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LYBALVI1

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What is LYBALVI?

  • LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist
  • 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
  • The mechanism of action of samidorphan could be mediated through opioid receptor antagonism

Learn more about LYBALVI

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What is LYBALVI indicated for?

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 Important Safety Information and full Prescribing Information, including Boxed Warning.

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What is the boxed warning for LYBALVI?

The Boxed Warning for LYBALVI is as follows:

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.

Please see Important Safety Information and full Prescribing Information, including Boxed Warning.

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What are the contraindications associated with LYBALVI?

LYBALVI is contraindicated in patients:

  • who are using opioids
  • who 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.

See full Prescribing Information

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Since olanzapine is one of the components of LYBALVI, are they indicated to treat the same conditions?

  • LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist
  • LYBALVI does not have all the same indications as olanzapine
  • 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
  • LYBALVI is indicated for the treatment of schizophrenia in adults

Please see Important Safety Information and full Prescribing Information, including Boxed Warning.

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Do drug interactions need to be considered when prescribing LYBALVI?

  • Yes. LYBALVI is contraindicated in patients who are taking opioids or are undergoing acute opioid withdrawal. Concomitant use is not recommended with strong CYP3A4 inducers, levodopa, or dopamine agonists. Use caution with diazepam, alcohol, or other CNS-acting drugs, as well as with medications having anticholinergic (antimuscarinic) effects. Consider reducing dosage of the olanzapine component of LYBALVI when used with strong CYP1A2 inhibitors. Consider increasing the dosage of the olanzapine component of LYBALVI with CYP1A2 inducers. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling.
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Could LYBALVI interfere with laboratory tests for opioid detection?

  • LYBALVI contains samidorphan, an opioid antagonist. LYBALVI may be crossreactive with urinary immunoassay methods used for detecting opioids, resulting in false positive results. Use an alternative analytical technique (eg, chromatographic methods) to confirm positive opioid urine drug screen result.

Weight gain

How much weight did patients with schizophrenia gain on average in LYBALVI clinical trials?

  • In the 24-week trial evaluating weight changes for patients taking LYBALVI vs olanzapine, patients treated with LYBALVI gained on average 4.2% of baseline body weight and those taking olanzapine gained 6.6%
  • In the 4-week, placebo-controlled trial of adult patients with schizophrenia, mean changes in weight were 3.0 kg (6.6 lbs) in patients treated with LYBALVI, 2.4 kg (5.3 lbs) in patients treated with olanzapine, and 0.2 kg (0.4 lbs) in patients treated with placebo. This study evaluated antipsychotic efficacy and safety of LYBALVI vs placebo and was not designed to assess or compare the weight effects of LYBALVI vs olanzapine

See ENLIGHTEN-2 data

Dosing and administration

What are the dosage and administration recommendations for LYBALVI?

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

Can LYBALVI be initiated in patients using opioids?

  • No, 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

Recommended Dosage in Bipolar I Disorder (Manic or Mixed Episodes)

  • Monotherapy: Initiate LYBALVI at 10 mg/10 mg or 15 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily. The maximum recommended dosage is 20 mg/10 mg once daily
    • Dosage adjustments should occur at intervals of not less than 24 hours. When dosage adjustments are necessary, dose increments/decrements of 5 mg (based on the olanzapine component of LYBALVI) are recommended
  • Maintenance monotherapy: Administer LYBALVI at 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily
  • Adjunctive to lithium or valproate: Initiate LYBALVI at 10 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg or 20 mg/10 mg, once daily.
    • Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of LYBALVI) depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily

Recommended Dosage in Schizophrenia

  • Initiate LYBALVI at 5 mg/10 mg (contains 5 mg of olanzapine and 10 mg of samidorphan) or 10 mg/10 mg (contains 10 mg of olanzapine and 10 mg of samidorphan) orally once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg (contains 15 mg of olanzapine and 10 mg of samidorphan), or 20 mg/10 mg (contains 20 mg of olanzapine and 10 mg of samidorphan) once daily
  • Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of LYBALVI) depending upon clinical response and tolerability, up to a maximum recommended dosage of 20 mg/10 mg once daily

Dosage Recommendations in Specific Populations

  • The recommended starting dosage of LYBALVI is 5 mg/10 mg once daily in patients who have a higher risk of hypotensive reactions, are at risk of slower olanzapine metabolism, or may be more pharmacodynamically sensitive to olanzapine
  • If dose escalation is necessary, increase the dosage slowly in these patients

Dosage recommendations

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Can patients split LYBALVI tablets in half?

  • Do not divide tablets or combine strengths

Mechanism of action

What is the mechanism of action (MOA) for LYBALVI in bipolar I disorder and schizophrenia?

LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan (as samidorphan L-malate), an opioid antagonist.

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

Learn more about the science of LYBALVI

LYBALVI clinical data

What is the basis for the approval of LYBALVI in bipolar I disorder?

  • There are no clinical data with LYBALVI in patients with bipolar I disorder
  • 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

Data in bipolar I disorder

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What is the Young Mania Rating Scale (YMRS) that was used in the studies of olanzapine in adults with bipolar I disorder?

  • The YMRS is one of the most frequently used rating scales to assess manic symptoms2
  • The YMRS is traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score)1
  • The YMRS combines severity scores from the following symptoms
    • Elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech, language-disordered thoughts, thought content (grandiosity, paranoia, delusions, or hallucinations), disruptive or aggressive behavior, appearance, insight into mental illness3
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What is the Hamilton Depression Rating Scale (HAM-D 21) that was used in the maintenance study of olanzapine in adults with bipolar I disorder?

  • HAM-D 21 is one of the most widely used measures of the severity of depressive symptoms4,5
  • The HAM-D 21 scores 17 of 21 symptom categories for depressive states including those experienced during mixed episodes of bipolar I disorder. Higher scores indicate greater symptom severity5,6
  • Symptoms of depressive states assessed by the HAM-D 21 include depressed mood, guilt, suicide, insomnia (initial), insomnia (middle), insomnia (delayed), work and interests, retardation, agitation, anxiety (psychic), anxiety (somatic), somatic symptoms (gastrointestinal), somatic symptoms (general), somatic symptoms (genital), hypochondriasis, loss of insight, and loss of weight6
    • Diurnal variation, depersonalization, paranoid symptoms, and obsessional symptoms are not included in the assessment because they occur so infrequently or do not measure intensity of depression6
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What are the efficacy data for LYBALVI in the treatment of schizophrenia?

ENLIGHTEN-1

  • Evaluated the efficacy and safety of LYBALVI in schizophrenia7

ENLIGHTEN-1 efficacy and safety data

ENLIGHTEN-2

  • Evaluated safety and changes in body weight with LYBALVI relative to olanzapine in schizophrenia1,8

ENLIGHTEN-2 efficacy and safety data

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What is the Positive and Negative Syndrome Scale (PANSS) that was used in the ENLIGHTEN-1 study in adults with schizophrenia?

  • The PANSS is a 30-item scale that is used to measure and assess the severity of positive and negative symptoms of schizophrenia, and general psychopathology, each rated on a scale of 1 (absent) to 7 (extreme)1
  • Total PANSS scores range from 30 to 210, with a higher score reflecting greater symptom severity1
  • Symptoms of schizophrenia measured by the PANSS include9
    • Positive symptoms (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness, hostility)
    • Negative symptoms (blunted affect, emotional withdrawal, poor rapport, passive-apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking)
    • General psychopathology (somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgement and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance)
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What are the common adverse reactions associated with the use of LYBALVI?

The safety of LYBALVI for treatment of bipolar I disorder relies on olanzapine studies. In trials of olanzapine in bipolar I disorder, the most common adverse reactions (incidence of ≥5% of patients exposed to olanzapine and ≥2x placebo) were:

  • 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, and paresthesia

Most common adverse reactions (incidence ≥5% and at least twice that of placebo) were:

  • Schizophrenia: weight increased, somnolence, dry mouth, and headache

For a complete list of adverse reactions, please refer to the full Prescribing Information for LYBALVI.

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References: 1. LYBALVI [prescribing information]. Alkermes, Inc. 2. Sajatovic M, Chen P, Young RC. Rating scales in bipolar disorder. In: Tohen M, Bowden CL, Nierenberg AA, Geddes JR, eds. Clinical Trial Design Challenges in Mood Disorders. Academic Press; 2015:105-136. 3. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435. 4. Rohan KJ, Rough JN, Evans M, et al. A protocol for the Hamilton Rating Scale for Depression: item scoring rules, rater training, and outcome accuracy with data on its application in a clinical trial. J Affect Disord. 2016;200:111-118. 5. Montes JM, Pascual A, Pascual SM, Loeck C, Gutiérrez Bermejo MB, Jenaro C. Assessment tool of bipolar disorder for primary health care: the SAEBD. Int J Environ Res Public Health. 2021;18:1-16. 6. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56-62. 7. 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):e1-e9. 8. 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. 9. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-276.

Important Safety Information

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:

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.

Indications

LYBALVI is indicated for the treatment of:

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

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