Pharmacists dispensing Lybalvi should understand that potentially life-threatening consequences can occur if opioids are taken concurrently.
This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
On May 28, 2021, the FDA approved Lybalvi, a drug combination of olanzapine and samidorphan. Lybalvi is indicated for the treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes in adults with bipolar I disorder as monotherapy and as an adjunct to lithium or valproate, or as maintenance monotherapy treatment.1,2
Lybalvi is available as a single tablet, in multiple strengths that is dosed once daily with dosage recommendations based on the disease state being treated.
Schizophrenia is a mental disorder marked by hallucinations, delusions, unusual ways of thinking, reduced expression of emotions, apathy, difficulty with social relationships, and cognitive impairment. While the prevalence of schizophrenia is difficult to obtain, it is estimated that schizophrenia affects up to 0.64% of the US population.3
Bipolar I disorder is a mental disorder defined by manic episodes that last at least 7 days, or by manic symptoms that are so severe that most patients need immediate hospital care. During a manic episode, most patients experience symptoms such as having increased energy, feeling on top of the word, irritability, faster speech, uncontrollable racing thoughts, quickly changing ideas or topics when speaking, hypersexuality, and other compulsive behaviors.4
Often, depressive episodes occur after a manic episode or simultaneously, typically lasting at least 2 weeks.5 It is estimated that 4.4% of US adults will experience bipolar disorder at some time in their lives.6
Olanzapine is an atypical antipsychotic that was first approved by the FDA for the treatment of schizophrenia in 1996, and later for the treatment of bipolar I disorder in 2000.7
Though the mechanism of action of olanzapine is unknown, it is thought that its efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. One of the most common adverse events (AEs) associated with olanzapine therapy is weight gain.8
Samidorphan, the second active ingredient in Lybalvi, is an opioid antagonist. Notably, samidorphan is not FDA-approved in the United States as a standalone product.
Samidorphan is an antagonist at the mu-opioid receptors with partial agonist activity at the kappa- and delta-opioid receptors.2 The intent of combining samidorphan with olanzapine is to mitigate the weight gain associated with olanzapine therapy. Samidorphan has been studied since the mid-late 2000s.9
The first studies that investigated the effects of samidorphan in humans were conducted by Turncliff R, DiPetrillo L, Silverman B, and colleagues. They evaluated the safety, tolerability, and pharmacokinetic properties of samidorphan in healthy adults in 2 studies.9
In both studies, samidorphan had a time to peak concentration (Tmax) of 1 hour and its half-life (t1/2) ranged from approximately 7-9 hours. Somnolence (60.0%–67.7%) and nausea (33.3%–46.7%) were the most commonly reported adverse drug reactions in both studies.
Due to its mechanism of action, samidorphan may reduce the efficacy of pain control in patients who require opioids for unexpected severe pain (e.g., trauma or emergency surgery). Because of its opioid antagonism, samidorphan can also cause unintended consequences for patients dependent on opioids by precipitating opioid withdrawal.
The non-opioid-related risks associated with Lybalvi are similar to those of other atypical antipsychotics, due to the olanzapine component. Specifically, Lybalvi has a boxed warning for increased mortality in elderly patients with dementia-related psychosis.
In addition, some similar warnings and precautions include cerebrovascular AEs, including stroke in elderly patients with dementia-related psychosis, neuroleptic malignant syndrome, metabolic changes, tardive dyskinesia, orthostatic hypotension and syncope, falls, leukopenia, neutropenia, and agranulocytosis, dysphagia, seizures, potential for cognitive and motor impairment, and body temperature dysregulation.
Additional warnings and precautions due to the olanzapine component that are not commonly associated with other atypical antipsychotics include: drug reaction with eosinophilia and systemic symptoms, anticholinergic (antimuscarinic effects), hyperprolactinemia, and risks associated with combination treatment with lithium or valproate. We encourage the reader to refer to the FDA-approved prescribing information for Lybalvi for further information pertaining to the boxed warning, contraindications, and warnings and precautions.
Lybalvi is contraindicated in patients who are using opioids and in patients who are undergoing acute withdrawal. Opioid-related risks with Lybalvi are further described inthe warnings and precautions, drug interactions, and patient counseling information sections of the prescribing information. Below, we focus on the opioid-related risk information found in the warnings and precautions section of the prescribing information.
Section 5.3 of the prescribing information explains the risk of severe opioid withdrawal in patients who are physiologically dependent on opioids, which can sometimes require hospitalization. The various dosing scenarios that are provided below have been derived from Lybalvi prescribing information.2
These scenarios include initiating Lybalvi in patients who use opioids and emergent situations in which patients already taking Lybalvi may require opioid treatment as part of anesthesia or analgesia. There is also a dosing scenario in non-emergency situations for Lybalvi-treated patients who are expected to require opioid-treatment.
It is important that patients and/or caregivers give an accurate account of last opioid use. The pharmacist will play an instrumental role in being able to provide critical information such as the last fill date and date of medication pick-up for opioid prescription(s).
It is recommended that the pharmacist ask the patient about all opioid use, including both prescribed and illicitly obtained opioids; however, there are limitations to this information. For example, patients may start taking the opioid(s) several days after picking up the prescription. When prescribing and dispensing Lybalvi, health care providers must explain to the patient and/or caregiver that giving an inaccurate account of last opioid use can lead to severe opioid withdrawal, which can result in hospitalization.
Section 5.4 of the prescribing information explains the risk of vulnerability to life-threatening opioid overdose. If a patient taking Lybalvi attempts to overcome the drug’s opioid blockade with high or repeated doses of exogenous opioids, a life-threatening or fatal opioid intoxication can occur.
In addition, a life-threatening opioid overdose can particularly occur at times when Lybalvi is interrupted or discontinued, because the opioid agonist will have less competition as the blockade of samidorphan wanes. When prescribing Lybalvi, health care providers must counsel patients about this risk, which can result in a life-threatening emergency. Pharmacists who dispense Lybalvi should also counsel patients about this serious risk.
As more prescribers and pharmacists become familiar with Lybalvi as an additional therapeutic option for treating bipolar I disorder and schizophrenia, there is potential for more Lybalvi prescriptions to be written and dispensed. Pharmacists dispensing Lybalvi should understand that potentially life-threatening consequences can occur if opioids are taken concurrently with Lybalvi.
There are strict guidelines for resuming opioids or resuming Lybalvi after opioid use in specific situations as mentioned above. In collaborative practice settings, prescribers may request pharmacist assistance with determining when it is safe to resume an opioid or when it is safe to resume Lybalvi after opioid therapy. Prescribers will also rely on pharmacists to provide an accurate record of prescription history, especially when starting Lybalvi.
When dispensing Lybalvi to patients with a history of opioid use disorder, pharmacists should counsel them that they may have a decreased opioid tolerance if Lybalvi therapy is interrupted or discontinued. In such cases, patients should be cautioned not to resume their previously tolerated opioid dose, as this may lead to an increased risk of opioid overdose.
Pharmacists should also advise patients to alert other health care providers that they take Lybalvi, particularly in emergency situations or if a need for opioids is anticipated. We recommend that the pharmacist dispensing Lybalvi utilize the patient counseling information section (section 17) of the prescribing information and discuss the contents of the medication guide with patients. The medication guide contains critical information pertaining to the aforementioned risks and explains this information in clear language that most patients should understand.
Pharmacists can play a crucial role in counseling Lybalvi-treated patients and their caregivers to help avoid problematic drug interactions with opioids. Additionally, pharmacists can play a role in stressing medication adherence to Lybalvi, which can help mitigate lapses in therapy, and the potential serious consequences of using opioids concurrently.
Lybalvi offers an additional treatment option for vulnerable patients with bipolar I disorder and schizophrenia; however, if an opioid is involved, its use comes with potentially life-threatening risks. It is vital that pharmacists who dispense Lybalvi understand these risks and understand their role in mitigating the potential for these opioid-related risks in patients.
About the Authors
Domenic D’Alessandro PharmD, MBA, BCPS, CDCES, is a regulatory review officer for psychiatry drug products at the FDA Center for Drug Evaluation and Research’s Office of Prescription Drug Promotion, in the Office of Medical Policy.
Sapna Shah, PharmD, is a regulatory review officer for neurology drug products at the FDA Center for Drug Evaluation and Research’s Office of Prescription Drug Promotion, in the Office of Medical Policy.
Mark A. Liberatore, PharmD, RAC, is deputy director for safety in the Division of Anesthesiology, Addiction Medicine and Pain Medicine at the FDA Center for Drug Evaluation and Research’s Office of New Drugs.
Marc Stone, MD, is deputy director for safety in the Division of Psychiatry at the FDA Center for Drug Evaluation and Research’s Office of New Drugs.
D’Alessandro, Shah, Liberatore, and Stone have no relevant financial disclosures.