Olanzapine And Samidorphan L-Malate

5 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. 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. In emergency situations, if a LYBALVI-treated patient requires opioid treatment as part of anesthesia or analgesia: Discontinue LYBALVI, Opioids should be administered by individual(s) trained in the use of anesthetic drugs and the management of the respiratory effects of opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation, and Appropriately trained personnel should continuously monitor the patient in a setting equipped and staffed for cardiopulmonary resuscitation. For recommendations on starting opioids in LYBALVI-treated patients in non-emergent situations, see Drug Interactions ( 7.3 ). Risk of Resuming Opioids in Patients with Prior Opioid Use Patients with a history of chronic opioid use prior to treatment with LYBALVI may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Advise patients that this decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage. 5.5 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue LYBALVI and provide intensive symptomatic treatment and monitoring. 5.6 Drug Reaction with Eosinophilia and Systemic Symptoms Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with exposure to olanzapine, a component of LYBALVI [see Adverse Reactions ( 6.2 )] . DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue LYBALVI if DRESS is suspected. 5.7 Metabolic Changes Atypical antipsychotic drugs, including LYBALVI, have been associated with metabolic changes that include hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain [see Adverse Reactions ( 6.1 )]. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with LYBALVI should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required anti-diabetic treatment despite discontinuation of the suspect drug. Patients starting treatment with LYBALVI should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Antipsychotics have caused adverse alterations in lipids. Patients starting treatment with LYBALVI should undergo fasting lipid profile testing at the beginning of treatment and periodically during treatment. Weight gain has been observed with use of antipsychotics. Monitor weight prior to initiating LYBALVI and frequently thereafter. 5.8 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on LYBALVI, drug discontinuation should be considered. However, some patients may require treatment with LYBALVI despite the presence of the syndrome. 5.9 Orthostatic Hypotension and Syncope Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the 4-week, placebo-controlled study, from analysis of the vital signs data, rates of orthostatic hypotension were less than 2% in LYBALVI- and placebo-, and olanzapine-treated patients. In the 24-week, olanzapine-controlled study, from analysis of the vital signs data, rates of orthostatic hypotension in LYBALVI-treated patients were 3.7%, compared to 0.4% in olanzapine-treated patients. Monitor orthostatic vital signs in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medications or CNS depressants [see Drug Interactions ( 7.1 , 7.2 )] , patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. LYBALVI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from the premarketing clinical trials. 5.10 Falls Antipsychotics, including LYBALVI, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.11 Leukopenia, Neutropenia, and Agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including LYBALVI [see Adverse Reactions ( 6 )] . Agranulocytosis (including fatal cases) has been reported with other agents in this class. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of LYBALVI at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue LYBALVI in patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) and follow their WBC until recovery. 5.12 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including LYBALVI, should be used cautiously in patients at risk for aspiration. 5.13 Seizures Like other antipsychotic drugs, LYBALVI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. 5.14 Potential for Cognitive and Motor Impairment LYBALVI, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, or motor skills. In a LYBALVI placebo-controlled study, somnolence occurred in 9% of LYBALVI-treated patients compared to 2.2% in patients treated with placebo. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that LYBALVI therapy does not affect them adversely. 5.15 Body Temperature Dysregulation Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use LYBALVI with caution in patients who may experience these conditions. 5.16 Anticholinergic (Antimuscarinic) Effects Olanzapine, a component of LYBALVI, exhibits in vitro muscarinic receptor affinity [see Clinical Pharmacology ( 12.2 )] . In premarketing clinical trials with oral olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for discontinuations, but LYBALVI should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications [see Drug Interactions ( 7.1 )]. 5.17 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, olanzapine, a component of LYBALVI, elevates prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology ( 13.1 )]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. In the 4-week placebo-controlled trial, shifts from normal to high prolactin values (>30 ng/mL for females; >20 ng/mL for males) occurred in 41.4% of females and 32.9% of males treated with LYBALVI, in 56.1% of females and 37.1% of males treated with olanzapine, and in 10% of females and 4.8% of males treated with placebo [see Use in Specific Populations ( 8.3 )] . In the 24-week, olanzapine-controlled study, shifts from normal to high prolactin values occurred in 32.9% of females and 22.5% of males treated with LYBALVI, and in 41.7% of females and 28.5% of males treated with olanzapine. 5.18 Risks Associated with Combination Treatment with Lithium or Valproate If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for a description of the risks for these products including, but not limited to, the warnings and precautions for lithium or valproate [see Contraindications ( 4 )] . 5.19 Interference with Laboratory Tests for Opioid Detection LYBALVI may cause false positive results with urinary immunoassay methods used for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results [see Contraindications ( 4 ) and Drug Interactions ( 7.4 )] .