Indications: LYBALVI® is indicated for the treatment of adults with bipolar I disorder for acute treatment of manic or mixed episodes as monotherapy and as an adjunct to lithium or valproate, or as a maintenance monotherapy treatment, or for the treatment of adults with schizophrenia.

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SCHIZOPHRENIA AND BIPOLAR I DISORDER

Pivotal Trials Summary

Data from pivotal trials

Bipolar I disorder

  • The efficacy and safety of LYBALVI in patients with bipolar I disorder have been established based on studies of orally administered olanzapine1
  • Olanzapine was evaluated in 2 studies in adults with bipolar I disorder, manic or mixed1
  • The studies evaluated the efficacy and safety of oral olanzapine in bipolar I disorder symptomology using YMRS as well as time to symptomatic relapse2

Learn more about the efficacy and safety of LYBALVI in patients with bipolar I disorder

Schizophrenia

  • The efficacy and safety of LYBALVI in patients with schizophrenia were evaluated in the ENLIGHTEN-1 and ENLIGHTEN-2 pivotal studies3-6
  • The studies evaluated the efficacy and safety of LYBALVI in schizophrenia symptomology, including changes in PANSS total score and body weight3-6

Learn more about the efficacy and safety of LYBALVI in patients with schizophrenia

ENLIGHTEN-Early

12-week weight change analysis in patients early in illness7

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  • ENLIGHTEN-Early was a 12-week, randomized, double-blind, Phase 3 study (N=428) comparing LYBALVI with olanzapine in adult patients with schizophrenia, schizophreniform disorder, or bipolar I disorder early in the course of their illness7
  • The primary endpoint was the percentage change from baseline in body weight at Week 127
    • A post hoc analysis of percentage change from baseline in body weight in adult patients with schizophrenia or bipolar I disorder was also conducted

LYBALVI is not approved for the treatment of schizophreniform disorder or patients under the age of 18 years with schizophrenia or bipolar I disorder.1

ENLIGHTEN-Early Study Design

ENLIGHTEN-Early: A Phase 3, multicenter, randomized, double-blind study7
Diagram illustrating the clinical study design, phases, and treatment arms.

Swipe chart to see more

aPatients assigned to the LYBALVI arm received 5 mg/10 mg for the initial dose, and patients assigned to the olanzapine arm received 5 mg for the initial dose. Dosing was flexible at 5 mg intervals per investigator discretion following the initial dose up to 20 mg/10 mg for the LYBALVI arm and 20 mg for the olanzapine arm.7

Key inclusion criteria7
  • Met DSM-V schizophrenia, schizophreniform disorder, or bipolar I disorder criteria
  • ≥16 (US)/18 (EU) and <40 years of age
  • BMI <30 kg/m2
  • Within 4 years of initial onset of active symptoms
  • <24 weeks of cumulative lifetime antipsychotic exposure
  • ≤14 days of olanzapine use within 6 months or ≤3 weeks of cumulative lifetime use
  • Outpatient ≤2 weeks after randomization

Primary endpoint: Percent change from baseline in body weight at Week 127,b

Primary endpoint
(Week 12)		LYBALVI
n=202		Olanzapine
n=206		LS mean (SE)
difference vs
olanzapine		95% CI
of LS mean
difference
LS mean (SE) percent change
from baseline in body weight		4.91 (0.60)6.77 (0.60)-1.87 (0.75)-3.33, -0.41

Swipe table to see more

bResults are from Full Analysis Set, randomized subjects who received at least one dose of study drug and who had at least one postbaseline weight assessment. The overall patient population included patients <18 years old, and patients with schizophrenia (n=268), schizophreniform disorder (n=66), or bipolar I disorder (n=92).3

Post hoc analysis of percent change from baseline in body weight in patients with schizophrenia or bipolar I disorder (≥18 years old) (n=364)3

The efficacy of LYBALVI in the treatment of adult patients with bipolar I disorder has been established based on adequate and well-controlled studies of orally administered olanzapine.1

LS mean of percent change from baseline in body weight by visit8
Subgroup: Adults with schizophrenia or bipolar I disorder
Data chart showing the change in body weight over the study duration.

Swipe chart to see more

Post hoc endpoint
(Week 12)8		LYBALVI
n=180		Olanzapine
n=184		LS mean (SE)
difference vs
olanzapine		95% CI
of LS mean
difference
LS mean (SE) percent
change from baseline		4.43 (0.583)6.52 (0.580)-2.09 (0.79)-3.64, -0.54

Swipe table to see more

Post hoc analysis considerations8
  • The following patients from the full analysis set were excluded from the post hoc analysis:
    • Patients <18 years old (n=7)
    • Patients with schizophreniform disorder who were diagnosed at the final visit (Week 12; n=37)
Post hoc analysis limitations7
  • The post hoc analysis described here is exploratory and only includes the on-label population
  • The ENLIGHTEN-Early study was not adequately powered for the subgroup analysis in patients ≥18 years with schizophrenia or bipolar I disorder
  • The effect of LYBALVI on weight in patients with bipolar I disorder has not been evaluated in adequate and well-controlled clinical trials
Secondary endpoints7
  • Tested hierarchically, secondary endpoints (all at Week 12) were proportions of patients with ≥10% and ≥7% weight gain from baseline; change from baseline in waist circumference and in CGI-S score within the LYBALVI treatment group
  • LS mean (SE) CGI-S change with LYBALVI was -0.8 (0.06); however, the first secondary endpoint—proportion of patients with ≥10% weight gain—was not statistically significant vs olanzapine, thus precluding further statistical evaluation of secondary endpoints

ENLIGHTEN-Early safety profile

Most common adverse events observed with the use of LYBALVI (incidence ≥5%)7,c
Adverse reactionLYBALVI (n=211)
Weight increased22%
Somnolence11%
Alanine aminotransferase increased8%
Headache6%
Sedation5%

Swipe table to see more

The incidence of weight increase with olanzapine was 26% (n=55).7

Numbers rounded to the nearest percentage.

cResults are from the safety population, randomized subjects who received at least one dose of study drug.7

4-Year Open-Label Safety Extension Study

LYBALVI (olanzapine and samidorphan) was evaluated for up to 4 years in a long-term safety extension study9

This long-term, open-label extension study evaluated the long-term safety, tolerability, and durability of treatment effect of LYBALVI in patients with schizophrenia or bipolar I disorder who completed one of the antecedent studies.9,d

dFifteen patients completed the study with a diagnosis of schizophreniform disorder. LYBALVI is not approved for the treatment of schizophreniform disorder.

Study design9

Diagram illustrating the clinical study design, phases, and treatment arms.

Swipe chart to see more

eAll patients in the long-term, open-label safety extension study were maintained on the daily dose of olanzapine component they were receiving at the end of the antecedent study. Dosing was flexible, but frequent dose adjustments were discouraged. Duration of planned treatment was between 2 and 4 years and varied by subject. Of 451 patients eligible for 2 years of treatment, 242 (53.7%) completed the 2-year treatment period; of 335 patients eligible for 4 years of treatment, 109 (32.5%) completed the 4-year treatment period.9

Objective9
  • To evaluate the long-term safety, tolerability, and durability of treatment effect of LYBALVI in patients with schizophrenia or bipolar I disorder
  • The original protocol was designed as a 2-year open-label treatment period but was amended to 4 years
Select inclusion criteria8,9
  • Completion of one of the antecedent studies within the prior 7 days
Select exclusion criteria8,9
  • Any patients that had any findings that may compromise their safety or affect ability to fulfill the protocol visit schedule or visit requirements
Study limitations9
  • Open-label study design with no comparator arm/loss of randomization limits interpretation of efficacy and safety
  • Missing data may have impacted the findings, as approximately two-thirds of patients discontinued before 4 years
  • Patients with less favorable outcomes may have dropped out of the parent trials, creating potential selection bias
  • Patient baseline characteristics in this study may be variable due to differences in inclusion and exclusion criteria of the 3 parent studies
  • Fasting status was based solely on self-report

Change in CGI-S score and body weight

Mean symptom severity remained stable, with small changes observed in mean body weight9

  • The long-term safety extension study was an open-label study in which all participants received LYBALVI9
  • The study was not designed to prospectively assess or evaluate the efficacy of LYBALVI or its effect on body weight9
  • No conclusions of efficacy can be drawn from these data9
Observed change in CGI-S score from baseline9
Graph showing safety for population.

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Observed change in body weight from baseline9
Data chart illustrating the mean change in body weight for patients over the study duration.

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The patient numbers indicate the number of subjects with assessment at each corresponding visit.9
All patients who received at least 1 dose of LYBALVI were included in the safety populations.9

f1 kg = 2.2 lb.

Waist circumference, metabolic parameters, and HbA1c

  • The long-term safety extension study was an open-label study in which all participants received LYBALVI9
  • The study was not designed to prospectively assess or evaluate the effect of LYBALVI on change in waist circumference or metabolic parameters or the effect of LYBALVI on HbA1c9
  • No conclusions of efficacy can be drawn from these data9
Observed change in waist circumference from baseline9
Data chart illustrating the mean change in waist circumference (cm) for patients over the study duration.

Swipe chart to see more

Baseline was defined as the last nonmissing value before the first dose of study drug in the current study.9

Observed change in metabolic parameters from baseline9
Chart showing metabolic parameters using lybalvi.

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Patients were instructed not to eat or drink (except water) for 8 hours prior to laboratory blood draws. Fasting status was self-reported and not otherwise confirmed. Lipid values were reported only for patients who reported fasting.9

Observed mean change in HbA1c from baseline9
Bar chart showing the mean HbA1c levels and change from baseline for patients treated with LYBALVI.

Swipe chart to see more

4-year open-label safety extension study safety profile

Treatment-emergent adverse events with the use of LYBALVI (>5%)9
Adverse eventAll patients (N=523)
Weight increased10%
Headache7%
Anxiety6%
Insomnia6%
Somnolence6%
Nausea6%
Weight decreased6%

Swipe table to see more

All patients who received at least 1 dose of LYBALVI were included in the safety population.9

Numbers rounded to the nearest percentage.

Discontinuation rates9

The median time to study discontinuation was 588 days.

The most common reasons for discontinuation were:

  • Withdrawal by patient (25.4%)
  • Other (17.6%, including discontinuation due to the Ukraine-Russia conflict)
  • Adverse events (8.4%)
  • Loss to follow-up (7.1%)
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Real-world evidence

LYBALVI has data from a real-world evidence study.

Dig into the data

BMI=body mass index; CGI-S=Clinical Global Impressions Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders; HbA1c=hemoglobin A1c; HDL=high-density lipoprotein; IQR=interquartile range; LDL=low-density lipoprotein; LS=least squares; PANSS=Positive and Negative Syndrome Scale; SD=standard deviation; SE=standard error.

References: 1. LYBALVI. Prescribing Information. Alkermes, Inc. 2. Tohen M, Jacobs TG, Grundy SL, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2000;57(9):841-849. 3. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 Study. J Clin Psychiatry. 2020;81(2):19m12769. 4. Yagoda S, Graham C, Simmons A, Arevalo C, Jiang Y, McDonnell D. Long-term safety and durability of effect with a combination of olanzapine and samidorphan in patients with schizophrenia: results from a 1-year open-label extension study. CNS Spectr. 2021;26(4):383-392. 5. Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020;177(12):1168-1178. 6. Kahn RS, Silverman BL, DiPetrillo L, et al. A phase 3, multicenter study to assess the 1-year safety and tolerability of a combination of olanzapine and samidorphan in patients with schizophrenia: results from the ENLIGHTEN-2 long-term extension. Schizophr Res. 2021;232:45-53. 7. Kahn RS, Kane JM, Correll CU, et al. Olanzapine/samidorphan in young adults with schizophrenia, schizophreniform disorder, or bipolar I disorder who are early in their illness: results of the randomized, controlled ENLIGHTEN-Early study. J Clin Psychiatry. 2023;84(3):22m14764. 8. Data on file. Alkermes, Inc. 9. Ballon JS, Kahn RS, Arevalo C, et al. Long-term safety, tolerability, and durability of treatment effect of olanzapine and samidorphan: results of a 4-year open-label study. J Clin Psychiatry. 2024;86(1):24m15511.

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Important Safety Information

Important Safety Information

Lybalvi HCP ISI

Boxed Warning

Boxed Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI (olanzapine and samidorphan) is not approved for the treatment of patients with dementia-related psychosis.

ISI Copy

Contraindications:

LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products.

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

including stroke, transient ischemia attack, and fatalities. See Boxed Warning.

Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids:

LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in 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.

Vulnerability to Life-Threatening Opioid Overdose:

Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life-threatening or fatal opioid intoxication, 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 properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. 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,

a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),

a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include 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. Discontinue if DRESS is suspected.

Metabolic Changes,

including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. 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. 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. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically.

Tardive Dyskinesia (TD):

Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood 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, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered.

Orthostatic Hypotension and Syncope:

Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease.

Falls:

LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI.

Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases):

Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors.

Dysphagia:

Use LYBALVI with caution in patients at risk for aspiration.

Seizures:

Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment:

Because LYBALVI may cause somnolence, and may impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely.

Body Temperature Dysregulation:

Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Anticholinergic (Antimuscarinic) Effects:

Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications.

Hyperprolactinemia:

LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Risks Associated with Combination Treatment with Lithium or Valproate:

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.

Interference with Laboratory Tests for Opioid Detection:

LYBALVI may cause false positive results with urinary immunoassay methods for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results.

Most Common Adverse Reactions observed in clinical trials were:

  • Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache
  • Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor
  • 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

Concomitant Medication:

LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling.

Pregnancy:

May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy.

Renal Impairment:

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

To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or https://www.fda.gov/medwatch.

Indications

LYBALVI is indicated for the treatment of:

  • Bipolar I disorder in adults
    • Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
    • Maintenance monotherapy treatment
  • Schizophrenia in adults

Please see full Prescribing Information, including Boxed Warning, for LYBALVI.

Lybalvi HCP ISI

Boxed Warning

Boxed Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI (olanzapine and samidorphan) is not approved for the treatment of patients with dementia-related psychosis.

ISI Copy

Contraindications:

LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products.

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

including stroke, transient ischemia attack, and fatalities. See Boxed Warning.

Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids:

LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in 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.

Vulnerability to Life-Threatening Opioid Overdose:

Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life-threatening or fatal opioid intoxication, 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 properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. 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,

a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),

a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include 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. Discontinue if DRESS is suspected.

Metabolic Changes,

including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. 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. 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. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically.

Tardive Dyskinesia (TD):

Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood 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, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered.

Orthostatic Hypotension and Syncope:

Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease.

Falls:

LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI.

Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases):

Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors.

Dysphagia:

Use LYBALVI with caution in patients at risk for aspiration.

Seizures:

Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment:

Because LYBALVI may cause somnolence, and may impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely.

Body Temperature Dysregulation:

Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Anticholinergic (Antimuscarinic) Effects:

Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications.

Hyperprolactinemia:

LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Risks Associated with Combination Treatment with Lithium or Valproate:

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.

Interference with Laboratory Tests for Opioid Detection:

LYBALVI may cause false positive results with urinary immunoassay methods for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results.

Most Common Adverse Reactions observed in clinical trials were:

  • Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache
  • Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor
  • 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

Concomitant Medication:

LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling.

Pregnancy:

May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy.

Renal Impairment:

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

To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or https://www.fda.gov/medwatch.

Indications

LYBALVI is indicated for the treatment of:

  • Bipolar I disorder in adults
    • Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
    • Maintenance monotherapy treatment
  • Schizophrenia in adults

Please see full Prescribing Information, including Boxed Warning, for LYBALVI.

For Healthcare Professionals

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