTADA. The drug interaction data provided below is obtained from studies with oral aripiprazole. Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors.

After oral administration, a 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors. 23 Reference ID: 3829516 Figure 1: The Effects of Other Drugs on Aripiprazole Pharmacokinetics Figure 2:

The Effects of Other Drugs on Dehydro-aripiprazole Pharmacokinetics 24 Reference ID: 3829516 The effects of aripiprazole on the exposures of other drugs are summarized in Figure 3. Figure 3: The Effects of Oral Aripiprazole on Pharmacokinetics of Other Drugs

Specific Population Studies A population pharmacokinetic analysis showed no effect of sex, race or smoking on ARISTADA pharmacokinetics [see Use in Specific Populations (8.8)]. Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in Figure 4 and Figure 5, respectively. 25 Reference ID: 3829516 Figure 4: Effects of Intrinsic Factors on Aripiprazole Pharmacokinetics Figure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics 26 Reference ID: 3829516

USE IN SPECIFIC POPULATIONS

8.1. Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/

. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage.

No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to 6 and 18 times, respectively, the maximum recommended human dose (MRHD) of 882 mg based on body surface area (mg/m2). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data].

The background risk of major birth defects and miscarriage for the indicated population are unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Clinical Considerations

Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization.

Data Animal Data for Aripiprazole Lauroxil Aripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.7 to 6 times the maximum recommended human dose (MRHD) of 882 mg on mg/m2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 1 to 18 times the MRHD on mg/m2 basis.

However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data below]. 19 Reference ID: 3829516 Animal Data for Aripiprazole Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately 1 to 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight, and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m2 basis.

At 3 and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on mg/m2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD on mg/m2 basis of aripiprazole during the period of organogenesis decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the oral MRHD based on AUC. In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 times the oral MRHD on mg/m2 basis of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.

8.2. Lactation Risk Summary Aripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARISTADA and any potential adverse effects on the breastfed infant from ARISTADA or from the underlying maternal condition.

8.4. Pediatric Use Safety and effectiveness of ARISTADA in patients <18 years of age have not been evaluated.

8.5. Geriatric Use Safety and effectiveness of ARISTADA in patients >65 years of age have not been evaluated. 20 Reference ID: 3829516 8.6. CYP2D6 Poor Metabolizers Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations.

Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.7. Hepatic and Renal Impairment No dosage adjustment for ARISTADA is required based on a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)]. 8.8. Other Specific Populations No dosage adjustment for ARISTADA is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.3)]. 10.

10.1. OVERDOSAGE-

Human Experience The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor.

Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

10.2. Management of Overdosage In case of overdosage, call the Poison control center immediately at 1-800-222-1222.