b'Important Safety InformationDrug Reaction with Eosinophilia and Systemic SymptomsAnticholinergic (Antimuscarinic) Effects: Olanzapine, aLYBALVI (olanzapine and samidorphan) tablets, for oral use For recommendations on starting opioids in LYBALVI-treated patients in(DRESS), a potentially fatal condition reported with exposurecomponent of LYBALVI, was associated with constipation,BRIEF SUMMARY OF PRESCRIBING INFORMATION non-emergent situations, see DRUG INTERACTIONS section.to olanzapine, a component of LYBALVI. Symptoms includedry mouth, and tachycardia. Use LYBALVI with caution with(For complete details, see full Prescribing Information) Risk of Resuming Opioids in Patients with Prior Opioid UsePatients with a history of chronic opioid use prior to treatment with LYBALVI may a cutaneous reaction (such as rash or exfoliative dermatitis),other anticholinergic medications and in patients with urinaryWARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. eosinophilia, fever, and/or lymphadenopathy with systemicretention, prostatic hypertrophy, constipation, paralytic ileusDEMENTIA-RELATED PSYCHOSISAdvise patients that this decreased tolerance may increase the risk of opioid complications such as hepatitis, nephritis, pneumonitis,or related conditions. In postmarketing experience, the risk forElderly patients with dementia-related psychosis treated withoverdose if opioids are resumed at the previously tolerated dosage.myocarditis, and/or pericarditis. Discontinue if DRESS severe adverse reactions (including fatalities) was increasedantipsychotic drugs are at an increased risk of death. LYBALVI is notNeuroleptic Malignant Syndrome: Neuroleptic Malignant Syndrome (NMS), is suspected. with concomitant use of anticholinergic medications. approved for the treatment of patients with dementia-related psychosis.a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are Metabolic Changes, including hyperglycemia, diabetesHyperprolactinemia: LYBALVI elevates prolactin levels.INDICATIONS AND USAGE hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs mellitus, dyslipidemia, and weight gain. Hyperglycemia, inGalactorrhea, amenorrhea, gynecomastia, and impotence LYBALVI is indicated for the treatment of:may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and some cases extreme and associated with ketoacidosis orhave been reported in patients receiving prolactin- Schizophrenia in adults acute renal failure.hyperosmolar coma or death, has been reported in patientselevating compounds.Bipolar I disorder in adults If NMS is suspected, immediately discontinue LYBALVI and provide intensive treated with atypical antipsychotics. Any patient treated with| symptomatic treatment and monitoring.Acute treatment of manic or mixed episodes as monotherapy and as Risks Associated with Combination Treatment withadjunct to lithium or valproateDrug Reaction with Eosinophilia and Systemic Symptoms: Drug Reaction LYBALVI should be monitored for symptoms of hyperglycemia|with Eosinophilia and Systemic Symptoms (DRESS) has been reported with including polydipsia, polyuria, polyphagia, and weakness. InLithium or Valproate: If LYBALVI is administered with lithiumMaintenance monotherapy treatmentexposure to olanzapine, a component of LYBALVI. DRESS may present with a some cases, hyperglycemia has resolved when the atypicalor valproate, refer to the lithium or valproate PrescribingCONTRAINDICATIONS cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, antipsychotic was discontinued; however, some patientsInformation for a description of the risks for these products.LYBALVI is contraindicated in patients:and/or lymphadenopathy with systemic complications such as hepatitis, nephritis,who are using opioidspneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. required anti-diabetic treatment despite discontinuation of theMost common adverse reactions observed in clinical Discontinue LYBALVI if DRESS is suspected.suspect drug. Measure weight and assess fasting glucose andtrials were:who are undergoing acute opioid withdrawalMetabolic Changes: Atypical antipsychotic drugs, including LYBALVI, have been If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate lipids when initiating LYBALVI and monitor periodically. Schizophrenia (LYBALVI): weight increased, somnolence, dryPrescribing Information for the contraindications for these products. associated with metabolic changes that include hyperglycemia, diabetes mellitus,dyslipidemia, and body weight gain. While all drugs in the class have been shown to Tardive Dyskinesia (TD): Risk of developing TD (a syndromemouth, and headache WARNINGS AND PRECAUTIONS produce some metabolic changes, each drug has its own specific risk profile.of potentially irreversible, involuntary, dyskinetic movements)Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Hyperglycemia, in some cases extreme and associated with ketoacidosis or and the likelihood it will become irreversible increases with theare at an increased risk of death. In placebo-controlled clinical trials of elderlyhyperosmolar coma or death, has been reported in patients treated with atypical Bipolar I Disorder, Manic or Mixed Episodes (olanzapine):Elderly patients with dementia-related psychosis treated with antipsychotic drugs duration of treatment and the cumulative dose. The syndromeasthenia, dry mouth, constipation, increased appetite,patients with dementia-related psychosis, the incidence of death in olanzapine-somnolence, dizziness, tremorantipsychotics. Any patient treated with LYBALVI should be monitored for symptoms can develop after a relatively brief treatment period, even attreated patients was significantly greater than in placebo-treated patients (3.5%of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithiumvs 1.5%, respectively). Analyses of 17 placebo-controlled trials (modal duration ofwho develop symptoms of hyperglycemia during treatment with LYBALVI should low doses, or after discontinuation. Given these considerations,undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved LYBALVI should be prescribed in a manner that is most likely toor Valproate (olanzapine): dry mouth, dyspepsia, weight10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk ofwhen the atypical antipsychotic was discontinued; however, some patients required gain, increased appetite, dizziness, back pain, constipation,death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo- anti-diabetic treatment despite discontinuation of the suspect drug. Patients reduce the risk of tardive dyskinesia. If signs and symptoms oftreated patients. Over the course of a typical 10-week controlled trial, the rate of TD appear, drug discontinuation should be considered. speech disorder, increased salivation, amnesia, paresthesiadeath in drug-treated patients was about 4.5%, compared to a rate of about 2.6%starting treatment with LYBALVI should undergo fasting blood glucose testing at the in the placebo group. Although the causes of death were varied, most of the deathsbeginning of treatment and periodically during treatment.Orthostatic Hypotension and Syncope: Monitor orthostaticConcomitant Medication: LYBALVI is contraindicated inappeared to be either cardiovascular (e.g., heart failure, sudden death) or infectiousAntipsychotics have caused adverse alterations in lipids. Patients starting treatment vital signs in patients who are vulnerable to hypotension,patients who are using opioids or undergoing acute opioid(e.g., pneumonia) in nature. LYBALVI is not approved for the treatment of patientswith LYBALVI should undergo fasting lipid profile testing at the beginning of patients with known cardiovascular disease, and patients withwithdrawal. Concomitant use of LYBALVI is not recommendedwith dementia-related psychosis. treatment and periodically during treatment.cerebrovascular disease. with strong CYP3A4 inducers, levodopa and dopamineCerebrovascular Adverse Reactions, Including Stroke in Elderly Patients withWeight gain has been observed with use of antipsychotics. Monitor weight prior to agonists. Reduce dosage of LYBALVI when using with strongDementia-Related Psychosis: Cerebrovascular adverse reactions (e.g., stroke,initiating LYBALVI and frequently thereafter.Falls: LYBALVI may cause somnolence, postural hypotension,CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2transient ischemic attack), including fatalities, were reported in patients in trialsTardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially and motor and sensory instability, which may lead to falls, andof olanzapine in elderly patients with dementia-related psychosis. In placebo- irreversible, involuntary, dyskinetic movements, may develop in patients treated consequently, fractures or other injuries. Assess patients forinducers. Use caution with diazepam, alcohol, other CNS actingcontrolled trials, there was a significantly higher incidence of cerebrovascularwith antipsychotic drugs. The risk appears to be highest among the elderly, drugs, or in patients receiving anticholinergic (antimuscarinic)adverse reactions in patients treated with olanzapine compared to patients treatedespecially elderly women, but it is not possible to predict which patients are likely to risk when using LYBALVI. medications. Monitor blood pressure and reduce dosage ofwith placebo. LYBALVI is not approved for the treatment of patients with dementia- develop the syndrome. Whether antipsychotic drug products differ in their potential Leukopenia, Neutropenia, and Agranulocytosis (includingantihypertensive drug in accordance with its approved related psychosis. to cause tardive dyskinesia is unknown. fatal cases): Perform complete blood counts in patients withproduct labeling. Precipitation of Severe Opioid Withdrawal in Patients Who AreThe risk of developing tardive dyskinesia and the likelihood that it will become Physiologically Dependent on Opioids: Samidorphan, an opioid antagonist thatirreversible increases with the duration of treatment and the cumulative dose. The a history of a clinically significant low white blood cell (WBC)Pregnancy: May cause extrapyramidal and/or withdrawalis a component of LYBALVI, can precipitate opioid withdrawal in patients whosyndrome can develop after a relatively brief treatment period, even at low doses. It count or history of leukopenia or neutropenia. Discontinuesymptoms in neonates with third trimester exposure. Adviseare dependent on opioids, which can lead to an opioid withdrawal syndrome,may also occur after discontinuation of treatment. LYBALVI if clinically significant decline in WBC occurs in thesometimes requiring hospitalization. Therefore, LYBALVI is contraindicated inTardive dyskinesia may remit, partially or completely, if antipsychotic treatment absence of other causative factors. patients to notify their healthcare provider if they becomepatients who are using opioids or undergoing acute opioid withdrawal. Prior tois discontinued. Antipsychotic treatment itself, however, may suppress (or pregnant or intend to become pregnant during treatment withinitiating LYBALVI, there should be at least a 7-day opioid-free interval from last usepartially suppress) the signs and symptoms of the syndrome, possibly masking Dysphagia: Use LYBALVI with caution in patients at risk LYBALVI. Inform patients that there is a pregnancy exposureof short-acting opioids, and at least a 14-day opioid-free interval from the last usethe underlying process. The effect of symptomatic suppression on the long-term for aspiration. registry that monitors pregnancy outcomes in women exposedof long-acting opioids. Explain the risks associated with precipitated withdrawalcourse of the syndrome is unknown. and the importance of giving an accurate account of last opioid use to patientsto LYBALVI during pregnancy. and caregivers. Given these considerations, LYBALVI should be prescribed in a manner that is most Seizures: Use LYBALVI with caution in patients with a history oflikely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment seizures or with conditions that lower the seizure threshold. Renal Impairment: LYBALVI is not recommended for patientsVulnerability to Life-Threatening Opioid Overdose should generally be reserved for patients: 1) who suffer from a chronic illness that with end-stage renal disease (eGFR of 15 mL/minute/1.73 m 2 ). Risk of Opioid Overdose from Attempts to Overcome Samidorphan Blockade:is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, Potential for Cognitive and Motor Impairment: BecauseLYBALVI contains samidorphan, an opioid antagonist. Attempting to overcomebut potentially less harmful treatments are not available or appropriate. In patients LYBALVI may cause somnolence, impair judgment, thinking,To report SUSPECTED ADVERSE REACTIONS, contactLYBALVIs opioid blockade with high or repeated doses of exogenous opioids (e.g.,who do require chronic treatment, use the lowest dose and the shortest duration of or motor skills, caution patients about operating hazardousAlkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 orbecause of ineffective analgesia or opioid withdrawal symptoms) could lead to life- treatment producing a satisfactory clinical response should be sought. Periodically threatening or fatal opioid intoxication (e.g., respiratory arrest, circulatory collapse), machinery, including motor vehicles, until they are certain thatwww.fda.gov/medwatch. particularly if LYBALVI therapy is interrupted or discontinued, subjecting the patientreassess the need for continued treatment. LYBALVI does not affect them adversely. to high levels of unopposed opioid agonist as the samidorphan blockade wanes.If signs and symptoms of tardive dyskinesia appear in a patient on LYBALVI, Please see the Brief Summary of full PrescribingInform patients of the potential consequences of trying to overcome the opioiddrug discontinuation should be considered. However, some patients may require Body Temperature Dysregulation: Use LYBALVI with cautionInformation, including Boxed Warning, for LYBALVI on theblockade and the serious risks of taking opioids concurrently with LYBALVI or whiletreatment with LYBALVI despite the presence of the syndrome.in patients who may experience conditions that increase corefollowing pages. transitioning off LYBALVI.Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic body temperature (e.g., strenuous exercise, extreme heat,In emergency situations, if a LYBALVI-treated patient requires opioid treatment ashypotension and syncope. Generally, the risk is greatest during initial dosedehydration, or concomitant use with anticholinergics). part of anesthesia or analgesia:titration and when increasing the dose. In the 4-week, placebo-controlled study, Discontinue LYBALVI,from analysis of the vital signs data, rates of orthostatic hypotension were lessthan 2% in LYBALVI- and placebo-, and olanzapine-treated patients. In theOpioids should be administered by individual(s) trained in the use of anesthetic24-week, olanzapine-controlled study, from analysis of the vital signs data, ratesdrugs and the management of the respiratory effects of opioids, specifically theof orthostatic hypotension in LYBALVI-treated patients were 3.7%, compared to establishment and maintenance of a patent airway and assisted ventilation, and 0.4% in olanzapine-treated patients.Appropriately trained personnel should continuously monitor the patient in a ALKERMES is a registered trademark of Alkermes, Inc. LYBALVI is a registered trademark and the LYBALVIsetting equipped and staffed for cardiopulmonary resuscitation.logo is a trademark of Alkermes Pharma Ireland Limited, both used by Alkermes, Inc., under license. 2021 Alkermes, Inc. All rights reserved. LYB-001755'