HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LYBALVI™ safely and effectively. See full prescribing information for LYBALVI™.

LYBALVI™ (olanzapine and samidorphan) tablets, for oral use Initial U.S. Approval: 2021

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Seefull prescribing informationfor complete boxed warning.

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

-------------------------------INDICATIONS AND USAGE ------------------------------

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)

o    Acute treatment of manic or mixed episodes as monotherapy and as

adjunct to lithium or valproate

o    Maintenance monotherapy treatment

--------------------------DOSAGE AND ADMINISTRATION-------------------------

•   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)

------------------------ DOSAGE FORMS AND STRENGTHS------------------------

T ablets (olanzapine/samidorphan):  5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg

and 20 mg/10 mg. (3)

----------------------------------CONTRAINDICATIONS  --------------------------------

•   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)

-------------------------- WARNINGS AND PRECAUTIONS --------------------------

•  Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-

Related Psychosis: Increased incidence of cerebrovascular  adverse

reactions (e.g., stroke, transient ischemic attack, including fatalities). (5.2)

•  Precipitation of Opioid Withdrawal in Patients Who are Dependent on

Opioids: LYBALVI can precipitate 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 to avoid precipitation of opioid withdrawal. (2.1, 5.3)

•  Vulnerability to Life-Threatening Opioid Overdose:

o   Risk of Opioid Overdose from Attempts to Overcome LYBALVI Opioid

Blockade:Attempts to overcome LYBALVI opioid blockade with high or repeated doses of opioids may lead to fatal opioid intoxication,

particularly if LYBALVI therapy is interrupted or discontinued. (5.4) o   Risk of Resuming Opioids in Patients with Prior Opioid Use: Patients with a history of chronic opioid use prior to LYBALVI treatment may have decreased  opioid tolerance if LYBALVI therapy is interrupted or

discontinued. (5.4)

•  Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.5)

•  Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):

Discontinue if DRESS is suspected. (5.6)

•  Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. (5.7)

•  Tardive Dyskinesia: Discontinue if clinically appropriate. (5.8)

•  Orthostatic Hypotension and Syncope: Monitor heart rate and blood

pressure and warn patients with known cardiovascular or cerebrovascular

disease, and risk of dehydration or syncope. (5.9)

•  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. (5.11)

•  Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.13)

•  Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.14)

•  Anticholinergic (Antimuscarinic) Effects:Use with caution with other

anticholinergic drugs and in patients with urinary retention, prostatic

hypertrophy, constipation, paralytic ileus or related conditions. (5.16)

•  Hyperprolactinemia: May elevate prolactin levels. (5.17)

----------------------------------ADVERSE REACTIONS----------------------------------

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):asthenia, dry

mouth, constipation, increased appetite, somnolence, dizziness, tremor.

(6.1)

•  Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine):dry mouth, dyspepsia, 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.

---------------------------------- 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)

-------------------------- 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)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 5/2021

1

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

1            INDICATIONS AND USAGE

2            DOSAGE AND ADMINISTRATION

2.1       LYBALVI Initiation In Patients Using Opioids

2.2       Recommended Dosage in Schizophrenia

2.3       Recommended Dosage in Bipolar I Disorder (Manic or Mixed

Episodes)

2.4       Administration Information

2.5       Dosage Recommendations in Specific Populations

3            DOSAGE FORMS AND STRENGTHS

4            CONTRAINDICATIONS

5            WARNINGS AND PRECAUTIONS

5.1       Increased Mortality in Elderly Patients with Dementia-Related Psychosis

5.2       Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related  Psychosis

5.3       Precipitation of Severe Opioid Withdrawal in Patients Who Are Physiologically Dependent on Opioids

5.4       Vulnerability to Life-T hreatening  Opioid Overdose

5.5       Neuroleptic Malignant Syndrome

5.6       Drug Reaction with Eosinophilia and Systemic Symptoms

5.7       Metabolic Changes

5.8       T ardive Dyskinesia

5.9       Orthostatic Hypotension and Syncope

5.10    Falls

5.11    Leukopenia, Neutropenia, and Agranulocytosis

5.12    Dysphagia

5.13    Seizures

5.14    Potential for Cognitive and Motor Impairment

5.15    Body T emperature Dysregulation

5.16    Anticholinergic (Antimuscarinic) Effects

5.17    Hyperprolactinemia

5.18    Risks Associated with Combination T reatment with Lithium or Valproate

6            ADVERSE REACTIONS

6.1       Clinical Studies Experience

6.2       Postmarketing Experience

7            DRUG INTERACTIONS

7.1       Effects  of Other Drugs on LYBALVI

7.2       Effects  of LYBALVI on Other Drugs

7.3       Opioids

8            USE IN SPECIFIC POPULATIONS

8.1       Pregnancy

8.2       Lactation

8.3       Females and Males of Reproductive Potential

8.4       Pediatric Use

8.5       Geriatric Use

8.6       Hepatic Impairment

8.7       Renal Impairment

10         OVERDOSAGE

11         DESCRIPTION

12         CLINICAL PHARMACOLOGY

12.1    Mechanism of Action

12.2    Pharmacodynamics

12.3    Pharmacokinetics

13         NONCLINICAL TOXICOLOGY

13.1    Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2    Animal T oxicology and/or Pharmacology

14         CLINICAL STUDIES

14.1    Schizophrenia

14.2    Bipolar I Disorder

16         HOW SUPPLIED/ STORAGE AND HANDLING

17         PATIENT COUNSELING INFORMATION

*  Sections or subsections omitted from the full prescribing information are not listed.

2

Elde rly patie nts with de me ntia-re late d psychosis tre ated with antipsychotic drugs are at an incre ase d risk of de ath. LYBALVI is not approve d for the tre atme nt of patie nts with de me ntia-re late d psychosis[seeWarnings and Precautions(5.1)].

1                                INDICATIONS AND USAGE

LYBALVI is indicated for the treatment of:

•      Schizophrenia  in adults

•      Bipolar I disorder in adults

o        Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium  or valproate

o        Maintenance monotherapy treatment

2                                DOSAGE AND ADMINISTRATION

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  [seeWarnings andPrecautions(5.3)].

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.

3

Monothe rapy: 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.

Maintena nc e Monothe rapy: Administer LYBALVI at 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily.

Adjunc tive  to lithium  or va lproa te: 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.

Administer LYBALVI orally once daily with or without food as a single tablet. Do not divide tablets or combine strengths.

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  [seeWarnings and Precautions(5.9),DrugInteractions(7.2),Use in Specific Populations(8.5), andClinical Pharmacology(12.3)]. If dose escalation is necessary, increase the dosage slowly in these patients.

LYBALVI tablets are available in four strengths (Table 1).

4

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[seeWarnings 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 [seeWarnings andPrecautions(5.18)].

Elderly patients with dementia-related psychosis treated with antipsychotic  drugs are at an increased risk of death. In placebo-controlle d  clinical trials of elderly patients with dementia- related psychosis, the incidence of death in olanzapine-treated patients was significantly  greater than in placebo-treated patients (3.5% vs 1.5%, respectively). Analyses of 17 placebo-controlle d trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic  drugs,

revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in

placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in

drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)  in nature.

LYBALVI is not approved for the treatment of patients with dementia-related psychosis

[seeWarnings and Precautions(5.2)].

5.2                        Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including  fatalities, were reported in patients in trials of olanzapine  in elderly patients with dementia-related psychosis. In placebo-controlle d  trials, there was a significantly  higher incidence of

cerebrovascular adverse reactions in patients treated with olanzapine  compared to patients

treated with placebo. LYBALVI is not approved for the treatment of patients with dementia- related psychosis[seeWarnings and Precautions(5.1)].

Samidorphan, an opioid  antagonist that is a component of LYBALVI, can precipitate opioid withdrawal in patients who are dependent on opioids,  which can lead to an opioid  withdrawal syndrome, sometimes requiring hospitalization.  Therefore, LYBALVI is contraindicated in

5

patients who are using opioids  or undergoing  acute opioid  withdrawal. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from last use of short-acting opioids,  and at least a 14-day opioid-free interval from the last use of long-acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving  an accurate account of last opioid use to patients and caregivers [seeDosage and Administration(2.1),Drug Interactions(7.3)].

Risk of Opioid Ove rdose from Attempts to Ove rcome Samidorpha n Bloc ka de

LYBALVI contains samidorphan, an opioid  antagonist. Attempting to overcome LYBALVI’s opioid blockade with high or repeated doses of exogenous opioids  (e.g., because of ineffective analgesia or opioid  withdrawal symptoms) could lead to life-threatening  or fatal opioid intoxication (e.g., respiratory arrest, circulatory collapse), particularly if LYBALVI therapy is interrupted or discontinued,  subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes. Inform patients of the potential consequences of trying to overcome the opioid  blockade and the serious risks of taking opioids  concurrently with LYBALVI or while transitioning  off LYBALVI.

In emergency situations, if a LYBALVI-treated patient requires opioid treatment as part of anesthesia or analgesia:

•      Discontinue LYBALVI,

•      Opioids should be administered by individua l(s)  trained in the use of anesthetic drugs and the management of the respiratory effects of opioids,  specifically the

establishment and maintenance of a patent airway and assisted ventilation, and

•      Appropriately  trained personnel should continuously  monitor  the patient in a setting equipped and staffed for cardiopulmonary  resuscitation.

For recommendations on starting opioids  in LYBALVI-treated patients in non-emergent situations,seeDrug Interactions(7.3).

Risk of Resuming Opioids  in Patients with Prior Opioid  Use

Patients with a history of chronic opioid  use prior to treatment with LYBALVI may have

decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued.  Advise patients

that this decreased tolerance may increase the risk of opioid overdose if opioids  are resumed at the previously tolerated dosage.

Neuroleptic Malignant Syndrome (NMS), a potentially  fatal symptom complex, has been reported in association with administration  of antipsychotic drugs. Clinical manifestations  of NMS are hyperpyrexia, muscle rigidity,  delirium,  and autonomic instability.  Additional  signs may include elevated creatine phosphokinase,  myoglobinuria  (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately  discontinue  LYBALVI and provide intensive symptomatic treatment and monitoring.

6

Drug Reaction with Eosinophilia  and Systemic Symptoms (DRESS) has been reported with exposure to olanzapine,  a component of LYBALVI [seeAdverse Reactions(6.2)]. DRESS may present with a cutaneous reaction (such as rash or exfoliative  dermatitis), eosinophilia , fever, and/or lymphadenopathy  with systemic complications  such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue LYBALVI if DRESS is suspected.

Atypical antipsychotic  drugs, including  LYBALVI, have been associated with metabolic changes that include hyperglycemia,  diabetes mellitus, dyslipidemia , and body weight gain [seeAdverseReactions(6.1)].While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia  including polydipsia , polyuria, polyphagia ,  and weakness. Patients who develop symptoms of hyperglycemia  during treatment with LYBALVI should undergo fasting blood glucose testing. In some cases, hyperglycemia  has resolved when the atypical antipsychotic was discontinued;  however, some patients required anti-diabetic  treatment despite discontinuation  of the suspect drug. Patients starting treatment with LYBALVI should undergo fasting blood glucose testing at the beginning of treatment and periodically  during treatment.

Antipsychotics have caused adverse alterations in lipids. Patients starting treatment with LYBALVI should undergo fasting lipid profile testing at the beginning of treatment and periodically during treatment.

Weight gain has been observed with use of antipsychotics. Monitor weight prior to initiating LYBALVI and frequently thereafter.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary,  dyskinetic movements, may develop in patients treated with antipsychotic  drugs. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely  to develop the syndrome. Whether antipsychotic  drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation  of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic  treatment is discontinued. Antipsychotic  treatment itself, however, may suppress (or partially  suppress) the signs and symptoms of the syndrome, possibly masking the underlying  process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

7

Given these considerations, LYBALVI should be prescribed in a manner that is most likely  to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic  drugs; and 2) for whom alternative, effective, but potentially  less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing  a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on LYBALVI, drug discontinuation  should be considered. However, some patients may require treatment with LYBALVI despite the presence of the syndrome.

Atypical antipsychotics  cause orthostatic hypotension  and syncope. Generally, the risk is greatest during initial  dose titration and when increasing the dose. In the 4-week, placebo-controlled  study, from analysis of the vital signs data, rates of orthostatic hypotension  were less than 2% in LYBALVI- and placebo-, and olanzapine-treated patients. In the 24-week, olanzapine-controlled study, from analysis of the vital signs data, rates of orthostatic hypotension  in LYBALVI-treated patients were 3.7%, compared to 0.4% in olanzapine-treated patients.

Monitor orthostatic vital signs in patients who are vulnerable  to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia,  concomitant treatment with antihypertensive medications or CNS depressants [seeDrug Interactions(7.1,7.2)], patients with known

cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities),  and patients with cerebrovascular disease. LYBALVI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from the premarketing clinical trials.

Antipsychotics, including  LYBALVI, may cause somnolence, postural hypotension,  motor and sensory instability,  which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete

fall risk assessments when initiating  antipsychotic  treatment and recurrently for patients on long- term antipsychotic  therapy.

Leukopenia and neutropenia have been reported during treatment with antipsychotic  agents, including  LYBALVI [seeAdverse Reactions(6.1)]. Agranulocytosis (including  fatal cases) has been reported with other agents in this class.

Possible risk factors for leukopenia and neutropenia include pre-existing  low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia  or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation  of LYBALVI at the first sign of a

clinically  significant  decline in WBC in the absence of other causative factors.

8

Monitor patients with clinically significant  neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue LYBALVI in patients with severe neutropenia (absolute neutrophil count <1000/mm3)  and follow their WBC until recovery.

Esophageal dysmotility  and aspiration have been associated with antipsychotic  drug use. Antipsychotic  drugs, including  LYBALVI, should be used cautiously  in patients at risk for aspiration.

Like other antipsychotic  drugs, LYBALVI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions  that lower the seizure threshold. Conditions  that lower the seizure threshold may be more prevalent in older patients.

LYBALVI, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking,  or motor skills.  In a LYBALVI placebo-controlled  study, somnolence occurred in 9% of LYBALVI-treated patients compared to 2.2% in patients treated with placebo.

Patients should be cautioned about operating hazardous machinery, including  motor vehicles, until they are reasonably certain that LYBALVI therapy does not affect them adversely.

Atypical antipsychotics  may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic  medications  may contribute to an elevation in core body temperature; use LYBALVI with caution in patients who may experience these conditions.

Olanzapine, a component of LYBALVI, exhibits in vitro muscarinic receptor affinity

[seeClinical Pharmacology(12.2)]. In premarketing clinical trials with oral olanzapine,

olanzapine  was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly  related to cholinergic  antagonism. Such adverse reactions were not often the basis for discontinuations,  but LYBALVI should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant  prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions.  In postmarketing  experience, the risk for severe adverse reactions (including  fatalities) was increased with concomitant use of anticholinergic medications [seeDrug Interactions(7.1)].

As with other drugs that antagonize dopamine D2 receptors, olanzapine,  a component of LYBALVI, elevates prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia  may suppress hypothalamic  GnRH, resulting in reduced pituitary

9

gonadotropin  secretion. This, in turn, may inhibit  reproductive function by impairing  gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating  compounds.

Long-standing  hyperprolactinemia  when associated with hypogonadism  may lead to decreased

bone density in both female and male subjects.

Tissue culture experiments indicate that approximately  one-third of human breast cancers are prolactin-dependent  in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected  breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine  carcinogenicity studies conducted in mice and rats [seeNonclinical Toxicology

(13.1)].Neither clinical studies nor epidemiologic  studies conducted to date have shown an

association between chronic administration  of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

In the 4-week placebo-controlled trial, shifts from normal to high prolactin values (>30 ng/mL for females; >20 ng/mL for males) occurred in 41.4% of females and 32.9% of males treated with LYBALVI, in 56.1% of females and 37.1% of males treated with olanzapine,  and in 10% of females and 4.8% of males treated with placebo [seeUse in Specific Populations(8.3)].

In the 24-week, olanzapine-controlled  study, shifts from normal to high prolactin values occurred in 32.9% of females and 22.5% of males treated with LYBALVI, and in 41.7% of females and 28.5% of males treated with olanzapine.

If LYBALVI is administered with lithium  or valproate, refer to the lithium  or valproate Prescribing Information for a description  of the risks for these products including, but not limited to, the warnings and precautions for lithium  or valproate [seeContraindications(4)].

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[seeWarnings 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[seeWarnings and Precautions(5.4)]

•      Neuroleptic Malignant Syndrome[seeWarnings and Precautions(5.5)]

•      Drug Reaction with Eosinophilia  and Systemic Symptoms[seeWarnings andPrecautions(5.6)]

10

•      Metabolic Changes[seeWarnings and Precautions(5.7)]

•      Tardive Dyskinesia[seeWarnings and Precautions(5.8)]

•      Orthostatic Hypotension and Syncope[seeWarnings and Precautions(5.9)]

•      Falls[seeWarnings and Precautions(5.10)]

•      Leukopenia, Neutropenia, and Agranulocytosis  [seeWarnings and Precautions(5.11)]

•      Dysphagia[seeWarnings and Precautions(5.12)]

•      Seizures[seeWarnings and Precautions(5.13)]

•      Potential for Cognitive  and Motor Impairment[seeWarnings and Precautions(5.14)]

•      Body Temperature Regulation[seeWarnings and Precautions(5.15)]

•      Anticholinergic  (Antimuscarinic)  Effects[seeWarnings and Precautions(5.16)]

•      Hyperprolactinemia  [seeWarnings and Precautions(5.17)]

•      Risks Associated with Combination  Treatment with Lithium or Valproate[seeWarnings and Precautions(5.18)]

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.

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.

11

Adverse reactions that led to discontinuation  in LYBALVI-treated patients in the short-term placebo-controlled  trial in adults with schizophrenia  include schizophrenia  (1%) and abnormal liver function tests (1%).

Adverse Reactions in the Long-Term (24-week), Active-Controlled Trial in Adults with Schizophrenia

In the 24-week, olanzapine-controlled  trial in patients with stable schizophrenia,  adverse reactions associated with the use of LYBALVI (incidence of 2% or greater) include: weight increased (25%), somnolence (21%), dry mouth (13%), increased appetite (11%), waist

circumference increased (6%), blood creatine phosphokinase increased (5%), headache (4%),

lethargy (4%), sedation (4%), akathisia (3%), alanine aminotransferase increased (3%), aspartate

aminotransferase increased (3%), constipation (3%), dizziness (3%), fatigue (3%), nausea (3%), blood pressure increased (3%), neutrophil count decreased (3%), blood insulin  increased (2%), weight decreased (2%), and dyslipidemia  (2%).

Adverse reactions that led to LYBALVI treatment discontinuation  in more than one patient include somnolence (2%), weight increased (2%), neutropenia (2%), glycosylated hemoglobin increased (1%), schizophrenia  (1%), and liver function test abnormal (1%).

Hype rglyc emia

Mean increases in blood glucose have been observed in patients treated (median exposure of

9.2 months) with olanzapine  in phase 1 of the Clinical  Antipsychotic  Trials of Intervention

Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL. Hyperglycemia, as defined by fasting glucose ≥126 mg/dL, has been observed in patients treated with LYBALVI.

In the 4-week placebo-controlled  trial in adult patients with schizophrenia,  shifts in fasting glucose from normal to high occurred in 4% of patients treated with LYBALVI, 1% of patients treated with olanzapine, and no patients treated with placebo.

12

In the 24-week olanzapine-controlled  trial, patients treated with LYBALVI were more likely to experience abnormal shifts in glycemic parameters than patients treated with olanzapine

(Table 3).

*  n: number of patients with reported abnormal shifts; N: number of patients who had assessments at both baseline

and endpoint for mean change, or normal at baseline and at least 1 post-baseline assessment for shift.

Dyslipidemia

In the 4-week, placebo-controlled  trial in adult patients with schizophrenia,  shifts in fasting triglycerides  from normal to high occurred in 14% of patients treated with LYBALVI and 4% of patients treated with placebo.

In the 24-week olanzapine-controlled  study, mean changes in fasting total cholesterol, LDL

cholesterol, HDL cholesterol, and triglycerides were similar  in patients treated with LYBALVI and in patients treated with olanzapine.

Weight Gain

In the 4-week placebo-controlled study in adult patients with schizophrenia, mean changes in weight, and proportion  of patients with ≥7% weight increase, were greater in patients treated with LYBALVI and olanzapine  than in patients on placebo. In that study, mean weight gain was

3.0 kg in patients treated with LYBALVI, 2.4 kg in patients treated with olanzapine, and 0.2 kg in patients treated with placebo. The proportion of patients with ≥7% weight increase was 26% in patients treated with LYBALVI, 20% in patients treated with olanzapine, and 5% in patients treated with placebo.

In the 24-week trial, LYBALVI-treated patients gained on average 4.2% of baseline body weight. The proportion  of patients treated with LYBALVI with ≥10% body weight gain was 17.8% [seeClinical Studies(14)].

Extrapyramida l Symptoms

In the 4-week placebo-controlled  trial in adult patients with schizophrenia,  patients were assessed using the Simpson-Angus  Rating Scale (SAS) for extrapyramidal symptoms (EPS)

13

(total score ranges from 1 to 14), the Barnes Akathisia Rating Scale (BARS) for akathisia (total score ranges from 0 to 14), and the Abnormal Involuntary  Movement Scale (AIMS) for dyskinesias (total score ranges from 0 to 28). The mean changes from baseline to last study visit for the SAS, BARS, and AIMS was similar in LYBALVI-treated patients and in placebo-treated patients. The mean changes for LYBALVI- vs placebo-treated patients were 0.00 vs -0.2 for AIMS, 0.0 vs -0.1 for BARS, and 0.0 vs -0.3 for SAS, respectively. The rate of parkinsonism (SAS total score >3) was lower in patients treated with LYBALVI (4%) compared to those on placebo (10%). The rates of akathisia (BARS global clinical assessment score ≥2) and dyskinesia (AIMS score ≥3 on any of the first 7 items, or a score ≥2 on two or more of any of the first 7 items) were similar  in patients treated with LYBALVI and in those on placebo. Rates of  akathisia were 6.0% and 8.2% in patients treated with LYBALVI and placebo, respectively, and the rate of dyskinesia was 1.5% both in LYBALVI-treated and in placebo-treated patients.

The frequency of reported adverse reactions related to extrapyramidal symptoms, including akathisia, restlessness, muscle spasms, bradykinesia,  tremor, extrapyramidal disorder, and parkinsonism  was 2% both in LYBALVI-treated and in placebo-treated patients.

In the 24-week active-controlled trial, the mean change from baseline to the last visit for the SAS, BARS, and AIMS was similar  in LYBALVI-treated patients and in those treated with the active control. Extrapyramidal adverse reactions, including  parkinsonism,  akathisia, and dyskinesia, had a similar incidence in LYBALVI-treated patients and in those treated with the active control: any extrapyramidal symptom was 8%, akathisia was 3%.

Dystonia

Symptoms of dystonia, (prolonged abnormal contractions of muscle groups) may occur in susceptible individua ls  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. Although 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.

The safety of LYBALVI for the treatment of bipolar  I disorder (mixed or manic) monotherapy and adjunct to lithium  or valproate relies on information from adequate and well-controlled studies of olanzapine tablets in bipolar I disorder.

The most common adverse reactions (incidence of at least 5% of patients exposed to olanzapine and greater than or equal to twice the rate of placebo) from short-term trials of olanzapine (manic or mixed episodes) are somnolence, dry mouth, dizziness, asthenia, constipation,  dyspepsia,

increased appetite, and tremor.

The most common adverse reactions (incidence of at least 5% of patients exposed to olanzapine and greater than or equal to twice the rate of placebo) from short-term trials of olanzapine as adjunct to lithium or valproate (manic or mixed episodes) are dry mouth, weight gain, increased appetite, dizziness, back pain, constipation,  speech disorder, increased salivation,  amnesia,

paresthesia.

14

6.2                        Postmarketing Experience

The following  adverse reactions have been identified during post-approval use of olanzapine. Because these reactions are reported voluntarily  from a population  of uncertain size, it is difficult to reliably  estimate their frequency or evaluate a causal relationship  to drug exposure.

•      allergic reactions (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria)

•      cholestatic or mixed liver injury, hepatitis, jaundice

•      diabetic coma, diabetic ketoacidosis

•      discontinuation  reaction (diaphoresis, nausea or vomiting)

•      Drug reaction with eosinophilia  and systemic symptoms (DRESS)

•      hyperlipidemia  (random cholesterol levels of ≥240 mg/dL and random triglyceride

levels of ≥1000 mg/dL have been reported)

•      neutropenia

•      pancreatitis

•      priapism

•      rash

•      restless legs syndrome

•      rhabdomyolysis

•      salivary hypersecretion

•      stuttering1

•      venous thromboembolic  events (including  pulmonary embolism and deep venous thrombosis)

7.1                           Effects of Other Drugs on LYBALVI

Table 4 describes clinically significant  drug interactions where the concomitant use of other drugs affects LYBALVI.

1 Stuttering was only studied in oral and long acting injection  (LAI) formulations.

15

Table 5 describes clinically  significant  drug interactions where concomitant use of LYBALVI affects other drugs.

16

7.3                           Opioids

LYBALVI is contraindicated in patients who are using opioids  or undergoing acute opioid withdrawal[seeContraindications(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  [seeDosage and Administration(2.1),Warnings and

Precautions(5.3)].

In emergencysituations, if a LYBALVI-treated patient requires opioid  treatment for anesthesia or analgesia, discontinue LYBALVI. The opioid should be administered by properly trained individua l(s),  and the patient should be properly monitored in a setting equipped and staffed for cardiopulmonary  resuscitation [seeWarnings and Precautions(5.4)].

In non-emergencysituations, if a LYBALVI-treated patient is expected to require opioid treatment (e.g., for analgesia during or after an elective surgical procedure) discontinue LYBALVI at least 5 days before opioid treatment and start olanzapine  or another antipsychotic, if needed.

Given that LYBALVI contains samidorphan, an opioid  antagonist, opioid  treatment may be less effective or ineffective shortly after LYBALVI discontinuation  because of the presence of samidorphan.

8.1                           Pregnancy

Pregna nc y 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://womensmentalhe alth.or g/research/pregna nc yregistry/atyp icalant ipsyc hot ic/.

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 (seeClinical 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(seeData).There are no available data on the

17

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/m2 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/m2 body surface area and gestation was prolonged at 5 times the MRHD based on mg/m2  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/m2  body surface area(seeData).

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 (seeData).

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.

Clinic al 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 suicide. Schizophrenia  and bipolar  I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

18

Fetal/ Neonatal Risk s

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, including the olanzapine  component of LYBALVI, 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 recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics  during pregnancy do not report a clear association with antipsychotics  and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics  during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data LYBALVI

Olanzapine and samidorphan were orally administered to pregnant rats during the period of organogenesis at doses of 0.5/10, 2/50, 6/200, and 0/200 mg/kg/day

(olanzapine/samidorpha n)  which are approximately  <1/10 times to 6/448 times the MRHD of

20 mg/10 mg, olanzapine/samidorphan,  respectively, based on AUC. Maternal toxicity consisting of decreased body weight and food consumption  was observed at all dose levels. Administration  of samidorphan alone (200 mg/kg/day) and 6/200 mg/kg/day olanzapine/samidorpha n decreased mean fetal body weights, increased litter incidence of bent ribs and bent scapula; however, the incidence of bent scapula and bent ribs was not increased when samidorphan was administered in combination with olanzapine compared to the incidence with samidorphan alone. Administration  of olanzapine/samidorphan  at

6/200 mg/kg/day also increased resorptions and post-implantation  loss, with correlating

lower mean viable fetuses and litter size. The no observed adverse effect level (NOAEL) for embryofetal development is 2/50 mg/kg/day, which is approximately 1/80 times the MRHD of 20 mg/10 mg olanzapine/samidorpha n  respectively, based on AUC.

Olanzapine

Olanzapine was orally administered to pregnant rats and rabbits during the period of organogenesis at doses up to 18 mg/kg/day in rats and at doses up to 30 mg/kg/day in rabbits (9 times and 30 times the MRHD of 20 mg/day based on mg/m2  body surface area,

respectively), and no evidence of malformations  was observed. In an oral rat embryofetal

developmental toxicity  study, early resorptions and increased numbers of nonviable  fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD based on mg/m2  body surface area). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD based on mg/m2 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

19

toxic dose of olanzapine  at 30 mg/kg/day (30 times the MRHD based on mg/m2 body surface area).

Samidorphan

Samidorphan was orally administered to pregnant rats during the period of organogenesis at doses of 25, 100, and 300 mg/kg/day, which are approximately  29 to 742 times the MRHD of 10 mg/day based on AUC. Samidorphan was associated with an increased incidence of skeletal variations (unossified  sternebrae and bent ribs) at maternally toxic doses of

≥100 mg/kg/day, and skeletal malformations  (bent or misshapen forelimbs, hindlimbs,  and/or

scapula) at 300 mg/kg/day which are >248 and 742 times the MRHD based on AUC, respectively. The NOAEL for embryofetal development is 25 mg/kg/day, which is approximately  29 times the MRHD based on AUC.

Samidorphan  did not cause adverse effects on embryofetal development when orally administered to pregnant rabbits during the period of organogenesis at doses of 10, 30, and 90 mg/kg/day, which are up to approximately 143 times the MRHD based on AUC.

Samidorphan was orally administered to pregnant rats during pregnancy and lactation at doses of 10, 30, or 100 mg/kg/day, which are approximately  7 to 188 times the MRHD based on AUC. Reduced pup survival, lower birth weights, and decreased pup body weight gains were observed at 100 mg/kg/day, which is 188 times the MRHD based on AUC. The NOAEL of 30 mg/kg/day is approximately  36 times the MRHD based on AUC. There were no adverse effects on pup developmental landmarks, learning, memory, reflexes, or fertility.

Risk Summary

Olanzapine is present in human milk. There are reports of excess sedation, irritability,  poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine  through breast milk. There is no information  on the effects of olanzapine on milk production. There are no data on the presence of samidorphan or the combination of olanzapine  and samidorphan in human milk, the effects on the breastfed infant or the effects on milk production.  When samidorphan was administered to lactating rats, samidorphan and a

metabolite were detected in the plasma of nursing pups, likely due to the presence of

samidorphan in milk. Infants exposed to LYBALVI should be monitored for excess sedation, irritability, poor feeding and extrapyramidal symptoms (tremors and abnormal muscle movements).

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

20

Infertilit y

Females

Based on the pharmacologic action of olanzapine (D2 antagonism), treatment with LYBALVI may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility  in females of reproductive potential [seeWarnings and Precautions(5.17)].

The safety and effectiveness of LYBALVI have not been established in pediatric patients.

Clinical studies of LYBALVI did not include sufficient numbers of patients 65 years of age and older to determine whether they responded differently than younger adult patients.

Olanzapine

Of the 2,500 patients in premarketing clinical studies with orally administered olanzapine,  11%

(263)   were 65 years of age or over. Elderly patients with dementia-related psychosis treated with

antipsychotic drugs are at an increased risk of death. LYBALVI is not approved for the treatment of patients with dementia-related psychosis[seeDosage and Administration(2.5),Warnings andPrecautions(5.1)].

Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability  profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine  are at an increased risk of death compared to placebo.

•      In placebo-controlled studies of olanzapine  in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events

(e.g., stroke, transient ischemic attack) in patients treated with olanzapine,  compared

to patients treated with placebo.

•      In five placebo-controlled  studies of olanzapine  in elderly patients with dementia- related psychosis (n=1,184), the following  adverse reactions were reported in olanzapine-treated  patients at an incidence of at least 2% and significantly  greater than in placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations.  The rate of discontinuation  due to adverse reactions was greater with olanzapine  than with placebo (13% vs 7%).

Consider a lower dosage of the olanzapine  component of LYBALVI in geriatric patients who may have decreased clearance or an exaggerated pharmacodynamic  response to olanzapine (e.g., oversedation) [seeDosage and Administration(2.5)].

21

Olanzapine and samidorphan plasma exposures were found to be higher in subjects with moderate hepatic impairment  than in subjects with normal hepatic function. The effect of severe hepatic impairment  was not studied. The higher plasma exposure in patients with moderate

hepatic impairment  was not expected to be clinically  relevant. No dose adjustment of LYBALVI is needed in patients with hepatic impairment  [seeClinical Pharmacology(12.3)].

Plasma exposure to olanzapine  and samidorphan was higher in patients with severe renal impairment  (eGFR 15 to 29 mL/minute/1.73  m2) compared to those with normal renal function [seeClinical Pharmacology(12.3)].No dose adjustment of LYBALVI is needed in patients with mild (eGFR 60 to 89 mL/minute/1.73  m2), moderate (eGFR 30 to 59 mL/minute/1.73  m2), or

severe renal impairment  (eGFR 15 to 29 mL/minute/1.73  m2).

The effect of LYBALVI in patients with end-stage renal disease was not studied. LYBALVI is not recommended for patients with end-stage renal disease (eGFR of <15 mL/minute/1.73  m2).

Human Expe rienc e

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.

Mana ge ment of Ove rdose

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.

22

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)-10H-thieno[2,3-b][1,5]be nzodia zepine. The molecular formula of olanzapine is: C17H20N4S 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:

H

S        N

H3C

N N

N H3C

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 C21H26N2O4 • C4H6O5 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:

N                HO2C

OH

CO2H OH

H2N            OH          O O

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 colloida l  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)].

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 (5HT2) antagonism.

23

The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.

Olanzapine

Olanzapine binds with high affinity to the following  receptors: serotonin 5HT2A/2C, 5HT6 (Ki=4, 11, and 5 nM, respectively), dopamine D1-4 (Ki=11–31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5 (Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds with low affinity to GABAA, BZD, and β-adrenergic receptors (Ki>10 µM).

Samidorphan

Samidorphan binds to the mu-, kappa-, and delta-opioid  receptors (Ki=0.052, 0.23, and 2.7 nM, respectively). Samidorphan is an antagonist at the mu-opioid  receptors with partial agonist activity at kappa- and delta-opioid  receptors.

The N-dealkylated major human metabolite binds to the mu-, kappa-, and delta-opioid  receptors (Ki=0.26, 23, and 56 nM, respectively), and functions as a mu-opioid  receptor agonist. The

N-oxide major human metabolite binds to mu-, kappa-, and delta-opioid  receptors (Ki=8, 110, and 280 nM, respectively) and functions as a mu-opioid  receptor antagonist.

At doses up to 30 mg/30 mg (1.5 times and 3 times the maximum recommended daily dosage of olanzapine  and samidorphan, respectively), LYBALVI does not prolong QTc interval to any

clinically  relevant extent.

The pharmacokinetics  of both olanzapine  and samidorphan  are linear over the clinical dose range and there is no PK interaction between olanzapine  and samidorphan  after oral administration  of LYBALVI. Steady-state concentrations of olanzapine  and samidorphan are reached within

7 days of commencement of once-daily administration  of LYBALVI. The primary pharmacological  activities of LYBALVI are due to the parent drugs, olanzapine  and samidorphan.

Following  a single dose administration  of LYBALVI (10 mg olanzapine/10 mg samidorphan), the mean AUC0-inf and Cmax of olanzapine  was 628 ng·h/mL and 16 ng/mL, respectively. The

mean AUC0-inf and Cmax of olanzapine after 10 mg single dose administration  of olanzapine  tablet was 610 ng·h/mL and 16 ng/mL, respectively.

Pharmacokinetic properties of the components of LYBALVI are provided in Table 6.

24

Abbreviations: AUC24h=area under the concentration-time curve over the 24-hour dosing interval; Cm ax=maximum plasma concentration; CYP=cytochrome P450; NA=not applicable; Tm ax=time to Cm ax; t½=terminal elimination half-life; UGT=Uridine 5'-diphospho-glucuronosyltransferase.

a    Presented as arithmetic mean (standard deviation).

25

b   Presented as range of the median across multiple studies.

c    Geometric mean ratio (90% confidence interval) [high fat meal/fasting]. High fat meal defined as meal containing

approximately 900-1000 calories and 50% fat content. No clinically relevant food effect.

d   Presented as range of the mean across multiple studies.

Spe cific Populations

Geriatric Patients

The pharmacokinetics  of olanzapine  may be altered in geriatric patients[seeDosage andAdministration(2.5),Use in Specific Populations(8.5)]. In a study involving  24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly subjects

(≥65 years) than in non-elderly  subjects (<65 years).

No effect of age on samidorphan pharmacokinetics was found in a study involving 12 elderly [aged 66-80 years old (6 male, 6 female)] and 24 young [aged 18-39 years old (12 male,

12 female)] healthy subjects administered a single oral dose of 10 mg samidorphan.

Male and Female Patients

Clearance of olanzapine  is approximately  30% lower in females than males. In clinical trials, however, there were no apparent differences between males and females in efficacy or adverse reactions. In clinical studies and population  pharmacokinetic analysis, LYBALVI pharmacokinetics  were consistent with that of olanzapine  (as monotherapy) with no apparent effect of sex on samidorphan pharmacokinetics.

Racial or Ethnic Groups

In vivostudies of olanzapine as monotherapy have shown that olanzapine exposures are similar among Japanese, Chinese, and Caucasians, especially after normalization  for body weight difference. A population  pharmacokinetic analysis found that the clearance of olanzapine  is

greater in Black subjects (N=255) than non-Black subjects (N=329 White and N=17 other races),

and that samidorphan pharmacokinetics are not affected by race.

Patients with Hepatic and Renal Impairment

Effects of hepatic and renal impairment  on the exposure of olanzapine and samidorphan are summarized in Figure 1.

26

Moderate Hepatic Impairment

Fold Change and 90% Confidence Intervals

Olanzapine

Cmax AUC∞

Samidorphan*

Cmax

AUC∞

Severe Renal Impairment

Olanzapine

Cmax

AUC∞

Samidorphan

Cmax AUC∞

0                              1                              2                              3                              4

Change relative to healthy control

*  Based on PBPK simulations, the predicted Cm ax and AUC ratios for samidorphan in subjects with severe hepatic impairment relative to healthy subjects were 2.1 and 2.3, respectively.

Smok ing Status

Olanzapine clearance was approximately  40% higher in smokers than in non-smokers. Samidorphan  pharmacokinetics were not affected by smoking.

Combined Effects

The combined effects of age, smoking, and sex could lead to substantial difference in olanzapine pharmacokinetics. The clearance of olanzapine  in young smoking males, for example, may be

3 times higher than that in elderly nonsmoking females. Population pharmacokinetic analysis indicated that samidorphan pharmacokinetics was not affected by age, sex, race, and smoking status.

Drug Interaction Studies

Effect of Other Drugs on LYBALVI

Coadministration  of LYBALVI with rifampin, a strong CYP3A4 inducer, decreased the total systemic exposure (based on area under the concentration-time  curve from time 0 extrapolated to infinity  [AUCinf]) of olanzapine and samidorphan by 48% and 73%, respectively (Figure 2).

Fluvoxamine,  a strong CYP1A2 inhibitor,  decreases clearance of olanzapine.  This results in a mean increase in olanzapine Cmax following fluvoxamine  of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine  AUC in female nonsmokers and male smokers is 52% and 108%, respectively.

27

Carbamazepine therapy (200 mg bid) causes an approximately  50% increased clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a CYP1A2 inducer.

Based on PBPK simulations,  Itraconazole, a strong CYP3A inhibitor,  is predicted to increase samidorphan Cmax by 25% and AUC by 56%.

Strong CYP3A4 Inducer: Rifampin

Geometric Mean Ratio and 90% Confidence Intervals

Olanzapine

Cmax

AUC∞

Samidorphan

Cmax

AUC∞

0.00                 0.25                 0.50                 0.75                 1.00                 1.25                 1.50

Change relative to reference (without rifampin)

Effect of LYBALVI on Other Drugs

Coadministration  of LYBALVI and lithium  or valproate did not have a clinically  significant effect on the PK of lithium  or valproate (Figure 3). Based on these results, no dosage adjustment of lithium or valproate is necessary when coadministered  with LYBALVI.

28

LYBALVI

Geometric Mean Ratio and 90% Confidence Intervals

Lithium

Cmax

AUC12h

Valproate

Cmax

AUC12h

0.00                  0.25                  0.50                  0.75                  1.00                  1.25                  1.50

Change relative to reference (without LYBALVI)

In vitro Studies

Cytochrome P450 (CYP) Enzymes: Olanzapine does not inhibit  CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Samidorphan  does not inhibit  CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Samidorphan  does not induce CYP1A2, CYP2B6, or CYP3A4/5.

Transporter Systems:Samidorphan is not a substrate of P-glycoprotein (P-gp; multidrug resistance protein 1), organic anion transporter (OATP) 1B1, or OATP1B3. Samidorphan does not inhibit  these transporters or breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, or organic cation transporter (OCT)2.

13.1                       Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinoge nesis

Olanzapine

Oral carcinogenicity  studies were conducted in mice and rats. Olanzapine was administered  to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8 to 5 times the MRHD of 20 mg/day based on mg/m2  body surface area) and 0.25, 2, 8 mg/kg/day (equivalent to

0.06 to 2 times the MRHD based on mg/m2  body surface area). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to

29

0.13 to 2 and 0.13 to 4 times the MRHD based on mg/m2  body surface area, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly  increased in 1 mouse study in female mice dosed at 8 mg/kg/day (2 times the MRHD based on mg/m2 body surface area). These tumors were not increased in another mouse study in females dosed at 10 or

30/20 mg/kg/day (2 to 5 times the MRHD based on mg/m2  body surface area); in this study, there was a high incidence of early mortalities  in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly  increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at ≥4 mg/kg/day (0.5 and 2 times the MRHD based on mg/m2  body surface area, respectively). Antipsychotic  drugs have been shown to chronically  elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine  carcinogenicity  studies; however, measurements during subchronic toxicity studies showed that olanzapine  elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity  study. An increase in mammary gland neoplasms has been found in rodents after chronic administration  of other antipsychotic  drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown [seeWarnings and Precautions(5.17)].

Samidorphan

Samidorphan  did not increase the incidence of tumors in rats administered oral doses of 20, 35, or 75 mg/kg/day (males) and 15, 30, or 60 mg/kg/day (females) for 96 (males) and 95 (females) weeks, which are up to 32 and 237 times the MRHD of 10 mg/day in males and females, respectively based on AUC. Samidorphan  did not increase the incidence of tumors in transgenic rasH2 mice administered  oral doses of 125, 250, or 500 mg/kg/day for 26 weeks.

Mutage nesis

Olanzapine

No evidence of genotoxic potential for olanzapine was found in the Ames reverse mutation test, in vivomicronucleus  test in mice, the chromosome aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma  cells, or in vivosister chromatid exchange test in bone marrow of Chinese hamsters.

Samidorpha n

No evidence of genotoxicity  of samidorphan  was found in the in vitroAmes bacterial reverse mutation test, the in vitrochromosome aberration assay in human peripheral blood lymphocytes or in the in vivomouse bone marrow micronucleus  assay.

Impair ment of Fertilit y

Olanzapine

In an oral fertility  and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the MRHD of 20 mg/day based on mg/m2  body surface area,

respectively). Discontinuance of olanzapine  treatment reversed the effects on male mating

performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the MRHD based on mg/m2  body surface area). Diestrus was prolonged

30

and estrus delayed at 1.1 mg/kg/day (0.6 times the daily oral MRHD based on mg/m2 body surface area); therefore, olanzapine may produce a delay in ovulation.

Samidorphan

Samidorphan  did not impair fertility  when administered  orally to female rats at doses of 30, 150, or 450 mg/kg/day prior to and throughout  mating and continuing  to gestation day 7. The doses are approximately 32, 297, and >680 times the MRHD of 10 mg/day based on AUC,

respectively. However, estrous cycle lengths were increased, and the total number of estrous cycles were decreased in females at the highest dose of 450 mg/kg/day. Samidorphan did not

affect fertility  when orally administered to male rats at doses of 10, 30, or 100 mg/kg/day prior to and throughout  mating; the highest dose is approximately  16 times the MRHD based on AUC.

Olanzapine

In animal studies with olanzapine, the principal hematologic  findings  were reversible peripheral cytopenia in individua l  dogs dosed at 10 mg/kg (17 times the MRHD of 20 mg olanzapine  based on mg/m2  body surface area), dose-related decreases in lymphocytes  and neutrophils  in mice, and lymphopenia  in rats. A few dogs treated with 10 mg/kg developed reversible neutropenia and/or reversible hemolytic  anemia between 1 and 10 months of treatment. Dose-related decreases in lymphocytes and neutrophils  were seen in mice given doses of 10 mg/kg (equal to  2 times the MRHD based on mg/m2  body surface area) in studies of 3 months’ duration.

Nonspecific lymphopenia,  consistent with decreased body weight gain, occurred in rats receiving

22.5 mg/kg (11 times the MRHD based on mg/m2 body surface area) for 3 months or 16 mg/kg

(8 times the MRHD based on mg/m2  body surface area) for 6 or 12 months. No evidence of bone marrow cytotoxicity  was found in any of the species examined. Bone marrows were normocellular  or hypercellular,  indicating  that the reductions in circulating blood cells were probably due to peripheral (non-marrow) factors.

14.1                       Schizophrenia

The efficacy of LYBALVI in the treatment of schizophrenia  in adults is based, in part, upon

adequate and well-controlled studies of orally administered olanzapine. Efficacy of LYBALVI was also evaluated in a 4-week, randomized, double-blind, placebo- and active-controlled study (Study 1).

In Study 1 (NCT02634346),  adult patients who met DSM-5 criteria for schizophrenia  were randomized  in a 1:1:1  ratio to LYBALVI, olanzapine, or placebo for 4 weeks of daily dosing. Dosing was flexible  based on clinical response and tolerability for the first 2 weeks of the study; doses thereafter were fixed. Patients assigned to LYBALVI could receive either 10 mg/10 mg or 20 mg/10 mg, and patients assigned to olanzapine  could receive either 10 mg or 20 mg. The study was designed to compare LYBALVI with placebo, not with olanzapine.

Eligible  patients were 18 to 70 years of age, with a body mass index (BMI) of 18.0–40.0 kg/m2, Positive and Negative Syndrome Scale (PANSS) total score of ≥80, and a score of ≥4 on at least

31

3 of the selected Positive Scale items. Patients were also required to have a Clinical Global Impression-Severity (CGI-S) score ≥4.

The primary efficacy endpoint  was change from baseline in PANSS total score at Week 4. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia  (7 items), negative symptoms of schizophrenia  (7 items), and general psychopathology  (16 items), each rated on a scale of 1 (absent) to 7 (extreme). Total PANSS scores range from 30 to 210, with a higher score reflecting greater symptom severity. The secondary efficacy endpoint was defined as the change from baseline in CGI-S score at Week 4. The CGI-S is a validated scale that requires clinicians

to rate a patient’s current illness severity and overall clinical state based on experience with the

illness population.  Scores range from 1 (normal, not at all ill) to 7 (extremely ill).

Compared with patients on placebo, a statistically significant  improvement  in the change from baseline in PANSS total score at Week 4 was observed in patients treated with LYBALVI (Table 7). The inclusion  of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic  efficacy of olanzapine.