Mechanism of Action: samidorphan is a novel naltrexone analogue containing a 3-carboxamido group that functions as an opioid receptor modulator, both in vitro and in vivo.1,11 Numerous in vitro studies have demonstrated that samidorphan binds with high affinity to the μ-, κ-, and δ-opioid receptors with Ki values of 0.052 ± 0.0044, 0.23 ± 0.018, and 2.7 ± 0.36 nM, respectively.2,3,4,11 Samidorphan acts as an antagonist at the μ-opioid receptor when it signals through Gαi proteins, a partial agonist when the receptor signals through GαoA, GαoB, and Gαz proteins, and essentially lacks β-arrestin-mediated signalling; samidorphan also acts as a partial agonist at both the κ- and δ-opioid receptors in vitro.2 In addition, both the major N-dealkylated and the major N-oxide human metabolites bind to the μ-, κ-, and δ-opioid receptors (Ki values of 0.26, 23, and 56, and 8, 110, and 280 nM, respectively); the former functions as a μ-opioid receptor agonist and the latter as an antagonist.11 Overall, samidorphan functions primarily as a μ-opioid antagonist in vivo.1
Olanzapine is an efficacious antipsychotic whose use is limited, in part, by known adverse effects mediated through metabolic dysfunction: hyperglycemia/diabetes mellitus, hyperlipidemia, and weight gain.1,5 The exact mechanisms behind this metabolic dysfunction are incompletely understood, but it is known that opioid signalling is involved in feeding and metabolism.5 Clinical studies have demonstrated that the addition of samidorphan to olanzapine helps mitigate its metabolic-related adverse effects; presumably, this is due to opioid receptor signalling, though the exact mechanism remains to be determined.1,6,5 The appropriateness of samidorphan in combination therapy is due in part to its relatively mild side effect profile and low abuse potential.6,7 –DrugBank
Indications: The Food and Drug Administration (FDA) approved Lybalvi in 2021 to treat schizophrenia and bipolar I disorder in adults. In combination with valproate or lithium to treat manic or mixed episodes that happen with bipolar I disorder –Drugs.com
Interactions: There are 673 drugs known to interact with Lybalvi (olanzapine/samidorphan), along with 19 disease interactions, and 4 alcohol/food interactions. Of the total drug interactions, 52 are major, 614 are moderate, and 7 are minor. –Drugs.com
Dosing Forms: Lybalvi comes as a tablet and in four strengths (also see above and below)
Pros
- Ground-breaking use of combining medications, a similar concept to how buprenorphine/naloxone or bupropion/naltrexone is paired together. Newer medications are headed in this direction.
- Reduce/prevent the metabolic effects of olanzapine, which has the worse compared to the other antipsychotics.
Cons
- Cannot use Lybalvi with opioids, there’s a risk of withdrawals and/or relapsing. Lybalvi and the reps, won’t say it’s contraindicated, other sources do…I personally wouldn’t risk it.
- Confusing Dosages: with antipsychotics, you can double the dose, half it, etc. with Lybalvi you can’t, i.e. if you want to trial Lybalvi 10mg, the patient can’t take 5mg x2 or half the 10mg related to the samidorphan dosage that has to remain the same. This could lead to over-sedating and there’s not a smaller dosage available.
- Need more research/Not tested with children/pregnancy/breastfeeding. I wouldn’t prescribe this to these groups due to the risk of sedation, including with the elderly.
- Costs/coverage: at least many samples are offered and there’s a coupon program.
Additional Information
Official Medication Website: Lybalvi (Olanzapine-and-Samidorphan)
- Combination products containing opioid antagonists: What prescribers need to know –Healio
- Olanzapine-samidorphan combination for schizophrenia or bipolar I disorder –MD Edge (graphic below)
