Do Not Use: Olanzapine/Samidorphan (LYBALVI) for Schizophrenia or Bipolar I Disorder

In May 2021, the U.S. Food and Drug Administration (FDA) approved the drug LYBALVI — a combination of the antipsychotic olanzapine and the opioid antagonist (opioid-blocking drug) samidorphan (never before approved for human use) — for the treatment of schizophrenia in adults.[1],[2] The FDA further approved Lybalvi for treatment of adults with bipolar I disorder, alone or in combination with injectable valproate (available in generic only) or oral lithium (LITHOBID).

The manufacturer of Lybalvi, Alkermes, claims that the addition of samidorphan offsets weight gain and other metabolic illnesses that are a distinctive set of adverse effects associated with olanzapine.[3] Public Citizen’s Health Research Group (HRG) testified in opposition to the approval of Lybalvi because of questionable effectiveness and safety data, especially because samidorphan use plausibly increases the risk of opioid overdose.[4] Accordingly, HRG has designated Lybalvi as Do Not Use.

Background on schizophrenia, bipolar I disorder

Schizophrenia[5] and bipolar I disorder[6] (formerly known as manic-depressive illness) are both serious forms of mental illness that involve persistent and debilitating symptoms and, typically, declines in emotion and energy (depression), and in the case of schizophrenia, markedly distorted thinking patterns and behaviors, including delusions, hallucinations, illogical reasoning and difficulties with attention and memory.

These illnesses are often chronic and difficult to treat, but antipsychotic drugs, especially second-generation (or atypical) antipsychotic drugs like olanzapine (ZYPREXA), have become a mainstay of treatment for schizophrenia, an FDA-approved treatment for bipolar I disorder and other depressive disorders,[7] and a distinctively safer alternative to first-generation antipsychotics, which carry a high risk of a neurologic disorder known as tardive dyskinesia that is characterized by repetitive, involuntary body or facial movements.[8]

Unfortunately, second-generation antipsychotics, especially olanzapine, increase the risk of metabolic illness, including weight gain and altered sugar and fat metabolism known to increase the risk of other illnesses such as diabetes and cardiovascular disease.

Combining samidorphan with olanzapine to create Lybalvi was conceived as a way to inhibit olanzapine’s known and serious metabolic adverse effects.[9]

Effectiveness of Lybalvi to mitigate metabolic risks of olanzapine

The key study cited by the FDA[10] in support of the effectiveness of Lybalvi to deliver olanzapine therapy while minimizing metabolic adverse effects of that drug was a 24-week, double-blinded, randomized clinical trial (RCT).[11]

The 24-week RCT indeed found that Lybalvi slowed, but did not eliminate, olanzapine-associated weight gain. More specifically, that pivotal trial revealed that among 266 subjects randomized to receive Lybalvi, the mean weight gain from the start of the trial (baseline) was 4.2%, compared with 6.6% for the 272 subjects randomized to receive olanzapine alone. This corresponds to a net difference in mean weight gain from baseline of just 2.4% attributable to Lybalvi versus olanzapine monotherapy use — notably below the 5% to 10% threshold the FDA uses to judge the clinical effectiveness of weight-loss drugs.

Moreover, this same clinical trial did not reveal any Lybalvi advantage regarding other important measures of metabolic control, including waist circumference and cholesterol and blood sugar levels. Accordingly, one 2022 scientific review concluded that Lybalvi “has limited effect on medication-induced weight-gain often associated with antipsychotic olanzapine monotherapy.”[12]

Safety of Lybalvi

In addition to weight gain and other serious metabolic problems, olanzapine has many additional safety concerns, including the risks of developing very low blood pressure, seizures, cognitive and motor impairment, constipation and dry mouth.[13] The olanzapine product labeling also contains a black-box warning (the most prominent warning the FDA can require) that cautions prescribers and consumers that olanzapine use (and the use of any antipsychotic) in elderly patients with dementia-related psychosis can lead to premature death.

The FDA’s review of Lybalvi did not reveal any striking adverse interactions between samidorphan and olanzapine, meaning no strong evidence was found of an increase in olanzapine’s adverse effects with the use of Lybalvi (although drowsiness, fatigue and dry mouth were more frequent with Lybalvi than olanzapine alone in one study).[14]

However, samidorphan itself, because it is an opioid-receptor antagonist, does increase the risk of problems with opioids during and after the use of samidorphan. Those problems plausibly include increased risk of inadequate analgesia (requiring higher doses to get adequate pain relief), withdrawal (negative symptoms when an opioid drug is discontinued) and overdose (which can lead to decreased breathing, lost consciousness and death). Accordingly, the product labeling for Lybalvi specifically states that the drug is not to be used if the patient is using or currently withdrawing from opioids legally (for pain control or another approved indication) or illegally.[15]

The concern about the use of Lybalvi in patients taking opioids is especially relevant because persons with schizophrenia or bipolar illness are more likely than others to use opioids for pain and to develop opioid-use disorder. Data compiled by the FDA and the manufacturer of Lybalvi detailed this point.[16] Specifically, in documents presented to the FDA advisory committee convened to consider the safety and effectiveness of Lybalvi, the drug’s manufacturer cited data indicating that approximately 5% of persons diagnosed with schizophrenia and 4% to 9% of those with bipolar I disorder have been formally diagnosed with an opioid-use disorder, compared with just 1% to 2% of the general U.S. population.[17] Additionally, the FDA cited its own drug-utilization research that approximately one in five adults aged 18 to 64 using olanzapine were concurrently receiving opioid prescriptions in outpatient or long-term care settings. The FDA’s analysis was based on a review of the medical records of over 1.6 million patients prescribed olanzapine in 2019.

What You Can Do

You should not use Lybalvi for the treatment of schizophrenia or bipolar I disorder. If you are currently using Lybalvi, do not discontinue it abruptly on you own. Instead, work with your prescribing physician to develop a plan for switching to alternative medication to manage your mental illness and weight-related concerns. If you are using Lybalvi, be aware that it likely compromises your ability to obtain severe pain relief, and it increases your risk of opioid overdose.
 

References

[1] Paik J. Olanzapine/samidorphan: First approval. Drugs. 2021;81(12):1431-1436.

[2] Alkermes. Label: olanzapine and samidorphan (Lybalvi), May 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213378s000lbl.pdf. Accessed March 8, 2023.

[3] FDA briefing document. Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Meeting. October 9, 2020. Topic: New drug application 213378. ALKS 3831 (olanzapine/samidorphan) for the treatment of schizophrenia and bipolar I disorder. https://www.fda.gov/media/142784/download. Accessed March 10, 2023.

[4] Abrams MT. Testimony before the Psychopharmacologic Drug and Drug Safety and Risk Management Advisory Committees. Topic: olanzapine/samidorphan (OLZ/SAM), NDA 213,378 (ALK3831) for schizophrenia or bipolar. U.S. Food and Drug Administration via webinar. https://www.citizen.org/wp-content/uploads/2548t.pdf. October 9, 2020. Accessed March 8, 2023.

[5] National Institute of Mental Health. Schizophrenia. May 2022. https://www.nimh.nih.gov/health/topics/schizophrenia#part_2276. Accessed March 8, 2023.

[6] National Institute of Mental Health. Bipolar disorder. February 2023. https://www.nimh.nih.gov/health/topics/bipolar-disorder. Accessed March 8, 2023.

[7] Ascend Laboratories. Label: olanzapine. September 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e8626e68-088d-47ff-bf06-489a778815aa&type=display. Accessed March 8, 2023.

[8] Jibson MD. Second-generation antipsychotic medications: pharmacology, administration, and side effects. UpToDate. May 11, 2022.

[9] 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 (June):45-53.

[10] FDA Briefing document. Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee meeting. October 9, 2020. Topic: New drug application 213378. ALKS 3831 (olanzapine/samidorphan) for the treatment of schizophrenia and bipolar I disorder. https://www.fda.gov/media/142784/download. Accessed March 10, 2023.

[11] 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.

[12] Monahan C, McCoy L, Powell J, Gums JG. Olanzapine/samidorphan: New drug approved for treating bipolar I disorder and schizophrenia. Ann Pharmacother. 2022;56(9):1049-1057.

[13] Ascend Laboratories. Label: olanzapine. September 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e8626e68-088d-47ff-bf06-489a778815aa&type=display. Accessed March 8, 2023.

[14] FDA briefing document. Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee meeting. October 9, 2020. Topic: New Drug Application 213378. ALKS 3831 (olanzapine/samidorphan) for the treatment of schizophrenia and bipolar I disorder. https://www.fda.gov/media/142784/download. Accessed March 10, 2023.

[15] Ascend Laboratories. Label: olanzapine. September 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e8626e68-088d-47ff-bf06-489a778815aa&type=display. Accessed March 8, 2023.

[16] Abrams MT. Testimony before the Psychopharmacologic Drug and Drug Safety and Risk Management Advisory Committee. Topic: olanzapine/samidorphan (OLZ/SAM), NDA 213,378 (ALK3831) for schizophrenia or bipolar. U.S. Food and Drug Administration via webinar. https://www.citizen.org/wp-content/uploads/2548.pdf. October 9, 2020. Accessed March 8, 2023.

[17] Ibid.