Introduction
Lybalvi (olanzapine and samidorphan) is a novel antipsychotic medication approved by the FDA in May 2021 for the treatment of schizophrenia and bipolar I disorder. This fixed-dose combination product combines the established efficacy of olanzapine with samidorphan, an opioid antagonist designed to mitigate olanzapine-associated weight gain.
Mechanism of Action
Lybalvi exerts its therapeutic effects through two distinct mechanisms:
- Olanzapine: A second-generation antipsychotic that acts as a multireceptor antagonist with high affinity for serotonin 5-HT₂A, dopamine D₁-D₄, muscarinic M₁-M₅, histamine H₁, and adrenergic α₁ receptors
- Samidorphan: A μ-opioid receptor antagonist that binds preferentially to μ-opioid receptors without activating them, thereby modulating the reward pathway associated with weight gain
The combination is designed to provide the antipsychotic efficacy of olanzapine while attenuating its propensity for causing significant weight gain through opioid receptor modulation.
Indications
- Treatment of schizophrenia in adults
- Monotherapy or adjunctive therapy for acute manic or mixed episodes associated with bipolar I disorder in adults
- Maintenance treatment of bipolar I disorder in adults
Dosage and Administration
Available strengths: 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, 20 mg/10 mg (olanzapine/samidorphan) Initial dosing:- Schizophrenia: 5 mg/10 mg or 10 mg/10 mg once daily
- Bipolar I disorder: 10 mg/10 mg or 15 mg/10 mg once daily
- Renal impairment: No dose adjustment required
- Hepatic impairment: Use caution in moderate to severe impairment
- Elderly: Consider lower starting dose (2.5 mg/10 mg)
- CYP2D6 poor metabolizers: No dose adjustment required
Pharmacokinetics
Absorption:- Olanzapine: Tmax 6 hours, bioavailability not affected by food
- Samidorphan: Tmax 1-2 hours, bioavailability not affected by food
- Olanzapine: Vd ~1000 L, 93% protein bound
- Samidorphan: Vd ~400 L, 23% protein bound
- Olanzapine: Primarily via direct glucuronidation and CYP1A2
- Samidorphan: Primarily via UGT2B10 and CYP3A4
- Olanzapine: Half-life ~30 hours, primarily renal elimination (57%)
- Samidorphan: Half-life ~7 hours, primarily fecal elimination (64%)
Contraindications
- Known hypersensitivity to olanzapine, samidorphan, or any component of the formulation
- Patients taking opioids or undergoing opioid withdrawal
- Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine)
Warnings and Precautions
Boxed Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death Additional warnings:- Cerebrovascular adverse events in elderly patients with dementia
- Neuroleptic malignant syndrome
- Tardive dyskinesia
- Metabolic changes (hyperglycemia, dyslipidemia, weight gain)
- Orthostatic hypotension
- Leukopenia/neutropenia
- Seizures
- Cognitive and motor impairment
- Dysphagia
- Potential for overdose in CYP2D6 poor metabolizers
Drug Interactions
Clinically significant interactions:- Opioids: Samidorphan may precipitate withdrawal in opioid-dependent patients
- CNS depressants: Additive sedative effects
- Strong CYP3A4 inducers: Decreased samidorphan exposure
- Antihypertensive agents: Enhanced hypotensive effects
- Levodopa and dopamine agonists: May antagonize effects
- Fluvoxamine: Increases olanzapine concentrations
Adverse Effects
Common adverse reactions (≥5% and at least twice placebo):- Weight gain
- Somnolence
- Dry mouth
- Headache
- Increased appetite
- Neuroleptic malignant syndrome
- Tardive dyskinesia
- Metabolic syndrome
- Orthostatic hypotension
- Hepatotoxicity
- Blood dyscrasias
Monitoring Parameters
Baseline assessment:- Weight, BMI, waist circumference
- Fasting blood glucose and HbA1c
- Lipid profile
- Liver function tests
- Complete blood count
- Blood pressure and heart rate
- Weight and metabolic parameters every 3 months for first year, then annually
- Abnormal involuntary movement scale (AIMS) assessment every 6 months
- Mental status examination
- Signs of infection (for leukopenia/neutropenia)
- Orthostatic blood pressure changes
Patient Education
Key points for patients:- Take medication exactly as prescribed, once daily with or without food
- Avoid alcohol and other CNS depressants
- Rise slowly from sitting or lying position to prevent dizziness
- Report any unusual movements, fever, muscle rigidity, or confusion immediately
- Monitor weight regularly and maintain healthy diet and exercise routine
- Do not stop taking abruptly without medical supervision
- Inform all healthcare providers about Lybalvi use, especially before surgery
- Use caution when driving or operating machinery until effects are known
- Notify physician if pregnant, planning pregnancy, or breastfeeding
References
1. FDA prescribing information: Lybalvi (olanzapine and samidorphan) tablets. May 2021. 2. Correll CU, et al. Efficacy and safety of olanzapine/samidorphan in patients with schizophrenia: Phase 3 randomized clinical trial. JAMA Psychiatry. 2021;78(9):914-924. 3. Potkin SG, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with schizophrenia: outcomes from the ENLIGHTEN clinical trials. CNS Drugs. 2021;35(8):849-865. 4. Martin WF, et al. Samidorphan/olanzapine combination therapy for schizophrenia: efficacy, tolerability, and safety. CNS Spectr. 2022;27(1):21-29. 5. Sun L, et al. Pharmacokinetics of samidorphan and olanzapine when administered together in healthy volunteers. Clin Drug Investig. 2021;41(4):337-347.