Samidorphan

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 (5HT 2 ) antagonism. The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.

• LYBALVI is indicated for the treatment of: Schizophrenia in adults 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 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 ) Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate Maintenance monotherapy treatmentICD-10: F20.9, F31.9

• 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 [see Warnings and Precautions ( 5.3 , 5.4 ), Drug Interactions ( 7.3 )] .contraindicated

Indication Recommended Starting Dose (olanzapine/samidorphan) Recommended Dose (olanzapine/samidorphan) Schizophrenia ( 2.2 ) 5 mg/10 mg or 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder (manic or mixed episodes) ( 2.3 ) 10 mg/10 mg or 15 mg/10 mg 5 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder adjunct to lithium or valproate ( 2.3 ) 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg 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 ) 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 [see Warnings and Precautions ( 5.3 )]. 2.2 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.

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 : 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 ) 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.

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 [see Warnings 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 [see Warnings and Precautions ( 5.4 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.5 )] Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions ( 5.6 )] Metabolic Changes [see Warnings and Precautions ( 5.7 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.14 )] Body Temperature Regulation [see Warnings and Precautions ( 5.15 )] Anticholinergic (Antimuscarinic) Effects [see Warnings and Precautions ( 5.16 )] Hyperprolactinemia [see Warnings and Precautions ( 5.17 )] Risks Associated with Combination Treatment with Lithium or Valproate [see Warnings and Precautions ( 5.18 )] Most common adverse reactions (incidence ≥5% an…

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 ) 8.1 Pregnancy Pregnancy 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://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/ . 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 (see Clinical 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 (see Data ) . There are no available data on the 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.

Metabolism

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.

Human Experience 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.

• May 28, 2021NDANDA213378Alkermes Inc

1. 1Off Label Use28119%
2. 2Contraindicated Product Administered986.5%
3. 3Dizziness835.5%
4. 4Weight Increased775.1%
5. 5Insomnia704.7%
6. 6Weight Decreased674.5%
7. 7Nausea624.1%
8. 8Vomiting583.9%
9. 9Feeling Abnormal553.7%
10. 10Decreased Appetite533.5%
11. 11Fatigue523.5%
12. 12Somnolence523.5%
13. 13Sedation493.3%
14. 14Anxiety432.9%
15. 15Hypersomnia412.7%

The 10 most recently updated of 30 ClinicalTrials.gov registrations naming Samidorphan as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Study to Evaluate Weight Gain as Assessed by Change in BMI Z-score in Pediatric Subjects With Schizophrenia or Bipolar I Disorder
  Recruiting · Phase 3 · Interventional · 220 enrolled · Alkermes, Inc.
  NCT05303064updated 2026-06-03
• Long-term Safety Extension Study of OLZ/SAM in Pediatric Subjects
  Enrolling by invitation · Phase 3 · Interventional · 236 enrolled · Alkermes, Inc.
  NCT04987229updated 2026-06-02
• National Pregnancy Registry for Psychiatric Medications
  Recruiting · Observational · 5,000 enrolled · Massachusetts General Hospital
  NCT01246765updated 2025-10-24
• Exercise and Olanzapine-samidorphan
  Recruiting · Phase 4 · Interventional · 30 enrolled · New York State Psychiatric Institute
  NCT06740890updated 2025-07-11
• A Study of Olanzapine-Samidorphan Tablets in Adults With Schizophrenia
  Not yet recruiting · Phase 3 · Interventional · 654 enrolled · Qilu Pharmaceutical Co., Ltd.
  NCT06649214updated 2024-10-21
• Study to Evaluate the Long-term Safety, Tolerability, and Durability of Treatment Effect of ALKS 3831
  Completed · Phase 3 · Interventional · 523 enrolled · Alkermes, Inc.
  NCT03201757updated 2024-09-26
• Phase 1 Study of OLZ/SAM in Pediatric Subjects With Bipolar I Disorder
  Completed · Phase 1 · Interventional · 7 enrolled · Alkermes, Inc.
  NCT04987658updated 2023-11-22
• Study of the Breast Milk Pharmacokinetics of Olanzapine and Samidorphan
  Completed · Phase 1 · Interventional · 12 enrolled · Alkermes, Inc.
  NCT05547100updated 2023-02-10
• Study to Evaluate the Efficacy of ALKS 3831 on Body Weight in Young Adults Who Have Been Recently Diagnosed With Schizophrenia, Schizophreniform, or Bipolar I Disorder
  Completed · Phase 3 · Interventional · 426 enrolled · Alkermes, Inc.
  NCT03187769updated 2023-01-19
• A Study of ALKS 3831 in Subjects With Schizophrenia and Alcohol Use Disorder
  Completed · Phase 2 · Interventional · 300 enrolled · Alkermes, Inc.
  NCT02161718updated 2021-10-08

Frequently asked questions

How does Samidorphan work?

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 (5HT 2 ) antagonism. The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.

What is Samidorphan used for?

According to FDA labeling, Samidorphan carries indications including: LYBALVI is indicated for the treatment of: Schizophrenia in adults 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 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 ) Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate Maintenance monotherapy treatment. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Samidorphan?

Samidorphan is classified as Opioid Antagonist, Opioid Antagonists.

What are the brand names for Samidorphan?

Samidorphan is marketed under brand names including Lybalvi.

What are the contraindications for Samidorphan?

Samidorphan labeling lists contraindications including: 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 [see Warnings and Precautions ( 5.3 , 5.4 ), Drug Interactions ( 7.3 )] .. Always consult the full prescribing information and a clinician.