Asenapine

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). ( 5.2 ) • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. ( 5.3 ) • Tardive Dyskinesia: Discontinue if clinically appropriate. ( 5.4 ) • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. ( 5.5 ) • Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. ( 5.7 ) • Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing asenapine if a clinically significant decline in WBC occurs in absence of other causative factors. ( 5.9 ) • QT Prolongation: Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. ( 5.10 ) • Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.12 ) • Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.13 ) 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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death 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. Asenapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)]. 5.2 Cerebrovascular Adverse Events, Including Stroke, In Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Asenapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]. 5.3 Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) 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 asenapine and provide intensive symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including asenapine. 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 tardive dyskinesia and the likelihood that it will become irreversible increase 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. There is no known treatment for tardive dyskinesia, although the syndrome 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 that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, asenapine should be prescribed in a manner 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 TD appear in a patient on asenapine, drug discontinuation should be considered. However, some patients may require treatment with asenapine despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs, including asenapine, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with asenapine. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. Adult Patients: Pooled data from the short-term placebo-controlled bipolar mania trials are presented in Table 1. Table 1 : Changes in Fasting Glucose in Adult Patients Bipolar I Disorder (3-weeks) Placebo Asenapine 5 mg twice daily 10 mg twice daily 5 mg or 10 mg twice daily † Mean Change from Baseline in Fasting Glucose at Endpoint Change from Baseline (mg/dL) (N * ) 0 (174) 4.1 (84) 3.5 (81) 1.7 (321) Proportion of Patients with Shifts from Baseline to Endpoint Normal to High <100 to ≥126 mg/dL (n/N ** ) 2.4% (3/126) 0% (0/53) 1.7% (1/60) 1.8% (4/224) Borderline to High ≥100 and <126 to ≥126 mg/dL (n/N ** ) 0% (0/39) 12.5% (3/24) 15.8% (3/19) 12.8% (10/78) N * = Number of patients who had assessments at both Baseline and Endpoint. N ** = Number of patients at risk at Baseline with assessments at both Baseline and Endpoint. † Includes patients treated with flexible dose of asenapine 5 mg or 10 mg twice daily (N=379). In a 52-week, double-blind, comparator-controlled trial, the mean increase from baseline of fasting glucose was 2.4 mg/dL. Pediatric Patients: Data from the short-term, placebo-controlled trial in pediatric patients with bipolar I disorder are shown in Table 2 . Table 2 : Changes in Fasting Glucose in Pediatric Subjects Bipolar I Disorder (3-weeks) Placebo Asenapine2.5 mg twice daily Asenapine5 mg twice daily Asenapine10 mg twice daily Mean Change from Baseline in Fasting Glucose at Endpoint Change from Baseline (mg/dL) (N * ) -2.24 (56) 1.43 (51) -0.45 (57) 0.34 (52) Proportion of Subjects with Shifts from Baseline to Endpoint Normal to High >45 & <100 to ≥126 mg/dL 0% 0% 1.8% 0% (n/N * ) (0/56) (0/51) (1/57) (0/52) N * = Number of subjects who had assessments at both Baseline and Endpoint Dyslipidemia Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Adult Patients: Pooled data from the short-term, placebo-controlled bipolar mania trials are presented in Table 3. Table 3: Changes in Lipids in Adult Patients Bipolar I Disorder (3-weeks) Placebo Asenapine 5 mg twice daily 10 mg twice daily 5 mg or 10 mg twice daily † Mean Change from Baseline (mg/dL) Total cholesterol (N * ) -1.6 (278) -1.6 (108) -4.7 (95) -0.5 (525) LDL (N * ) 1.4 (271) -2.5 (101) -4.1 (94) -0.3 (499) HDL (N * ) 0.2 (278) 0.1 (108) 0.7 (95) 0.7 (525) Fasting triglycerides (N * ) -16.9 (222) 3.9 (89) -8.5 (85) -3 (411) Proportion of Patients with Shifts from Baseline to Endpoint Total cholesterol Normal to High <200 to ≥240 (mg/dL) (n/N * ) 1.2% (2/174) 3% (2/66) 0 (0/63) 2.1% (7/333) LDL Normal to High <100 to ≥160 (mg/dL) (n/N * ) 1.9% (2/108) 2.4% (1/41) 0 (0/41) 0.5% (1/223) HDL Normal to Low ≥40 to <40 (mg/dL) (n/N * ) 7.4% (16/215) 4.1% (4/97) 5.1% (4/78) 7% (29/417) Fasting triglycerides Normal to High <150 to ≥200 (mg/dL) (n/N * ) 4.6% (7/153) 8.2% (5/61) 1.6% (1/64) 6.2% (17/273) N * = Number of subjects who had assessments at both Baseline and Endpoint. † Includes patients treated with flexible dose of asenapine 5 mg or 10 mg twice daily (N=379). In short-term, placebo-controlled bipolar mania trials, the proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 7.8% for asenapine-treated patients versus 7.9% for placebo-treated patients. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 13.1% for asenapine-treated patients versus 8.6% for placebo-treated patients. Pediatric Patients: Data from the short-term, placebo-controlled bipolar mania trial are presented in Table 4 . Table 4: Changes in Fasting Lipids in Pediatric Subjects Bipolar I Disorder (3-weeks) Placebo Asenapine2.5 mg twice daily Asenapine5 mg twice daily Asenapine10 mg twice daily Mean Change from Baseline (mg/dL) Total Fasting cholesterol (N * ) -2.3 (57) 3.7 (50) 7.2 (57) 9.3 (52) Fasting LDL (N * ) -2.5 (57) -0.2 (50) 3 (57) 4.9 (51) Fasting HDL (N * ) 1.6 (57) 2.3 (50) 1.5 (57) 1.7 (52) Fasting triglycerides (N * ) -6.6 (57) 8.7 (50) 13.4 (57) 14.7 (52) Proportion of Subjects with Shifts from Baseline to Endpoint Total Fasting cholesterol Normal to High <170 to > = 200 (mg/dL) (n/N * ) 1.8% (1/57) 0% (0/50) 1.8% (1/57) 0% (0/52) Fasting LDL Normal to High <110 to > = 130 (n/N * ) 1.8% (1/57) 2% (1/50) 1.8% (1/57) 0% (0/51) Fasting HDL Normal to Low ≥40 to <40 (mg/dL) (n/N * ) 3.5% (2/57) 6% (3/50) 3.5% (2/57) 9.6% (5/52) Fasting triglycerides Normal to High <150 to ≥200 (mg/dL) (n/N * ) 0% (0/57) 4% (2/50) 3.5% (2/57) 1.9% (1/52) N* = Number of patients who had assessments at both Baseline and Endpoint Weight Gain Weight gain has been observed in patients treated with atypical antipsychotics, including asenapine. Monitor weight at baseline and frequently thereafter. Adult Patients: Pooled data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥7% of body weight from the short-term, placebo-controlled bipolar mania trials are presented in Table 5. Table 5: Change in Body Weight in Adult Patients from Baseline Bipolar I Disorder (3-weeks) Placebo Asenapine 5 mg twice daily 10 mg twice daily 5 mg or 10 mg twice daily † Change from Baseline (kg) (N * ) 0.2 (288) 1.4 (110) 1.3 (98) 1.3 (544) Proportion of Patients with a ≥7% Increase in Body Weight % with ≥7% increase in body weight 0.4% 6.4% 1% 5.5% N * = Number of subjects who had assessments at both Baseline and Endpoint. † Includes patients treated with flexible dose of asenapine 5 mg or 10 mg twice daily (n=379). Adult Patients: In a 52-week, double-blind, comparator-controlled adult trial, the mean weight gain from baseline was 0.9 kg. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 14.7%. Table 6 provides the mean weight change from baseline and the proportion of patients with a weight gain of ≥7% categorized by Body Mass Index (BMI) at baseline. Table 6: Weight Change Results Categorized by BMI at Baseline: Comparator- Controlled 52-Week Study in Adult Patients BMI <23 Asenapine N=295 BMI 23 - ≤27 Asenapine N=290 BMI >27 Asenapine N=302 Mean change from Baseline (kg) 1.7 1 0 % with ≥7% increase in body weight 22% 13% 9% Pediatric Patients: Data on mean changes in body weight and the proportion of pediatric patients meeting a weight gain criterion of ≥7% of body weight from the short-term, placebo-controlled bipolar mania trial are presented in Table 7 . To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients by comparisons to age-and sex-matched population standards. The distance of a z-score from 0 represents the distance of a percentile from the median, measured in standard deviations (SD). After adjusting for age and sex, the mean change from baseline to endpoint in weight z-score for asenapine 2.5 mg, 5 mg, and 10 mg twice daily, was 0.11, 0.08 and 0.09 SD versus 0.02 SD for placebo, respectively. When treating pediatric patients, weight gain should be monitored and assessed against that expected for normal growth. Table 7: Change in Body Weight in Pediatric Subjects from Baseline Bipolar I Disorder (3-weeks) Placebo Asenapine 2.5 mg twice daily Asenapine 5 mg twice daily Asenapine 10 mg twice daily Change from Baseline (kg) (N * ) 0.5 (89) 1.7 (92) 1.6 (90) 1.4 (87) Proportion of Subjects with a ≥7% Increase in Body Weight % with ≥7% increase in body weight 1.1% 12% 8.9% 8% N * = Number of subjects who had assessments at both Baseline and Endpoint. 5.6 Hypersensitivity Reactions Hypersensitivity reactions have been observed in patients treated with asenapine. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash. 5.7 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In short-term bipolar mania adult trials, syncope was reported in 0.2% (1/620) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of asenapine, compared to 0% (0/329) of patients treated with placebo. During adult pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with asenapine. In a 3-week, bipolar mania pediatric trial, syncope was reported in 1% (1/104) of patients treated with asenapine 2.5 mg twice daily, 1% (1/99) of patients treated with asenapine 5 mg twice daily, and 0% (0/99) for patients treated with asenapine 10 mg twice daily compared to 0% (0/101) for patients treated with placebo. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medications, patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Asenapine should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7.1)] . Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. 5.8 Falls Asenapine 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. 5.9 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including asenapine. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug induced leukopenia/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) during the first few months of therapy. In such patients, consider discontinuation of asenapine 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 asenapine in patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) and follow their WBC until recovery. 5.10 QT Prolongation The effects of asenapine on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved asenapine doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, asenapine was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with asenapine experienced QTc increases ≥60 msec from baseline measurements, nor did any patient experience a QTc of ≥500 msec. Electrocardiogram (ECG) measurements were taken at various time points during the asenapine clinical trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for asenapine and placebo in these short-term trials. There were no reports of Torsade de Pointes or any other adverse reactions associated with delayed ventricular repolarization. The use of asenapine should be avoided in combination with other drugs known to prolong QTc including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin). Asenapine should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval. 5.11 Hyperprolactinemia Like other drugs that antagonize dopamine D 2 receptors, asenapine can elevate 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. In asenapine adult pre-marketing clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo. In a 3-week, bipolar mania pediatric trial, the incidence of adverse events related to abnormal prolactin levels were 0% in the asenapine 2.5 mg twice daily treatment group, 2% in the asenapine 5 mg twice daily treatment group, and 1% in the asenapine 10 mg twice daily treatment group versus to 1% for patients treated with placebo [see Adverse Reactions (6.1)]. 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. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer. 5.12 Seizures Seizures were reported in 0% and 0.3% (0/572, 1/379) of adult patients treated with doses of 5 mg and 10 mg twice daily of asenapine, respectively, compared to 0% (0/203) of patients treated with placebo in pre-marketing short-term bipolar mania trials. During adult pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1953) of patients treated with asenapine. There were no reports of seizures in pediatric patients treated with asenapine in a 3-week-term, bipolar mania trial. As with other antipsychotic drugs, asenapine should be used with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older. 5.13 Potential for Cognitive and Motor Impairment Somnolence was reported in patients treated with asenapine. It was usually transient with the highest incidence reported during the first week of treatment. In short-term, placebo-controlled bipolar mania adult trials of therapeutic doses (5 to 10 mg twice daily), somnolence was reported in 23% (145/620) of patients on asenapine compared to 5% (18/329) of placebo patients. In another study, somnolence occurred at a lower rate in the 5 mg twice daily dose 20% (24/122) versus the 10 mg twice daily dose 26% (31/119) compared to 4% (5/126) in placebo patients. During adult pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with asenapine. Somnolence led to discontinuation in 0.6% (12/1953) of patients in short-term, placebo-controlled trials. In a 3-week, placebo-controlled, bipolar I pediatric trial, the incidence of somnolence (including sedation and hypersomnia) for placebo, asenapine 2.5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, was 12% (12/101), 46% (48/104), 53% (52/99), and 49% (49/99), respectively. Somnolence led to discontinuation in 0%, 3%, 1%, and 2% of patients treated with placebo, and asenapine 2.5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, respectively. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that asenapine therapy does not affect them adversely. 5.14 Body Temperature Regulation Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. In the pre-marketing short-term placebo-controlled trials for acute bipolar I disorder and another indication, the incidence of adverse reactions suggestive of body temperature increases was low (≤1%) and comparable to placebo (0%). During pre-marketing clinical trials with asenapine, including long-term trials without comparison to placebo, the incidence of adverse reactions suggestive of body temperature increases (pyrexia and feeling hot) was ≤1%. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use asenapine with caution in patient who may experience these conditions. 5.15 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with asenapine. Asenapine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.