LYBALVI™: New Medication FDA Approved for Schizophrenia & Bipolar Disorder

June 01, 2021

Today FDA approved LYBALVI 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

What is Lybalvi?

  • Lybalvi = Olanzapine + Samidorphan

Samidorphan:

  • novel opioid system modulator: μ-opioid receptor antagonist.
  • The role behind adding Samidorphan is to mitigate the olanzapine-induced weight gain.

Available Dosage Strengths (Olanzapine/Samidorphan):

  • 5 mg /10 mg
  • 10 mg /10 mg
  • 15 mg /10 mg
  • 20 mg /10 mg

Starting & Recommended Dose:

(A) Schizophrenia:

  • Starting Dose: 5 mg/10 mg or 10 mg/10 mg
  • Recommended Dose: 10 mg/10 mg; 15 mg/10 mg; 20 mg/10 mg

(B) Bipolar I disorder (manic or mixed episodes):

  • Starting Dose: 10 mg/10 mg or 15 mg/10 mg
  • Recommended Dose: 5 mg/10 mg; 10 mg/10 mg; 15 mg/10 mg; 20 mg/10 mg

(C) Bipolar I disorder adjunct to lithium or valproate:

  • Starting Dose: 10 mg/10 mg
  • Recommended Dose: 10 mg/10 mg; 15 mg/10 mg; 20 mg/10 mg

 

The recommended starting dosage of LYBALVI is 5 mg/10 mg once daily in patients who have:

  • higher risk of hypotensive reactions,
  • are at risk of slower olanzapine metabolism, or
  • may be more pharmacodynamically sensitive to olanzapine

Contraindications:

  • Patients using opioids: 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
  • Patients undergoing acute opioid withdrawal

Drug Interactions:

  1. Strong CYP3A4 Inducers: Not recommended.
  2. Strong CYP1A2 Inhibitors: Consider dosage reduction of olanzapine component of LYBALVI.
  3. CYP1A2 Inducer: Consider dosage increase of the olanzapine component of LYBALVI.
  4. CNS Acting Drugs: May potentiate orthostatic hypotension.
  5. Anticholinergic Drugs: Can increase risk for severe gastrointestinal adverse reactions.
  6. Antihypertensive Agents: Monitor blood pressure.
  7. Levodopa and Dopamine Agonists: Not recommended.

Use with Renal & Hepatic Impairment:

  • Use is not recommended in patients with end-stage renal disease.
  • No dosage adjustment with hepatic impairment.

Common Adverse Events:

  • Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and
    headache.
  • Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): asthenia, dry
    mouth, constipation, increased appetite, somnolence, dizziness, tremor.
  • Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or
    Valproate (olanzapine): dry mouth, dyspepsia, weight gain, increased
    appetite, dizziness, back pain, constipation, speech disorder, increased
    salivation, amnesia, paresthesia.

Can Samidorphan affect Olanzapine’s Pharmacokinetics?

  • According to a multicenter, randomized, open-label, Phase I study: combining olanzapine with samidorphan does not affect the pharmacokinetic profile of either drug. (2) 

Co-administration of Lybalvi with Lithium or Valproate:

  • Administration of multiple doses of Olanzapine/Samidorphan did not have a clinically significant effect on the pharmacokinetics of lithium or valproate.
  • This combination was well tolerated. (3)

Randomized Double-Blind Phase 2 Study of Olanzapine/Samidorphan in Schizophrenia:

This study (4) found that:

  • antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo.
  • Olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo.
  • Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Double-Blind Phase 3 Study of Olanzapine/Samidorphan compared with Olanzapine in Schizophrenia:

This study (5) found that:

  • Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine.
  • This combination was well tolerated.
  • The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy

Weight Change Comparison between Olanzapine & Lybalvi:

Here is the summary tables from the ENLIGHTEN-2 long-term extension study (pubmed):

References:

  1. Lybalvi Package insert (PDF)
  2. Sun L, McDonnell D, von Moltke L. Pharmacokinetics and Short-term Safety of ALKS 3831, a Fixed-dose Combination of Olanzapine and Samidorphan, in Adult Subjects with Schizophrenia. Clin Ther. 2018 Nov;40(11):1845-1854.e2. (pubmed)
  3. Sun L, Yagoda S, Yao B, Graham C, von Moltke L. Combination of Olanzapine and Samidorphan Has No Clinically Significant Effect on the Pharmacokinetics of Lithium or Valproate. Clin Drug Investig. 2020 Jan;40(1):55-64. (pubmed)
  4. Martin WF, Correll CU, Weiden PJ, Jiang Y, Pathak S, DiPetrillo L, Silverman BL, Ehrich EW. Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia. Am J Psychiatry. 2019 Jun 1;176(6):457-467. (pubmed)
  5. Correll CU, Newcomer JW, Silverman B, DiPetrillo L, Graham C, Jiang Y, Du Y, Simmons A, Hopkinson C, McDonnell D, Kahn RS. Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study. Am J Psychiatry. 2020 Aug 14:appiajp202019121279. (pubmed)
  6. Kahn RS, Silverman BL, DiPetrillo L, Graham C, Jiang Y, Yin J, Simmons A, Bhupathi V, Yu B, Yagoda S, Hopkinson C, McDonnell D. A phase 3, multicenter study to assess the 1-year safety and tolerability of a combination of olanzapine and samidorphan in patients with schizophrenia: Results from the ENLIGHTEN-2 long-term extension. Schizophr Res. 2021 May 17;232:45-53. doi: 10.1016/j.schres.2021.04.009. Epub ahead of print. (PMID: 34015555)

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Responses

  1. can you put into easy to understand terms this question — how much does this reduce the weight gain associated with olanzapine — a little, a lot?

    ” clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo” — any idea of effect size?

    1. Summary tables from the ENLIGHTEN-2 long-term extension study added above to answer your question.

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