LYBALVI

1 INDICATIONS AND USAGE LYBALVI is indicated for the treatment of: Schizophrenia in adults Bipolar I disorder in adults Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate Maintenance monotherapy treatment LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, indicated for the treatment of: Schizophrenia in adults ( 1 ) Bipolar I disorder in adults ( 1 ) Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate Maintenance monotherapy treatment

2 DOSAGE AND ADMINISTRATION Indication Recommended Starting Dose (olanzapine/samidorphan) Recommended Dose (olanzapine/samidorphan) Schizophrenia ( 2.2 ) 5 mg/10 mg or 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder (manic or mixed episodes) ( 2.3 ) 10 mg/10 mg or 15 mg/10 mg 5 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder adjunct to lithium or valproate ( 2.3 ) 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg See the full prescribing information for the recommended titration and maximum recommended dosage. ( 2.2 , 2.3 ) Administer LYBALVI once daily with or without food. Do not divide tablets or combine strengths. ( 2.4 ) Recommended starting dosage is 5 mg/10 mg once daily in patients who have a predisposition to hypotensive reactions, have potential for slower metabolism of olanzapine, or may be more pharmacodynamically sensitive to olanzapine. ( 2.5 ) 2.1 LYBALVI Initiation In Patients Using Opioids LYBALVI is contraindicated in patients using opioids or undergoing acute opioid withdrawal. In patients who use opioids, delay initiation of LYBALVI for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids [see Warnings and Precautions ( 5.3 )]. 2.2 Recommended Dosage in Schizophrenia Initiate LYBALVI at 5 mg/10 mg (contains 5 mg of olanzapine and 10 mg of samidorphan) or 10 mg/10 mg (contains 10 mg of olanzapine and 10 mg of samidorphan) orally once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg (contains 15 mg of olanzapine and 10 mg of samidorphan), or 20 mg/10 mg (contains 20 mg of olanzapine and 10 mg of samidorphan) once daily. Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of LYBALVI) depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily. 2.3 Recommended Dosage in Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy: Initiate LYBALVI at 10 mg/10 mg or 15 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily. The maximum recommended dosage is 20 mg/10 mg once daily. Dosage adjustments should occur at intervals of not less than 24 hours. When dosage adjustments are necessary, dose increments/decrements of 5 mg (based on the olanzapine component of LYBALVI) are recommended. Maintenance Monotherapy: Administer LYBALVI at 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily. Adjunctive to lithium or valproate: Initiate LYBALVI at 10 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg or 20 mg/10 mg, once daily. Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of LYBALVI), depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily. 2.4 Administration Information Administer LYBALVI orally once daily with or without food as a single tablet. Do not divide tablets or combine strengths. 2.5 Dosage Recommendations in Specific Populations The recommended starting dosage of LYBALVI is 5 mg/10 mg once daily in patients who have a higher risk of hypotensive reactions, are at risk of slower olanzapine metabolism, or may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.2 ), Use in Specific Populations ( 8.5 ), and Clinical Pharmacology ( 12.3 )] . If dose escalation is necessary, increase the dosage slowly in these patients.

3 DOSAGE FORMS AND STRENGTHS LYBALVI tablets are available in four strengths ( Table 1 ). Table 1: LYBALVI Tablet Strengths and Identifying Features Tablet Strength Tablet Color/Shape Tablet Markings 5 mg/10 mg (olanzapine/samidorphan) Yellow, capsule-shaped “OS” and “5” 10 mg/10 mg (olanzapine/samidorphan) Orange, capsule-shaped “OS” and “10” 15 mg/10 mg (olanzapine/samidorphan) Blue, capsule-shaped “OS” and “15” 20 mg/10 mg (olanzapine/samidorphan) Pink, capsule-shaped “OS” and “20” Tablets (olanzapine/samidorphan): 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg and 20 mg/10 mg. ( 3 )

4 CONTRAINDICATIONS LYBALVI is contraindicated in patients: who are using opioids [ see Warnings and Precautions ( 5.3 , 5.4 ), Drug Interactions ( 7.3 )] . who are undergoing acute opioid withdrawal [see Warnings and Precautions ( 5.3 , 5.4 ), Drug Interactions ( 7.3 )] . If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products [see Warnings and Precautions ( 5.18 )] . Patients using opioids. ( 4 ) Patients undergoing acute opioid withdrawal. ( 4 ) If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for those products. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail 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, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] Precipitation of Opioid Withdrawal in Patients Who Are Dependent on Opioids [see Warnings and Precautions ( 5.3 ) ] Vulnerability to Life-Threatening Opioid Overdose [see Warnings and Precautions ( 5.4 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.5 )] Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions ( 5.6 )] Metabolic Changes [see Warnings and Precautions ( 5.7 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.14 )] Body Temperature Regulation [see Warnings and Precautions ( 5.15 )] Anticholinergic (Antimuscarinic) Effects [see Warnings and Precautions ( 5.16 )] Hyperprolactinemia [see Warnings and Precautions ( 5.17 )] Risks Associated with Combination Treatment with Lithium or Valproate [see Warnings and Precautions ( 5.18 )] Most common adverse reactions (incidence ≥5% and at least twice placebo): Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache. ( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, tremor. ( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine): dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 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 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 clinical practice. Adverse Reactions in Patients with Schizophrenia Patient Exposure The safety of LYBALVI was evaluated in 1262 patients (18 to 67 years of age) diagnosed with schizophrenia in four double-blind, controlled studies and three long-term safety extension studies of up to 3 years of duration. This experience corresponds to approximately 910 person-years. In these studies, there were a total of 663 patients exposed to LYBALVI for at least 6 months, and 386 patients for at least one year. Adverse Reactions in the Short-Term (4 week) Placebo-Controlled Trial in Adults with Schizophrenia The most common adverse reactions (incidence of at least 5% of patients exposed to LYBALVI and greater than twice the rate of placebo) are weight increased, somnolence, dry mouth, and headache. Adverse reactions associated with the use of LYBALVI (incidence of 2% or greater and greater than in placebo-treated patients) are shown in Table 2 . Table 2: Adverse Reactions Reported in ≥2% of LYBALVI-Treated Patients and Greater than Placebo in a 4-Week Schizophrenia Trial Adverse Reaction Placebo (N=134) % LYBALVI (10 mg/10 mg, 20 mg/10 mg) (N=134) % Weight increased 3 19 Somnolence 2 9 Dry mouth 1 7 Headache 3 6 Blood insulin increased 1 3 Sedation 0 2 Dizziness 1 2 Neutrophil count decreased 0 2 Adverse reactions that led to discontinuation in LYBALVI-treated patients in the short-term placebo-controlled trial in adults with schizophrenia incl …

7 DRUG INTERACTIONS Strong CYP3A4 Inducers : Not recommended. ( 7.1 ) Strong CYP1A2 Inhibitors : Consider dosage reduction of olanzapine component of LYBALVI. ( 7.1 ) CYP1A2 Inducer : Consider dosage increase of the olanzapine component of LYBALVI. ( 7.1 ) CNS Acting Drugs : May potentiate orthostatic hypotension. ( 7.1 ) Anticholinergic Drugs: Can increase risk for severe gastrointestinal adverse reactions. ( 7.1 ) Antihypertensive Agents : Monitor blood pressure. ( 7.2 ) Levodopa and Dopamine Agonists : Not recommended. ( 7.2 ) 7.1 Effects of Other Drugs on LYBALVI Table 4 describes clinically significant drug interactions where the concomitant use of other drugs affects LYBALVI. Table 4: Effects of Other Drugs on LYBALVI Strong CYP3A4 Inducer Clinical Implication: Coadministration of LYBALVI with a strong CYP3A4 inducer decreases AUC inf of olanzapine and samidorphan [see Clinical Pharmacology ( 12.3 )], which may reduce LYBALVI efficacy. Prevention or Management: Concomitant use of LYBALVI with strong CYP3A4 inducers is not recommended. Strong CYP1A2 Inhibitor Clinical Implication: Concomitant use of LYBALVI with a strong CYP1A2 inhibitor increases olanzapine AUC and C max [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of LYBALVI adverse reactions. Prevention or Management: Consider reducing the dosage of the olanzapine component in LYBALVI when used concomitantly with strong CYP1A2 inhibitors. CYP1A2 Inducer Clinical Implication: Concomitant use of LYBALVI with CYP1A2 inducers decreases olanzapine exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce LYBALVI efficacy. Prevention or Management: Consider increasing the dosage of the olanzapine component in LYBALVI when used concomitantly with CYP1A2 inducers. Diazepam, Alcohol, and Other CNS Acting Drugs Clinical Implication: Concomitant use of diazepam, alcohol, or other CNS acting drugs with LYBALVI may potentiate the orthostatic hypotension observed with olanzapine [see Warnings and Precautions ( 5.9 )] . Prevention or Management: LYBALVI should be used with caution in patients receiving concomitantly diazepam or other CNS acting drugs, or using alcohol. Anticholinergic Drugs Clinical Implication: Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Prevention or Management: LYBALVI should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions ( 5.16 )] . 7.2 Effects of LYBALVI on Other Drugs Table 5 describes clinically significant drug interactions where concomitant use of LYBALVI affects other drugs. Table 5: Effects of LYBALVI on Other Drugs Antihypertensive Agents Clinical Implication: LYBALVI may enhance the effects of certain antihypertensive agents. Prevention or Management: Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling. Levodopa and Dopamine Agonists Clinical Implication: LYBALVI may antagonize the effects of levodopa and dopamine agonists. Prevention or Management: Concomitant use of LYBALVI is not recommended with levodopa and dopamine agonists. 7.3 Opioids LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal [see Contraindications ( 4 )]. LYBALVI increases the risk of precipitating acute opioid withdrawal in patients who are dependent on opioids. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.3 )] . In emergency situations, if a LYBALVI-treated patient requires opioid treatment for anesthesia or analgesia, discontinue LYBALVI. The opioid should be administered by properly trained individual …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Renal Impairment: Use is not recommended in patients with end-stage renal disease. ( 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including LYBALVI, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/ . Risk Summary Neonates exposed to antipsychotic drugs, including the olanzapine component of LYBALVI, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are no available data on the use of samidorphan or the combination of olanzapine and samidorphan in pregnant women to determine a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including LYBALVI, during pregnancy (see Clinical Considerations ) . LYBALVI In an animal reproduction study, oral administration of olanzapine and samidorphan to pregnant rats during the period of organogenesis produced adverse effects on embryofetal development and fetal toxicity at maternally toxic doses that are 6 times and >400 times the maximum recommended human dose (MRHD) of 20 mg/10 mg olanzapine/samidorphan in LYBALVI, respectively based on AUC. There were no adverse effects on embryofetal development at doses of olanzapine and samidorphan that are approximately 1 and 80 times, respectively, the MRHD based on AUC (see Data ) . Olanzapine In animal reproduction studies, there was no evidence of malformations in rats or rabbits when orally administered olanzapine at doses up to 9 and 30 times the MRHD dose (20 mg) based on mg/m 2 body surface area, respectively. In an oral rat embryofetal developmental toxicity study, early resorptions and increased numbers of nonviable fetuses were observed at a dose 9 times the MRHD based on mg/m 2 body surface area and gestation was prolonged at 5 times the MRHD based on mg/m 2 body surface area. In an oral rabbit embryofetal developmental toxicity study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of olanzapine which is 30 times the MRHD based on mg/m 2 body surface area (see Data ) . Samidorphan In animal reproduction studies, oral administration of samidorphan to pregnant rats and rabbits during the period of organogenesis caused fetal toxicities in rats only at maternally toxic doses that are >248 times the human exposure at the MRHD of 10 mg/day based on AUC. Oral administration of samidorphan to pregnant rats during pregnancy and lactation resulted in lower pup survival and decreased pup weights at 188 times the human exposure at the MRHD based on AUC (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk There is risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization and suicid …

12.1 Mechanism of Action The mechanism of action of olanzapine is unclear; however, its efficacy in the treatment of schizophrenia or bipolar I disorder could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism. The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.

11 DESCRIPTION LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan (as samidorphan L-malate), an opioid antagonist. Olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H -thieno[2,3- b ][1,5]benzodiazepine. The molecular formula of olanzapine is: C 17 H 20 N 4 S and the molecular weight is 312.44 g/mol. It is a yellow crystalline powder and has pKa values of 7.80 and 5.44. The chemical structure is: Samidorphan L-malate is morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4, 14-dihydroxy-6-oxo-, (2S)-2-hydroxybutanedioate. The molecular formula of samidorphan L-malate is C 21 H 26 N 2 O 4 • C 4 H 6 O 5 and the molecular weight is 504.54 g/mol. It is a white to off-white crystalline powder and has pKa values of 8.3 (amine) and 10.1 (phenol). The chemical structure is: LYBALVI is intended for oral administration and is available as film-coated, bilayer tablets in the following strengths: 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg of olanzapine and samidorphan (equivalent to 13.6 mg of samidorphan L-malate). Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating ingredients include hypromellose, titanium dioxide, triacetin, and color additives [iron oxide yellow (5 mg/10 mg); iron oxide yellow and iron oxide red (10 mg/10 mg); FD&C Blue No. 2/ indigo carmine aluminum lake (15 mg/10 mg); iron oxide red (20 mg/10 mg)]. Olanzapine Chemical Structure Samidorphan L-malate Chemical Structure

10 OVERDOSAGE Human Experience There is limited clinical experience with overdose with LYBALVI. In premarketing clinical trials of LYBALVI involving 861 patients, overdose of LYBALVI was identified in 7 patients. This included 4 patients with accidental overdose, 2 with intentional overdose, and 1 due to a medication administration error. None of the reported overdoses was associated with a fatal outcome. There was a reported ingestion of 11 tablets of LYBALVI 10 mg/10 mg (5.5 times and 11 times the maximum recommended daily dosage of the olanzapine and samidorphan components of LYBALVI, respectively). The patient was found unresponsive and admitted to the hospital. Medical treatment included fluids, electrolytes, a diuretic, and a detoxicant; the patient stabilized within 2 days. In postmarketing reports of overdose with olanzapine, a component of LYBALVI, symptoms included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Less commonly reported symptoms include: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2,000 mg. Management of Overdose No specific antidotes for LYBALVI are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a certified Poison Control Center (1-800-222-1222) for additional overdosage management recommendations.

16 HOW SUPPLIED/ STORAGE AND HANDLING How Supplied LYBALVI (olanzapine and samidorphan) tablets have markings on both sides and are available as described in Table 9 . Table 9: LYBALVI Tablet Presentations Tablet Strength(s) (olanzapine/samidorphan) Tablet Description Package Configuration NDC Number 5 mg/10 mg Yellow, capsule-shaped, debossed with “OS” on one side and “5” on the other side 30-count bottle with child resistant closure 65757-651-42 10 mg/10 mg Orange, capsule-shaped, debossed with “OS” on one side and “10” on the other side 30-count bottle with child resistant closure 65757-652-42 15 mg/10 mg Blue, capsule-shaped, debossed with “OS” on one side and “15” on the other side 30-count bottle with child resistant closure 65757-653-42 20 mg/10 mg Pink, capsule-shaped, debossed with “OS” on one side and “20” on the other side 30-count bottle with child resistant closure 65757-654-42 Storage and Handling Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep tightly closed and protect from moisture.