About LYBALVI

LYBALVI is indicated for the treatment of adults with schizophrenia. LYBALVI is also indicated for 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. 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. 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. Please see Important Safety Information contained in this video and full Prescribing Information, including Boxed Warning, at www.lybalvihcp.com.

Hello, I’m Dr. Stephen M. Stahl, a professor of psychiatry and neuroscience at the University of California, Riverside and the University of California, San Diego School of Medicine. I’m also an Honorary Visiting Senior Fellow at the University of Cambridge. During this video, I will introduce you to LYBALVI, a medication approved to treat adult patients living with schizophrenia or bipolar I disorder. This is a promotional program sponsored by Alkermes, Inc. and is not certified for continuing education credit. I am a paid consultant of Alkermes, Inc.

I am sure there are many questions about what LYBALVI is and how it may work. Let's first get started with the components of LYBALVI. LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist.

Olanzapine in an oral formulation was FDA-approved for the treatment of schizophrenia in 1996.^1-3 In 2000, the FDA approved the use of olanzapine for treatment of bipolar I disorder with manic or mixed episodes.^2,4 In 2003, the FDA approved olanzapine for use in adults with bipolar I disorder as an adjunct to lithium or valproate,^2,5 and in 2004, olanzapine was approved for maintenance treatment in adults with bipolar I disorder.^2,6 In 2021, LYBALVI was introduced, combining olanzapine with samidorphan.^7,8

Before describing the hypothesized mechanism of action of LYBALVI, it is helpful to define agonism and antagonism. A drug that acts as an antagonist binds to and occupies a receptor, blocking the receptor from becoming active. On the other hand, a drug that acts as an agonist binds to and activates a receptor.

Now, I know you are interested in better understanding how LYBALVI is believed to work. We will explore that in this section. Note that the clinical significance of the information presented in this section is unknown. First, let's look at the mechanism of action of the olanzapine component in LYBALVI. The mechanism of action of olanzapine is unclear.⁸ However, olanzapine’s efficacy in the treatment of schizophrenia or bipolar I disorder could be mediated through a combination of dopamine and serotonin type 2, or 5-HT₂, antagonism, as you can see represented in this illustration.⁸

The other component of LYBALVI, samidorphan, also has an unclear mechanism of action but is believed to be mediated through opioid receptor antagonism, as depicted in this illustration.⁹ As mentioned earlier, a drug that acts as an antagonist binds to and occupies a receptor, blocking the receptor from becoming active.⁹ As a reminder, LYBALVI is contraindicated in patients using opioids or undergoing acute opioid withdrawal. We will cover this point shortly as part of the Important Safety Information.⁸

It is important to note that there is no pharmacokinetic interaction between olanzapine and samidorphan after oral use of LYBALVI,^8,12 and that the samidorphan component of LYBALVI has shown no evidence of abuse potential.¹³

To recap, LYBALVI contains a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid receptor antagonist. LYBALVI is indicated for the treatment of adults with schizophrenia or 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. We will now go through the Important Safety Information.

Important Safety Information. 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 the 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 the 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 www.fda.gov/medwatch.

Thank you for taking the time to watch this educational video and to learn about LYBALVI. I hope this is helpful as you consider LYBALVI for your appropriate patients living with schizophrenia or bipolar I disorder.

References: 1. ZYPREXA [prescribing information]. Indianapolis, IN: Eli Lilly and Company. 2. Maloney AE, Sikich L. Olanzapine approved for the acute treatment of schizophrenia or manic/mixed episodes associated with bipolar I disorder in adolescent patients. Neuropsychiatr Dis Treat. 2010;6:749-766. 3. NDA 20-592 Approval Package. Drugs@FDA. Accessed March 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020592_Original_Approval_Pkg%20.pdf 4. NDA 20-592/S-006 Approval Package. Drugs@FDA. Accessed March 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/020592_S006_ZUPREXA_ORAL_TABS_AP.pdf 5. NDA 20-592/S-018 Approval Package. Drugs@FDA. Accessed March 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/020592_S018_ZYPREXA_AP.pdf 6. NDA 20-592/S-019 Approval Package. Drugs@FDA. Accessed March 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/020592_s019_Zyprexa.pdf 7. NDA 213378 Approval Package. Drugs@FDA. Accessed March 27, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213378Orig1Orig2s000Approv.pdf 8. LYBALVI [prescribing information]. Alkermes, Inc. 9. Hackney AC. Hormone and metabolic modulators. In: Doping, Performance-Enhancing Drugs, and Hormones in Sport: Mechanisms of Action and Methods of Detection. Elsevier; 2018:77-89. 10. Valbrun LP, Zvonarev V. The opioid system and food intake: use of opiate antagonists in treatment of binge eating disorder and abnormal eating behavior. J Clin Med Res. 2020;12(2):41-63. 11. Citrome L, Graham C, Simmons A, et al. An evidence-based review of OLZ/SAM for treatment of adults with schizophrenia or bipolar I disorder. Neuropsychiatr Dis Treat. 2021;17:2885-2904. 12. Sun L, McDonnell D, von Moltke L. Pharmacokinetics and short-term safety of ALKS 3831, a fixed-dose combination of olanzapine and samidorphan, in adult subjects with schizophrenia. Clin Ther. 2018;40(11):1845-1854.e2. 13. Pathak S, Vince B, Kelsh D, et al. Abuse potential of samidorphan: a phase I, oxycodone-, pentazocine-, naltrexone-, and placebo-controlled study. J Clin Pharmacol. 2019;59(2):218-228.