Out Of The Pipeline

Olanzapine-samidorphan combination for schizophrenia or bipolar I disorder

Current Psychiatry. 2022 January;21(1):35-40 | doi: 10.12788/cp.0203

References

1. US Food and Drug Administration. NDA 213378 approval letter. May 28, 2021. Accessed November 24, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213378Orig1Orig2s000Approv.pdf

2. Alkermes, Inc. LYBALVI™ (olanzapine and samidorphan) tablets, for oral use. Prescribing information. May 2021. Accessed November 24, 2021. https://www.lybalvi.com/lybalvi-prescribing-information.pdf

3. Citrome L, Graham C, Simmons A, et al. An evidence-based review of OLZ/SAM for treatment of adults with schizophrenia or bipolar I disorder. Neuropsychiatr Dis Treat. 2021;17:2885-2904.

4. Eli Lilly and Company. ZYPREXA (olanzapine) tablet for oral use; ZYPREXA ZYDIS (olanzapine) tablet, orally disintegrating for oral use; ZYPREXA intramuscular (olanzapine) injection, powder, for solution for intramuscular use. Prescribing information. February 2021. Accessed November 24, 2021. https://pi.lilly.com/us/zyprexa-pi.pdf

5. Citrome L, McEvoy JP, Todtenkopf MS, et al. A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future. Neuropsychiatr Dis Treat. 2019;15:2559-2569.

6. Meftah AM, Deckler E, Citrome L, et al. New discoveries for an old drug: a review of recent olanzapine research. Postgrad Med. 2020;132(1):80-90.

7. Citrome L, Holt RI, Walker DJ, et al. Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig. 2011;31(7):455-482.

8. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. J Clin Psychiatry. 2020;81(2):19m12769.

9. Yagoda S, Graham C, Simmons A, et al. Long-term safety and durability of effect with a combination of olanzapine and samidorphan in patients with schizophrenia: results from a 1-year open-label extension study. CNS Spectr. 2021;26(4):383-392.

10. Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020;177(12):1168-1178.

11. Kahn RS, Silverman BL, DiPetrillo L, et al. 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;232:45-53.

12. US Food and Drug Administration. Drug approval package: Lybalvi. June 26, 2021. Accessed November 24, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213378Orig1Orig2s000TOC.cfm

13. Sun L, Yagoda S, Yao B, et al. Combination of olanzapine and samidorphan has no clinically significant effect on the pharmacokinetics of lithium or valproate. Clin Drug Investig. 2020;40(1):55-64.

14. Eli Lilly and Company. SYMBYAX (olanzapine and fluoxetine) capsules for oral use. Prescribing information. September 2021. Accessed November 24, 2021. https://pi.lilly.com/us/symbyax-pi.pdf

15. Wentland MP, Lu Q, Lou R, et al. Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone. Bioorg Med Chem Lett. 2005;15(8):2107-2110.

16. Lee MW, Fujioka K. Naltrexone for the treatment of obesity: review and update. Expert Opin Pharmacother. 2009;10(11):1841-1845.

17. Sun L, Yagoda S, Xue H, et al. Combination of olanzapine and samidorphan has no clinically relevant effects on ECG parameters, including the QTc interval: results from a phase 1 QT/QTc study. Prog Neuropsychopharmacol Biol Psychiatry. 2020;100:109881.

18. Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009;11(3):481-494.

19. Citrome L, Stauffer VL, Chen L, et al. Olanzapine plasma concentrations after treatment with 10, 20, and 40 mg/d in patients with schizophrenia: an analysis of correlations with efficacy, weight gain, and prolactin concentration. J Clin Psychopharmacol. 2009;29(3):278-283.

20. Cerhan JR, Moore SC, Jacobs EJ, et al. A pooled analysis of waist circumference and mortality in 650,000 adults. Mayo Clin Proc. 2014;89(3):335-345.

21. Citrome L, Nasrallah HA. On-label on the table: what the package insert informs us about the tolerability profile of oral atypical antipsychotics, and what it does not. Expert Opin Pharmacother. 2012;13(11):1599-1613.

Approved by the FDA on May 28, 2021, olanzapine-samidorphan combination (OSC) (Lybalvi, manufactured and distributed by Alkermes, Inc. Waltham, MA USA) is intended to help mitigate some of the weight gain that can be anticipated with the use of olanzapine alone (Table).^1-3 Olanzapine (Zyprexa, originally manufactured and distributed by Eli Lilly and Company/Lilly USA, LLC, Indianapolis, IN USA) is a second-generation antipsychotic that has been available for a quarter century.⁴ Although highly efficacious,^5,6 olanzapine has been associated with weight gain, at times substantial, as well as disturbances in glucose and lipid metabolism.⁷ The addition of samidorphan, an opioid antagonist, to olanzapine in a single tablet may act to decrease the amount of long-term weight gain that can be expected for some patients taking olanzapine alone, consequently minimizing the anticipated increase in waist circumference (a proxy for the measurement of burden imposed by metabolically active adipose tissue). Approval of OSC for the treatment of schizophrenia was based on 2 pivotal randomized controlled trials and their extension studies.^8-11 Approval of OSC for bipolar I disorder (acute treatment of manic/mixed episodes as a monotherapy or adjunctive to lithium or valproate, and as a monotherapy maintenance treatment) was based on legacy studies conducted with olanzapine, after establishing that samidorphan does not alter the pharmacokinetics of olanzapine, including in combination with lithium or valproate.^3,12,13 OSC should be distinguished from a different combination product, olanzapine-fluoxetine combination (Symbyax, originally manufactured and distributed by Eli Lilly and Company/Lilly USA, LLC, Indianapolis, IN USA), approved for acute depressive episodes associated with bipolar I disorder and for treatment-resistant depression.¹⁴

OSC offers the potential to consider olanzapine earlier in the treatment of schizophrenia or bipolar I disorder, especially among practitioners who might otherwise be hesitant to prescribe this agent because of concerns over the risk of excessive weight gain.

OSC is available in 4 dosage strengths containing 5 mg, 10 mg, 15 mg, or 20 mg of olanzapine; all tablets contain 10 mg of samidorphan.² The recommended starting dose for OSC mirrors the language contained in the legacy olanzapine product label.⁴ For schizophrenia, the recommended initial dose (olanzapine/samidorphan) is 5 mg/10 mg or 10 mg/10 mg once daily. For bipolar I manic or mixed episodes, the recommended starting dose for monotherapy is 10 mg/10 mg or 15 mg/10 mg, and for use with lithium or valproate, 10 mg/10 mg. For all indications, the recommended target dose can be 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg, with 5 mg/10 mg as an additional potential dose for maintenance monotherapy of bipolar I disorder. The maximum dose is 20 mg/10 mg once daily. Because the amount of samidorphan in each tablet is fixed at 10 mg, combining tablets of OSC, or cutting OSC tablets in half, is not advisable.

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References

1. US Food and Drug Administration. NDA 213378 approval letter. May 28, 2021. Accessed November 24, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213378Orig1Orig2s000Approv.pdf

2. Alkermes, Inc. LYBALVI™ (olanzapine and samidorphan) tablets, for oral use. Prescribing information. May 2021. Accessed November 24, 2021. https://www.lybalvi.com/lybalvi-prescribing-information.pdf

3. Citrome L, Graham C, Simmons A, et al. An evidence-based review of OLZ/SAM for treatment of adults with schizophrenia or bipolar I disorder. Neuropsychiatr Dis Treat. 2021;17:2885-2904.

4. Eli Lilly and Company. ZYPREXA (olanzapine) tablet for oral use; ZYPREXA ZYDIS (olanzapine) tablet, orally disintegrating for oral use; ZYPREXA intramuscular (olanzapine) injection, powder, for solution for intramuscular use. Prescribing information. February 2021. Accessed November 24, 2021. https://pi.lilly.com/us/zyprexa-pi.pdf

5. Citrome L, McEvoy JP, Todtenkopf MS, et al. A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future. Neuropsychiatr Dis Treat. 2019;15:2559-2569.

6. Meftah AM, Deckler E, Citrome L, et al. New discoveries for an old drug: a review of recent olanzapine research. Postgrad Med. 2020;132(1):80-90.

7. Citrome L, Holt RI, Walker DJ, et al. Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig. 2011;31(7):455-482.

8. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. J Clin Psychiatry. 2020;81(2):19m12769.

9. Yagoda S, Graham C, Simmons A, et al. Long-term safety and durability of effect with a combination of olanzapine and samidorphan in patients with schizophrenia: results from a 1-year open-label extension study. CNS Spectr. 2021;26(4):383-392.

10. Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020;177(12):1168-1178.

11. Kahn RS, Silverman BL, DiPetrillo L, et al. 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;232:45-53.

12. US Food and Drug Administration. Drug approval package: Lybalvi. June 26, 2021. Accessed November 24, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213378Orig1Orig2s000TOC.cfm

13. Sun L, Yagoda S, Yao B, et al. Combination of olanzapine and samidorphan has no clinically significant effect on the pharmacokinetics of lithium or valproate. Clin Drug Investig. 2020;40(1):55-64.

14. Eli Lilly and Company. SYMBYAX (olanzapine and fluoxetine) capsules for oral use. Prescribing information. September 2021. Accessed November 24, 2021. https://pi.lilly.com/us/symbyax-pi.pdf

15. Wentland MP, Lu Q, Lou R, et al. Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone. Bioorg Med Chem Lett. 2005;15(8):2107-2110.

16. Lee MW, Fujioka K. Naltrexone for the treatment of obesity: review and update. Expert Opin Pharmacother. 2009;10(11):1841-1845.

17. Sun L, Yagoda S, Xue H, et al. Combination of olanzapine and samidorphan has no clinically relevant effects on ECG parameters, including the QTc interval: results from a phase 1 QT/QTc study. Prog Neuropsychopharmacol Biol Psychiatry. 2020;100:109881.

18. Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009;11(3):481-494.

19. Citrome L, Stauffer VL, Chen L, et al. Olanzapine plasma concentrations after treatment with 10, 20, and 40 mg/d in patients with schizophrenia: an analysis of correlations with efficacy, weight gain, and prolactin concentration. J Clin Psychopharmacol. 2009;29(3):278-283.

20. Cerhan JR, Moore SC, Jacobs EJ, et al. A pooled analysis of waist circumference and mortality in 650,000 adults. Mayo Clin Proc. 2014;89(3):335-345.

21. Citrome L, Nasrallah HA. On-label on the table: what the package insert informs us about the tolerability profile of oral atypical antipsychotics, and what it does not. Expert Opin Pharmacother. 2012;13(11):1599-1613.

Olanzapine-samidorphan combination for schizophrenia or bipolar I disorder

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