olanzapine samidorphan

General Information

Maintains olanzapine’s antipsychotic efficacy with approximately 2–3 kg less weight gain versus olanzapine alone, yet metabolic monitoring remains standard.

FDA-approved (2021) for adult schizophrenia and bipolar I disorder (acute manic/mixed episodes and maintenance); brand-only tablets combine 5–20 mg olanzapine with 10 mg samidorphan.

Comparisons against other SGAs can be made in the contrast view and the Lybalvi evidence feed can support review when addressing metabolic trade-offs or payer requests.

Often considered when olanzapine is clinically optimal but metabolic risk is high; payer authorization and structured metabolic counseling are common.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Olanzapine antagonizes dopamine D2/D3 and serotonin 5-HT2A/5-HT2C receptors, providing broad-spectrum antipsychotic and mood-stabilizing effects.

Samidorphan is a high-affinity µ-opioid antagonist (partial κ/δ activity) that dampens reward-driven appetite, mitigating olanzapine-related weight gain while maintaining psychiatric efficacy.

• Olanzapine: D2/D3, 5-HT2A/2C/6, H1, and α1 antagonism with anticholinergic activity.
• Samidorphan: sustained µ-opioid receptor blockade producing 24-hour antagonism.

Metabolism and Pharmacokinetics

• Olanzapine Cmax ~6 h; samidorphan Cmax ~1 h with minimal food effect.
• Olanzapine cleared via CYP1A2/UGT1A4 (minor CYP2D6); samidorphan primarily via CYP3A4 with glucuronidation.
• Half-life ≈30 h for olanzapine (shorter in smokers) and 7–9 h for samidorphan; ~50% of total radioactivity excreted in urine and ~40% in feces as metabolites.

Dosing and Administration

• Switching from olanzapine typically matches the prior oral olanzapine dose (e.g., 10 mg → 10/10 mg); olanzapine-naïve patients commonly start 5/10 mg or 10/10 mg once daily.
• Titration is typically in 5 mg olanzapine increments at ≥1-week intervals within the 5/10–20/10 mg daily range.
• An opioid-free interval ≥7 days is required pre-initiation and post-discontinuation; perioperative pain plans and emergency protocols are typically coordinated in advance.
• Strong CYP3A4 inhibitors/inducers are avoided; dose adjustments with moderate CYP3A4 or strong CYP1A2 inhibitors are often needed, and dosing is typically reassessed when smoking status changes.

Monitoring & Labs

• Metabolic monitoring on an olanzapine-equivalent cadence (weight/BMI, waist, blood pressure, fasting glucose/A1c, lipids) at baseline and periodically; track lifestyle goals alongside labs.
• Opioid exposure prevention: medication reconciliation at every visit (prescription/OTC), with explicit counseling about dental/ER encounters and cough/cold products.
• Perioperative and emergency pain planning, including documenting an opioid-avoidance plan and ensuring the wallet card is carried and presented to clinicians.
• Sedation, orthostasis, and falls risk—reassess driving/occupational safety after dose changes and when other CNS depressants are added.
• Smoking status and CYP modulators (CYP1A2 inhibitors; CYP3A4 inhibitors/inducers) that can change exposure; reassess dose needs when smoking stops/starts.
• AIMS/EPS monitoring (akathisia, parkinsonism) at routine intervals, because movement risks remain similar to olanzapine.

Olanzapine/samidorphan monitoring combines standard SGA metabolic safety with opioid-safety planning; the opioid contraindication is the defining risk that requires repeated reinforcement.

Adverse Effects

Interactions

• Opioid agonists (analgesics, MAT) contraindicated—coordinate alternative analgesia.
• Strong CYP3A4 inhibitors/inducers markedly alter samidorphan exposure; avoid combination.
• Strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) increase olanzapine exposure; consider dose reduction and monitor for sedation/orthostasis.
• Additive CNS depression with alcohol, benzodiazepines, sedative hypnotics.

Other Useful Information

• Document pain management plans and instruct patients to carry the Lybalvi wallet card.
• Maintain metabolic labs (baseline, 3 months, 6 months, annually) and lifestyle counseling comparable to olanzapine.
• Re-evaluate dosing when patients start/stop smoking or add metabolic inhibitors.
• Coordinate bipolar maintenance strategies with the bipolar disorder hub and loop in the LAI Navigator if transitioning from or to depot antipsychotics.
• For planned procedures, coordinate perioperative pain plans in advance (non-opioid regimens, documentation for outside teams) to reduce the risk of uncontrolled pain or inadvertent opioid exposure.

References

1. Lybalvi® (olanzapine and samidorphan) Prescribing Information. Alkermes; 2024.
2. Correll CU et al. ENLIGHTEN-2 weight outcomes with olanzapine/samidorphan. Am J Psychiatry. 2020;177:1129-1139.
3. Potkin SG et al. Metabolic profile of olanzapine/samidorphan combination. J Clin Psychiatry. 2021;82:20m13601.
4. Ma J et al. Real-world effectiveness of olanzapine/samidorphan. Schizophr Res. 2022;243:327-335.