LYBALVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LYBALVI (LYBALVI).
LYBALVI is a combination of olanzapine and samidorphan. Olanzapine is an atypical antipsychotic with high affinity for serotonin 5-HT2A and 5-HT2C, dopamine D1-D4, histamine H1, and alpha1-adrenergic receptors. Samidorphan is an opioid receptor antagonist with high affinity for mu-opioid receptors, hypothesized to reduce olanzapine-associated weight gain by blocking opioid receptors in the central nervous system.
| Metabolism | Olanzapine is extensively metabolized via direct glucuronidation and CYP1A2-mediated oxidation. Samidorphan is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. |
| Excretion | Renal: ~50% as unchanged drug and metabolites; Fecal: ~40%; Biliary: minor. |
| Half-life | Terminal half-life ~20-30 hours; supports once-daily dosing. |
| Protein binding | ~99% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 10-15 L/kg; indicates extensive tissue distribution. |
| Bioavailability | Oral: ~80% (tablet); not administered parenterally. |
| Onset of Action | Oral: 2-4 weeks for initial clinical response in schizophrenia; 1-2 weeks for bipolar depression. |
| Duration of Action | Sustained symptom control with chronic daily dosing; steady-state achieved in 5-7 days. |
Olanzapine 10 mg / samidorphan 10 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). Not recommended in severe renal impairment (eGFR <30 mL/min/1.73 m²) due to insufficient data. |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh A). Not recommended in moderate to severe hepatic impairment (Child-Pugh B or C) due to insufficient data. |
| Pediatric use | Safety and effectiveness in pediatric patients have not been established. |
| Geriatric use | No specific dose adjustment recommended; use with caution due to increased sensitivity to olanzapine (e.g., orthostatic hypotension, sedation) and limited data in patients ≥65 years. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LYBALVI (LYBALVI).
| Breastfeeding | Olanzapine is excreted into human breast milk with an estimated infant dose of 1-4% of maternal weight-adjusted dose; M/P ratio not specifically reported for samidorphan. Samidorphan is likely excreted based on molecular weight. Breastfeeding not recommended due to potential effects on infant CNS (sedation, irritability, poor feeding). |
| Teratogenic Risk | LYBALVI (olanzapine/samidorphan) is classified as Pregnancy Category C. First-trimester exposure: No adequate human studies; animal studies with olanzapine showed fetal toxicity (reduced fetal weight, delayed ossification) at doses >2 times MRHD; samidorphan animal studies showed no teratogenicity at clinically relevant doses. Second and third trimesters: Olanzapine may cause extrapyramidal symptoms and/or withdrawal symptoms in neonates; risk of gestational diabetes, weight gain, and hypertension. Use only if benefit clearly outweighs risk. |
■ FDA Black Box 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.
| Serious Effects |
["Hypersensitivity to olanzapine, samidorphan, or any component of the formulation","Concurrent use with opioid agonists (including partial agonists such as buprenorphine) or during opioid withdrawal","Patients receiving opioids for chronic pain or anticipated to require opioid therapy"]
| Precautions | ["Increased mortality in elderly patients with dementia-related psychosis","Neuroleptic malignant syndrome (NMS)","Tardive dyskinesia","Metabolic changes (hyperglycemia, dyslipidemia, weight gain)","Orthostatic hypotension and syncope","Falls","Seizures","Leukopenia, neutropenia, and agranulocytosis","Dysphagia","Body temperature dysregulation","Anticholinergic effects","Potential for opioid withdrawal with samidorphan component","Hepatic impairment"] |
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| Fetal Monitoring | Maternal: Blood glucose, weight, blood pressure, lipid profile, signs of EPS or metabolic syndrome. Fetal/Neonatal: Third-trimester exposure requires neonatal monitoring for extrapyramidal symptoms, withdrawal, sedation, respiratory distress. Consider ultrasound for fetal growth if prolonged use. |
| Fertility Effects | Olanzapine may cause hyperprolactinemia leading to menstrual irregularities, galactorrhea, and reduced fertility in females. Samidorphan has no known independent effects. In males, olanzapine may reduce libido and erectile function. Effects are reversible upon discontinuation. |