Lybalvi
olanzapine and samidorphan L-malate · Tablet, Film Coated · Oral
Uses
1 INDICATIONS AND USAGE LYBALVI is indicated 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 LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, indicated for the treatment of: Schizophrenia in adults ( 1 ) Bipolar I disorder in adults ( 1 ) Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate Maintenance monotherapy treatment
Dosage and administration
Indication Recommended Starting Dose (olanzapine/samidorphan) Recommended Dose (olanzapine/samidorphan) Schizophrenia ( 2.2 ) 5 mg/10 mg or 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder (manic or mixed episodes) ( 2.3 ) 10 mg/10 mg or 15 mg/10 mg 5 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg Bipolar I disorder adjunct to lithium or valproate ( 2.3 ) 10 mg/10 mg 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg See the full prescribing information for the recommended titration and maximum recommended dosage. ( 2.2 , 2.3 ) Administer LYBALVI once daily with or without food. Do not divide tablets or combine strengths. ( 2.4 ) Recommended starting dosage is 5 mg/10 mg once daily in patients who have a predisposition to hypotensive reactions, have potential for slower metabolism of olanzapine, or may be more pharmacodynamically sensitive to olanzapine. ( 2.5 ) 2.1 LYBALVI Initiation In Patients Using Opioids LYBALVI is contraindicated in patients using opioids or undergoing acute opioid withdrawal. 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 [see Warnings and Precautions ( 5.3 )]. 2.2 Recommended Dosage in Schizophrenia Initiate LYBALVI at 5 mg/10 mg (contains 5 mg of olanzapine and 10 mg of samidorphan) or 10 mg/10 mg (contains 10 mg of olanzapine and 10 mg of samidorphan) orally once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg (contains 15 mg of olanzapine and 10 mg of samidorphan), or 20 mg/10 mg (contains 20 mg of olanzapine and 10 mg of samidorphan) once daily. Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of LYBALVI) depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily. 2.3 Recommended Dosage in Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy: Initiate LYBALVI at 10 mg/10 mg or 15 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily. The maximum recommended dosage is 20 mg/10 mg once daily. Dosage adjustments should occur at intervals of not less than 24 hours. When dosage adjustments are necessary, dose increments/decrements of 5 mg (based on the olanzapine component of LYBALVI) are recommended. Maintenance Monotherapy: Administer LYBALVI at 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg once daily. Adjunctive to lithium or valproate: Initiate LYBALVI at 10 mg/10 mg once daily. The recommended dosage is 10 mg/10 mg, 15 mg/10 mg or 20 mg/10 mg, once daily. Dosage may be adjusted at weekly intervals of 5 mg (based on the olanzapine component of LYBALVI), depending upon clinical response and tolerability, up to the maximum recommended dosage of 20 mg/10 mg once daily. 2.4 Administration Information Administer LYBALVI orally once daily with or without food as a single tablet. Do not divide tablets or combine strengths. 2.5 Dosage Recommendations in Specific Populations The recommended starting dosage of LYBALVI is 5 mg/10 mg once daily in patients who have a higher risk of hypotensive reactions, are at risk of slower olanzapine metabolism, or may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.2 ), Use in Specific Populations ( 8.5 ), and Clinical Pharmacology ( 12.3 )] . If dose escalation is necessary, increase the dosage slowly in these patients.
Dosage forms and strengths
3 DOSAGE FORMS AND STRENGTHS LYBALVI tablets are available in four strengths ( Table 1 ). Table 1: LYBALVI Tablet Strengths and Identifying Features Tablet Strength Tablet Color/Shape Tablet Markings 5 mg/10 mg (olanzapine/samidorphan) Yellow, capsule-shaped “OS” and “5” 10 mg/10 mg (olanzapine/samidorphan) Orange, capsule-shaped “OS” and “10” 15 mg/10 mg (olanzapine/samidorphan) Blue, capsule-shaped “OS” and “15” 20 mg/10 mg (olanzapine/samidorphan) Pink, capsule-shaped “OS” and “20” Tablets (olanzapine/samidorphan): 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg and 20 mg/10 mg. ( 3 )
Contraindications
4 CONTRAINDICATIONS LYBALVI is contraindicated in patients: who are using opioids [ see Warnings and Precautions ( 5.3 , 5.4 ), Drug Interactions ( 7.3 )] . who are undergoing acute opioid withdrawal [see Warnings and Precautions ( 5.3 , 5.4 ), Drug Interactions ( 7.3 )] . If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products [see Warnings and Precautions ( 5.18 )] . Patients using opioids. ( 4 ) Patients undergoing acute opioid withdrawal. ( 4 ) If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for those products. ( 4 )
Warnings and precautions
Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis : Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities). ( 5.2 ) Precipitation of Opioid Withdrawal in Patients Who are Dependent on Opioids : LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids to avoid precipitation of opioid withdrawal. ( 2.1 , 5.3 ) Vulnerability to Life-Threatening Opioid Overdose : Risk of Opioid Overdose from Attempts to Overcome LYBALVI Opioid Blockade: Attempts to overcome LYBALVI opioid blockade with high or repeated doses of opioids may lead to fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued. ( 5.4 ) Risk of Resuming Opioids in Patients with Prior Opioid Use : Patients with a history of chronic opioid use prior to LYBALVI treatment may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. ( 5.4 ) Neuroleptic Malignant Syndrome : Manage with immediate discontinuation and close monitoring. ( 5.5 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue if DRESS is suspected. ( 5.6 ) Metabolic Changes : Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. ( 5.7 ) Tardive Dyskinesia : Discontinue if clinically appropriate. ( 5.8 ) Orthostatic Hypotension and Syncope : Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. ( 5.9 ) Leukopenia, Neutropenia, and Agranulocytosis : Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count. Consider discontinuation if clinically significant decline in WBC in the absence of other causative factors. ( 5.11 ) Seizures : Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.13 ) Potential for Cognitive and Motor Impairment : Use caution when operating machinery. ( 5.14 ) Anticholinergic (Antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. ( 5.16 ) Hyperprolactinemia : May elevate prolactin levels. ( 5.17 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than in placebo-treated patients (3.5% vs 1.5%, respectively). Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. LYBALVI is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.2 )]. 5.2 Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with olanzapine compared to patients treated with placebo. LYBALVI is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . 5.3 Precipitation of Severe Opioid Withdrawal in Patients Who Are Physiologically Dependent on Opioids Samidorphan, an opioid antagonist that is a component of LYBALVI, can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. Therefore, LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.3 )] . 5.4 Vulnerability to Life-Threatening Opioid Overdose Risk of Opioid Overdose from Attempts to Overcome Samidorphan Blockade LYBALVI contains samidorphan, an opioid antagonist. Attempting to overcome LYBALVI's opioid blockade with high or repeated doses of exogenous opioids (e.g., because of ineffective analgesia or opioid withdrawal symptoms) could lead to life-threatening or fatal opioid intoxication (e.g., respiratory arrest, circulatory collapse), particularly if LYBALVI therapy is interrupted or discontinued, subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes.
Side effects
The following adverse reactions are discussed in detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-related Psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] Precipitation of Opioid Withdrawal in Patients Who Are Dependent on Opioids [see Warnings and Precautions ( 5.3 ) ] Vulnerability to Life-Threatening Opioid Overdose [see Warnings and Precautions ( 5.4 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.5 )] Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions ( 5.6 )] Metabolic Changes [see Warnings and Precautions ( 5.7 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.14 )] Body Temperature Regulation [see Warnings and Precautions ( 5.15 )] Anticholinergic (Antimuscarinic) Effects [see Warnings and Precautions ( 5.16 )] Hyperprolactinemia [see Warnings and Precautions ( 5.17 )] Risks Associated with Combination Treatment with Lithium or Valproate [see Warnings and Precautions ( 5.18 )] Most common adverse reactions (incidence ≥5% and at least twice placebo): Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache. ( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, tremor. ( 6.1 ) Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine): dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Patients with Schizophrenia Patient Exposure The safety of LYBALVI was evaluated in 1262 patients (18 to 67 years of age) diagnosed with schizophrenia in four double-blind, controlled studies and three long-term safety extension studies of up to 3 years of duration. This experience corresponds to approximately 910 person-years. In these studies, there were a total of 663 patients exposed to LYBALVI for at least 6 months, and 386 patients for at least one year. Adverse Reactions in the Short-Term (4 week) Placebo-Controlled Trial in Adults with Schizophrenia The most common adverse reactions (incidence of at least 5% of patients exposed to LYBALVI and greater than twice the rate of placebo) are weight increased, somnolence, dry mouth, and headache. Adverse reactions associated with the use of LYBALVI (incidence of 2% or greater and greater than in placebo-treated patients) are shown in Table 2 . Table 2: Adverse Reactions Reported in ≥2% of LYBALVI-Treated Patients and Greater than Placebo in a 4-Week Schizophrenia Trial Adverse Reaction Placebo (N=134) % LYBALVI (10 mg/10 mg, 20 mg/10 mg) (N=134) % Weight increased 3 19 Somnolence 2 9 Dry mouth 1 7 Headache 3 6 Blood insulin increased 1 3 Sedation 0 2 Dizziness 1 2 Neutrophil count decreased 0 2 Adverse reactions that led to discontinuation in LYBALVI-treated patients in the short-term placebo-controlled trial in adults with schizophrenia include schizophrenia (1%) and abnormal liver function tests (1%). Adverse Reactions in the Long-Term (24-week), Active-Controlled Trial in Adults with Schizophrenia In the 24-week, olanzapine-controlled trial in patients with stable schizophrenia, adverse reactions associated with the use of LYBALVI (incidence of 2% or greater) include: weight increased (25%), somnolence (21%), dry mouth (13%), increased appetite (11%), waist circumference increased (6%), blood creatine phosphokinase increased (5%), headache (4%), lethargy (4%), sedation (4%), akathisia (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), constipation (3%), dizziness (3%), fatigue (3%), nausea (3%), blood pressure increased (3%), neutrophil count decreased (3%), blood insulin increased (2%), weight decreased (2%), and dyslipidemia (2%). Adverse reactions that led to LYBALVI treatment discontinuation in more than one patient include somnolence (2%), weight increased (2%), neutropenia (2%), glycosylated hemoglobin increased (1%), schizophrenia (1%), and liver function test abnormal (1%). Hyperglycemia Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL. Hyperglycemia, as defined by fasting glucose ≥126 mg/dL, has been observed in patients treated with LYBALVI. In the 4-week placebo-controlled trial in adult patients with schizophrenia, shifts in fasting glucose from normal to high occurred in 4% of patients treated with LYBALVI, 1% of patients treated with olanzapine, and no patients treated with placebo.
Drug interactions
Strong CYP3A4 Inducers : Not recommended. ( 7.1 ) Strong CYP1A2 Inhibitors : Consider dosage reduction of olanzapine component of LYBALVI. ( 7.1 ) CYP1A2 Inducer : Consider dosage increase of the olanzapine component of LYBALVI. ( 7.1 ) CNS Acting Drugs : May potentiate orthostatic hypotension. ( 7.1 ) Anticholinergic Drugs: Can increase risk for severe gastrointestinal adverse reactions. ( 7.1 ) Antihypertensive Agents : Monitor blood pressure. ( 7.2 ) Levodopa and Dopamine Agonists : Not recommended. ( 7.2 ) 7.1 Effects of Other Drugs on LYBALVI Table 4 describes clinically significant drug interactions where the concomitant use of other drugs affects LYBALVI. Table 4: Effects of Other Drugs on LYBALVI Strong CYP3A4 Inducer Clinical Implication: Coadministration of LYBALVI with a strong CYP3A4 inducer decreases AUC inf of olanzapine and samidorphan [see Clinical Pharmacology ( 12.3 )], which may reduce LYBALVI efficacy. Prevention or Management: Concomitant use of LYBALVI with strong CYP3A4 inducers is not recommended. Strong CYP1A2 Inhibitor Clinical Implication: Concomitant use of LYBALVI with a strong CYP1A2 inhibitor increases olanzapine AUC and C max [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of LYBALVI adverse reactions. Prevention or Management: Consider reducing the dosage of the olanzapine component in LYBALVI when used concomitantly with strong CYP1A2 inhibitors. CYP1A2 Inducer Clinical Implication: Concomitant use of LYBALVI with CYP1A2 inducers decreases olanzapine exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce LYBALVI efficacy. Prevention or Management: Consider increasing the dosage of the olanzapine component in LYBALVI when used concomitantly with CYP1A2 inducers. Diazepam, Alcohol, and Other CNS Acting Drugs Clinical Implication: Concomitant use of diazepam, alcohol, or other CNS acting drugs with LYBALVI may potentiate the orthostatic hypotension observed with olanzapine [see Warnings and Precautions ( 5.9 )] . Prevention or Management: LYBALVI should be used with caution in patients receiving concomitantly diazepam or other CNS acting drugs, or using alcohol. Anticholinergic Drugs Clinical Implication: Concomitant treatment with olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Prevention or Management: LYBALVI should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions ( 5.16 )] . 7.2 Effects of LYBALVI on Other Drugs Table 5 describes clinically significant drug interactions where concomitant use of LYBALVI affects other drugs. Table 5: Effects of LYBALVI on Other Drugs Antihypertensive Agents Clinical Implication: LYBALVI may enhance the effects of certain antihypertensive agents. Prevention or Management: Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling. Levodopa and Dopamine Agonists Clinical Implication: LYBALVI may antagonize the effects of levodopa and dopamine agonists. Prevention or Management: Concomitant use of LYBALVI is not recommended with levodopa and dopamine agonists. 7.3 Opioids LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal [see Contraindications ( 4 )]. LYBALVI increases the risk of precipitating acute opioid withdrawal in patients who are dependent on opioids. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.3 )] . In emergency situations, if a LYBALVI-treated patient requires opioid treatment for anesthesia or analgesia, discontinue LYBALVI. The opioid should be administered by properly trained individual(s), and the patient should be properly monitored in a setting equipped and staffed for cardiopulmonary resuscitation [see Warnings and Precautions ( 5.4 )]. In non-emergency situations, if a LYBALVI-treated patient is expected to require opioid treatment (e.g., for analgesia during or after an elective surgical procedure) discontinue LYBALVI at least 5 days before opioid treatment and start olanzapine or another antipsychotic, if needed. Given that LYBALVI contains samidorphan, an opioid antagonist, opioid treatment may be less effective or ineffective shortly after LYBALVI discontinuation because of the presence of samidorphan. 7.4 Interference with Laboratory Tests Interference with Laboratory Tests for Opioid Detection Because LYBALVI contains samidorphan, an opioid antagonist, LYBALVI may be cross-reactive with urinary immunoassay methods used for detecting opioids, resulting in false positive results. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results [see Contraindications ( 4 ) and Warnings and Precautions ( 5.19 )] .
Use in specific populations
Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Renal Impairment: Use is not recommended in patients with end-stage renal disease. ( 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including LYBALVI, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/ . Risk Summary Neonates exposed to antipsychotic drugs, including the olanzapine component of LYBALVI, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are no available data on the use of samidorphan or the combination of olanzapine and samidorphan in pregnant women to determine a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including LYBALVI, during pregnancy (see Clinical Considerations ) . LYBALVI In an animal reproduction study, oral administration of olanzapine and samidorphan to pregnant rats during the period of organogenesis produced adverse effects on embryofetal development and fetal toxicity at maternally toxic doses that are 6 times and >400 times the maximum recommended human dose (MRHD) of 20 mg/10 mg olanzapine/samidorphan in LYBALVI, respectively based on AUC. There were no adverse effects on embryofetal development at doses of olanzapine and samidorphan that are approximately 1 and 80 times, respectively, the MRHD based on AUC (see Data ) . Olanzapine In animal reproduction studies, there was no evidence of malformations in rats or rabbits when orally administered olanzapine at doses up to 9 and 30 times the MRHD dose (20 mg) based on mg/m 2 body surface area, respectively. In an oral rat embryofetal developmental toxicity study, early resorptions and increased numbers of nonviable fetuses were observed at a dose 9 times the MRHD based on mg/m 2 body surface area and gestation was prolonged at 5 times the MRHD based on mg/m 2 body surface area. In an oral rabbit embryofetal developmental toxicity study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of olanzapine which is 30 times the MRHD based on mg/m 2 body surface area (see Data ) . Samidorphan In animal reproduction studies, oral administration of samidorphan to pregnant rats and rabbits during the period of organogenesis caused fetal toxicities in rats only at maternally toxic doses that are >248 times the human exposure at the MRHD of 10 mg/day based on AUC. Oral administration of samidorphan to pregnant rats during pregnancy and lactation resulted in lower pup survival and decreased pup weights at 188 times the human exposure at the MRHD based on AUC (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk There is risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/ Neonatal Risks Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including the olanzapine component of LYBALVI, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data LYBALVI Olanzapine and samidorphan were orally administered to pregnant rats during the period of organogenesis at doses of 0.5/10, 2/50, 6/200, and 0/200 mg/kg/day (olanzapine/samidorphan) which are approximately <1/10 times to 6/448 times the MRHD of 20 mg/10 mg, olanzapine/samidorphan, respectively, based on AUC. Maternal toxicity consisting of decreased body weight and food consumption was observed at all dose levels. Administration of samidorphan alone (200 mg/kg/day) and 6/200 mg/kg/day olanzapine/samidorphan decreased mean fetal body weights, increased litter incidence of bent ribs and bent scapula; however, the incidence of bent scapula and bent ribs was not increased when samidorphan was administered in combination with olanzapine compared to the incidence with samidorphan alone.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including LYBALVI, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/ . Risk Summary Neonates exposed to antipsychotic drugs, including the olanzapine component of LYBALVI, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are no available data on the use of samidorphan or the combination of olanzapine and samidorphan in pregnant women to determine a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including LYBALVI, during pregnancy (see Clinical Considerations ) . LYBALVI In an animal reproduction study, oral administration of olanzapine and samidorphan to pregnant rats during the period of organogenesis produced adverse effects on embryofetal development and fetal toxicity at maternally toxic doses that are 6 times and >400 times the maximum recommended human dose (MRHD) of 20 mg/10 mg olanzapine/samidorphan in LYBALVI, respectively based on AUC. There were no adverse effects on embryofetal development at doses of olanzapine and samidorphan that are approximately 1 and 80 times, respectively, the MRHD based on AUC (see Data ) . Olanzapine In animal reproduction studies, there was no evidence of malformations in rats or rabbits when orally administered olanzapine at doses up to 9 and 30 times the MRHD dose (20 mg) based on mg/m 2 body surface area, respectively. In an oral rat embryofetal developmental toxicity study, early resorptions and increased numbers of nonviable fetuses were observed at a dose 9 times the MRHD based on mg/m 2 body surface area and gestation was prolonged at 5 times the MRHD based on mg/m 2 body surface area. In an oral rabbit embryofetal developmental toxicity study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of olanzapine which is 30 times the MRHD based on mg/m 2 body surface area (see Data ) . Samidorphan In animal reproduction studies, oral administration of samidorphan to pregnant rats and rabbits during the period of organogenesis caused fetal toxicities in rats only at maternally toxic doses that are >248 times the human exposure at the MRHD of 10 mg/day based on AUC. Oral administration of samidorphan to pregnant rats during pregnancy and lactation resulted in lower pup survival and decreased pup weights at 188 times the human exposure at the MRHD based on AUC (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk There is risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/ Neonatal Risks Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including the olanzapine component of LYBALVI, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data LYBALVI Olanzapine and samidorphan were orally administered to pregnant rats during the period of organogenesis at doses of 0.5/10, 2/50, 6/200, and 0/200 mg/kg/day (olanzapine/samidorphan) which are approximately <1/10 times to 6/448 times the MRHD of 20 mg/10 mg, olanzapine/samidorphan, respectively, based on AUC. Maternal toxicity consisting of decreased body weight and food consumption was observed at all dose levels. Administration of samidorphan alone (200 mg/kg/day) and 6/200 mg/kg/day olanzapine/samidorphan decreased mean fetal body weights, increased litter incidence of bent ribs and bent scapula; however, the incidence of bent scapula and bent ribs was not increased when samidorphan was administered in combination with olanzapine compared to the incidence with samidorphan alone. Administration of olanzapine/samidorphan at 6/200 mg/kg/day also increased resorptions and post-implantation loss, with correlating lower mean viable fetuses and litter size.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of LYBALVI have not been established in pediatric patients.
Geriatric use
8.5 Geriatric Use Clinical studies of LYBALVI did not include sufficient numbers of patients 65 years of age and older to determine whether they responded differently than younger adult patients. Olanzapine Of the 2,500 patients in premarketing clinical studies with orally administered olanzapine, 11% (263) were 65 years of age or over. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI is not approved for the treatment of patients with dementia-related psychosis [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 )] . Studies in elderly patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) in patients treated with olanzapine, compared to patients treated with placebo. In five placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1,184), the following adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than in placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual hallucinations. The rate of discontinuation due to adverse reactions was greater with olanzapine than with placebo (13% vs 7%). Consider a lower dosage of the olanzapine component of LYBALVI in geriatric patients who may have decreased clearance or an exaggerated pharmacodynamic response to olanzapine (e.g., oversedation) [see Dosage and Administration ( 2.5 )].
Overdosage
Human Experience There is limited clinical experience with overdose with LYBALVI. In premarketing clinical trials of LYBALVI involving 861 patients, overdose of LYBALVI was identified in 7 patients. This included 4 patients with accidental overdose, 2 with intentional overdose, and 1 due to a medication administration error. None of the reported overdoses was associated with a fatal outcome. There was a reported ingestion of 11 tablets of LYBALVI 10 mg/10 mg (5.5 times and 11 times the maximum recommended daily dosage of the olanzapine and samidorphan components of LYBALVI, respectively). The patient was found unresponsive and admitted to the hospital. Medical treatment included fluids, electrolytes, a diuretic, and a detoxicant; the patient stabilized within 2 days. In postmarketing reports of overdose with olanzapine, a component of LYBALVI, symptoms included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Less commonly reported symptoms include: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and 1 patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2,000 mg. Management of Overdose No specific antidotes for LYBALVI are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a certified Poison Control Center (1-800-222-1222) for additional overdosage management recommendations.
Description
11 DESCRIPTION LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan (as samidorphan L-malate), an opioid antagonist. Olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H -thieno[2,3- b ][1,5]benzodiazepine. The molecular formula of olanzapine is: C 17 H 20 N 4 S and the molecular weight is 312.44 g/mol. It is a yellow crystalline powder and has pKa values of 7.80 and 5.44. The chemical structure is: Samidorphan L-malate is morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4, 14-dihydroxy-6-oxo-, (2S)-2-hydroxybutanedioate. The molecular formula of samidorphan L-malate is C 21 H 26 N 2 O 4
• C 4 H 6 O 5 and the molecular weight is 504.54 g/mol. It is a white to off-white crystalline powder and has pKa values of 8.3 (amine) and 10.1 (phenol). The chemical structure is: LYBALVI is intended for oral administration and is available as film-coated, bilayer tablets in the following strengths: 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg of olanzapine and samidorphan (equivalent to 13.6 mg of samidorphan L-malate). Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating ingredients include hypromellose, titanium dioxide, triacetin, and color additives [iron oxide yellow (5 mg/10 mg); iron oxide yellow and iron oxide red (10 mg/10 mg); FD&C Blue No. 2/ indigo carmine aluminum lake (15 mg/10 mg); iron oxide red (20 mg/10 mg)]. Olanzapine Chemical Structure Samidorphan L-malate Chemical Structure
Mechanism of action
12.1 Mechanism of Action The mechanism of action of olanzapine is unclear; however, its efficacy in the treatment of schizophrenia or bipolar I disorder could be mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) antagonism. The mechanism of action of samidorphan could be mediated through opioid receptor antagonism.
How supplied
How Supplied LYBALVI (olanzapine and samidorphan) tablets have markings on both sides and are available as described in Table 9 . Table 9: LYBALVI Tablet Presentations Tablet Strength(s) (olanzapine/samidorphan) Tablet Description Package Configuration NDC Number 5 mg/10 mg Yellow, capsule-shaped, debossed with “OS” on one side and “5” on the other side 30-count bottle with child resistant closure 65757-651-42 10 mg/10 mg Orange, capsule-shaped, debossed with “OS” on one side and “10” on the other side 30-count bottle with child resistant closure 65757-652-42 15 mg/10 mg Blue, capsule-shaped, debossed with “OS” on one side and “15” on the other side 30-count bottle with child resistant closure 65757-653-42 20 mg/10 mg Pink, capsule-shaped, debossed with “OS” on one side and “20” on the other side 30-count bottle with child resistant closure 65757-654-42 Storage and Handling Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep tightly closed and protect from moisture.
Storage
Storage and Handling Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep tightly closed and protect from moisture.
Patient information
Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Concomitant Use with Opioids is Contraindicated Advise patients to inform their healthcare provider if they are taking, or plan to take any opioids for any reason, as LYBALVI is contraindicated with use of opioids or those undergoing acute opioid withdrawal [see Dosage and Administration ( 2.1 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.3 )] . Precipitation of Opioid Withdrawal Advise patients not to take LYBALVI when using opioids because of the risks of opioid withdrawal syndrome, sometimes requiring hospitalization. Advise patients that they should have an opioid-free period of a minimum of 7 days after last use of short-acting opioids and 14 days from last use of long-acting opioids before initiating LYBALVI [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] . Risk of Opioid Overdosage Advise patients that they may be at increased risk of opioid overdosage if they attempt to use high or repeated opioid doses. Inform patients of the potential consequences of trying to overcome the opioid blockade and the serious risks of taking opioids concurrently with LYBALVI or while transitioning off LYBALVI [see Warnings and Precautions ( 5.4 )] . Risk of Resuming Opioids in Patients with Prior Opioid Use Advise patients that if they used opioids prior to LYBALVI treatment, they may have decreased opioid tolerance if they use opioids after LYBALVI discontinuation or interruption [see Warnings and Precautions ( 5.4 )] . Neuroleptic Malignant Syndrome Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact the healthcare provider or to report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions ( 5.5 )] . Drug Reaction with Eosinophilia and Systemic Symptoms Advise patients to report to their health care provider at the earliest onset of any signs and symptoms that may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.6 )] . Metabolic Changes Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions ( 5.7 )]. Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions ( 5.8 )]. Orthostatic Hypotension and Syncope Educate patients about the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.2 )] . Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/ neutropenia that they should have their CBC monitored while taking LYBALVI [see Warnings and Precautions ( 5.11 )]. Potential for Cognitive and Motor Impairment Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that LYBALVI therapy does not affect them adversely [see Warnings and Precautions ( 5.14 )] . Concomitant Medication Advise patients to inform their healthcare providers if they are taking, or plan to take any other olanzapine containing medication. Advise patients to inform their healthcare providers of any changes to their current prescription or over-the-counter medications because there is a potential for interactions [see Drug Interactions ( 7.1 , 7.2 , 7.3 )] . Body Temperature Dysregulation Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions ( 5.15 )] . Alcohol Advise patients to use caution consuming alcohol while taking LYBALVI [see Drug Interactions ( 7.1 )] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Advise patients that LYBALVI used during the third trimester may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise breastfeeding women using LYBALVI to monitor infants for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] . Infertility Advise females of reproductive potential that LYBALVI may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Administration Information Advise patients to take LYBALVI once daily and not split or combine tablets [see Dosage and Administration ( 2.4 )] . Distributed by: Alkermes, Inc. Waltham, MA 02451 © 2026 Alkermes, Inc. All rights reserved. ALKERMES ® is a registered trademark of Alkermes, Inc. LYBALVI ® is a registered trademark of Alkermes Pharma Ireland Limited, used by Alkermes, Inc., under license. Printed in U.S.A. Alkermes Logo
Label text from the FDA structured product label by Alkermes, Inc. (revised Jan 31, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Olanzapine in 4 products
- Samidorphan L-malate in 4 products
Lybalvi NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 65757-651 | Olanzapine 5 mg/1; Samidorphan L-malate 10 mg/1 Tablet, Film Coated | Alkermes, Inc. | NDA |
| 65757-652 | Olanzapine 10 mg/1; Samidorphan L-malate 10 mg/1 Tablet, Film Coated | Alkermes, Inc. | NDA |
| 65757-653 | Olanzapine 15 mg/1; Samidorphan L-malate 10 mg/1 Tablet, Film Coated | Alkermes, Inc. | NDA |
| 65757-654 | Olanzapine 20 mg/1; Samidorphan L-malate 10 mg/1 Tablet, Film Coated | Alkermes, Inc. | NDA |
Frequently asked questions
What is Lybalvi used for?
1 INDICATIONS AND USAGE LYBALVI is indicated 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 LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, indicated for the treatment of:…
What are the side effects of Lybalvi?
The following adverse reactions are discussed in detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-related Psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] Precipitation of Opioid Withdrawal in… See the full label for the complete list.
Who makes Lybalvi?
Lybalvi is listed by 1 labeler in the FDA NDC directory, including Alkermes, Inc..