Building on the Legacy of Olanzapine in Today’s Psychiatric Treatment Landscape

LYBALVI: A treatment option for adults living with schizophrenia or bipolar I disorder 

Approved by the Food and Drug Administration (FDA) in May 2021, LYBALVI is a once-daily, oral tablet that combines olanzapine, an atypical antipsychotic, and samidorphan, an opioid receptor antagonist. 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. It is important to note that LYBALVI has a boxed warning for increased mortality in elderly patients with dementia-related psychosis and is not approved for the treatment of patients with dementia-related psychosis.² Please see additional Important Safety Information below and full
Prescribing Information, including Boxed Warning, for LYBALVI.

LYBALVI builds upon the established clinical data of olanzapine, one of its components, which has a history of use in treating schizophrenia or bipolar I disorder in adults.

The legacy of olanzapine

Originally approved in 1996,³ olanzapine is an atypical antipsychotic that may be used to treat schizophrenia and bipolar I disorder in adults.^4,5

In bipolar I disorder, use of olanzapine has been associated with reductions in manic symptoms and delayed time to relapse compared to placebo, with efficacy and safety supported by several
well-controlled trials.⁵ In a 3-week, double-blind, placebo-controlled trial of adults experiencing an acute manic or mixed episode of bipolar I disorder (n=67), olanzapine demonstrated superiority to placebo in the reduction of manic symptoms as measured by the Young Mania Rating Scale (YMRS).² In an identically designed 3-week study conducted simultaneously with the first study, olanzapine demonstrated a similar treatment difference but, possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.² In a subsequent
4-week study (n=115), olanzapine demonstrated superiority to placebo in reducing manic symptoms as measured by YMRS.²

Additionally, maintenance monotherapy with olanzapine was associated with a significantly longer time to relapse compared to placebo. In a randomized, double-blind trial of adults with
bipolar I disorder who had previously responded to olanzapine, the median time to symptomatic relapse, including hospitalization, was 174 days for olanzapine (n=225) versus 22 days for placebo (n=136).⁵

Olanzapine has demonstrated efficacy in the treatment of bipolar I disorder;^2,5 however, it may require careful patient selection due to its side effect profile, which includes a risk of gaining weight.⁶ This has contributed to declining use of olanzapine over time, as its metabolic side effect profile has led some treatment guidelines to position it as a second-line option.^4,7

In my clinical experience, especially among a newer generation of providers, the efficacy of olanzapine may not be well understood if they have not had direct experience prescribing the medication with appropriate patients or have been taught to avoid it due to tolerability concerns. As a result, they may not understand the potential utility of olanzapine when prescribed thoughtfully.⁷ The available clinical data for olanzapine have informed development of a treatment option that builds upon olanzapine’s clinical foundation.⁸

The LYBALVI clinical development program

The approval of LYBALVI for adults living with bipolar I disorder was based on adequate and
well-controlled studies of orally administered olanzapine, which demonstrated the efficacy and safety of olanzapine in this patient population.^2,5

In addition, the antipsychotic safety and efficacy of LYBALVI in the treatment of adult patients with schizophrenia were evaluated in ENLIGHTEN-1, a 4-week, randomized, double-blind,
placebo-controlled pivotal trial (n=403). The study included olanzapine as an active control; however, it was not designed to compare LYBALVI with olanzapine. The primary endpoint was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 4. LYBALVI demonstrated statistically significant improvement in PANSS least squares (LS) mean total score versus placebo (–23.9 vs –17.5; p<0.001), confirming its antipsychotic efficacy in this population.⁹ The inclusion of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic efficacy of olanzapine. The most common adverse reactions reported for LYBALVI vs placebo in this study included weight gain (19% vs 3%), somnolence (9% vs 2%), dry mouth
(7% vs 1%) and headache (6% vs 3%).² This study was followed by an open-label, 52-week ENLIGHTEN-1 safety extension that evaluated long-term safety and durability of effect of LYBALVI.¹⁰

The weight profile of LYBALVI versus olanzapine was evaluated in adult patients with schizophrenia in the ENLIGHTEN-2 study, a 24-week, Phase 3, randomized, double-blind trial (N=561). The
co-primary endpoints were percent change from baseline in body weight and the proportion of patients who gained ≥10% body weight at Week 24. Patients taking LYBALVI experienced a statistically significant lower LS mean percent weight gain compared to those on olanzapine at Week 24 (4.21% LYBALVI vs 6.59% olanzapine; p=0.003). Additionally, fewer patients taking LYBALVI experienced weight gain ≥10% at Week 24 (18% LYBALVI vs 30% olanzapine). The most common adverse reactions reported in the LYBALVI group included weight gain (25%), somnolence (21%), dry mouth (13%), increased appetite (11%), increased waist circumference (6%) and elevated blood creatine phosphokinase levels (5%).⁸ Patients who completed ENLIGHTEN-2 study were eligible for enrollment in the 52-week ENLIGHTEN-2 open-label safety extension study evaluating the long-term safety and tolerability of LYBALVI.¹¹

Also included in the ENLIGHTEN clinical trial program was the ENLIGHTEN-Early study. This
12-week, double-blind trial compared LYBALVI with olanzapine in adult patients with schizophrenia, schizoaffective disorder, or bipolar I disorder who were early in the course of their illness (N=428). Please note: LYBALVI is not approved for use in schizoaffective disorder or pediatric patients. The primary endpoint was percent change from baseline in body weight at Week 12.¹²

Patients who completed the aforementioned studies were eligible to enroll in the long-term
open-label safety study lasting up to 4 years. The study evaluated safety and tolerability, including the incidence of adverse events and observed change in body weight from baseline.¹³

Collectively, the LYBALVI clinical program provides insights into the profile of LYBALVI and allows healthcare providers to make informed decisions about the use of this medication with their patients.²

The role of advanced practice providers

Psychiatric care looks different today than it did when I first started practicing. Across healthcare settings, nurse practitioners and other advanced practice providers (APPs), such as physician assistants, are more commonly assuming roles in primary care. In mental healthcare, as APPs, we have an opportunity to communicate with the patients we serve about the symptoms they’re experiencing, their concerns and treatment goals, as well as their lifestyle and psychosocial needs so that we can have informed discussions about potential treatment options.

As healthcare professionals, APPs often develop trusted, ongoing relationships with the individuals we treat. This puts us in an important position to notice subtle changes in a patient’s response to treatment that may, for example, necessitate a supportive conversation about updates to dosing or other medication management, and have open conversations that can help patients navigate the emotional and physical complexities of long-term psychiatric care. We play a vital role in supporting shared decision-making between patients, care partners and healthcare providers, and ensuring that treatment choices align with both clinical goals and the patient’s lived experience.

Olanzapine is known as an efficacious agent for adults living with schizophrenia or
bipolar I disorder. While clinical use of olanzapine has changed over time, LYBALVI may be a treatment option to consider for appropriate patients.

While there is no one treatment that is right for every patient, additional options in psychiatric care, such as LYBALVI, reflect a growing effort to meet patients’ treatment needs. For nurse practitioners and other APPs, staying up to date on available treatments helps support informed conversations and shared decision-making with patients.

Please see additional Important Safety Information below and see full
Prescribing Information for LYBALVI.

IMPORTANT SAFETY INFORMATION AND INDICATIONS

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.

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 is available as 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg tablets.

ALKERMES® is a registered trademark of Alkermes, Inc. LYBALVI® and logo are registered trademarks of Alkermes Pharma Ireland Limited, used by Alkermes, Inc., under license. ©2026 Alkermes, Inc. All rights reserved. LYB-003393.

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