SECUADO

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 SECUADO 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 ) External Heat: Avoid exposing SECUADO to external heat sources during wear because both the rate and extent of absorption are increased. ( 5.16 ) Application Site Reactions: During wear time or immediately after removal of SECUADO, local skin reactions may occur. Instruct patients to select a different transdermal system application site each day to limit the occurrence of skin reactions. ( 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. 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. SECUADO 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 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. SECUADO is not approved for the treatment of patients with dementia-related psychosis [ see 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, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue SECUADO and provide intensive symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including SECUADO. 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 that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, SECUADO 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 SECUADO, drug discontinuation should be considered. However, some patients may require treatment with SECUADO despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs, including SECUADO, 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 sublingual asenapine. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. Reports of hyperglycemia in patients treated with SECUADO were <1% in the placebo-controlled trial. Data from the placebo-controlled schizophrenia trial are presented in Table 1 . Table 1: Changes in Fasting Glucose in Adult Patients in the 6-Week, Placebo-Controlled, Fixed Dose Schizophrenia Trial Placebo SECUADO 3.8 mg/24 hours 7.6 mg/24 hours N * = Number of patients who had assessments at both Baseline and Endpoint. Mean Change from Baseline in Fasting Glucose at Endpoint Change from Baseline (mg/dL) (N*) 0.03 (174) 3.28 (174) 3.72 (172) Proportion of Patients with Shifts from Baseline to Endpoint Normal to High <100 to ≥ 126 mg/dL (n/N*) 0% (0/198) 3.1% (6/196) 3.0% (6/199) Borderline to High ≥100 and < 126 to ≥126 mg/dL (n/N*) 2.0% (4/198) 1.0% (2/196) 1.0% (2/199) In the sublingual asenapine 52-week, double-blind, comparator-controlled trial that included primarily patients with schizophrenia, the mean increase from baseline of fasting glucose was 2.4 mg/dL. 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. Data from the placebo-controlled schizophrenia trial presented in Table 2 . Table 2: Changes in Lipids in Adult Patients in the 6-Week, Placebo-Controlled, Fixed Dose Schizophrenia Trial Placebo SECUADO 3.8 mg/24 hours 7.6 mg/24 hours N * = Number of patients who had assessments at both Baseline and Endpoint. Mean Change from Baseline Total Cholesterol (mg/dL) (N*) 0.7 (174) 5.1 (174) 4.5 (172) LDL (mg/dL) (N*) 1.6 (172) 1.4 (170) 4.2 (169) HDL (mg/dL) (N*) -0.8 (174) 0.2 (174) -0.7 (172) Fasting triglycerides (mg/dL) (N*) -2.6 (174) 17.3 (174) 6.7 (172) Proportion of Patients with Shifts from Baseline to Endpoint(n/N*) Total Cholesterol Normal to High <200 to ≥240 mg/dL (n/N*) 1.0% (2/197) 2.6% (5/196) 1.0% (2/199) LDL Normal to High <100 to ≥160 mg/dL (n/N*) 0.5% (1/195) 1.0% (2/194) 0% (0/197) HDL Normal to High ≥40 to <40 mg/dL (n/N*) 8.1% (16/197) 10.7% (21/196) 12.1% (24/199) Fasting Triglycerides Normal to High <150 to ≥200 mg/dL (n/N*) 1.1% (2/185) 7.0% (13/185) 3.2% (6/186) In the placebo-controlled schizophrenia trial with SECUADO, the proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 10.7% for patients treated with SECUADO 3.8 mg/24 hours and 13.6% for patients treated with SECUADO 7.6 mg/24 hours versus 10.2 % for placebo-treated patients. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 17.8% for SECUADO 3.8 mg/24 hours and 12.4% for SECUADO 7.6 mg/24 hours treated patients versus 10.3% for placebo-treated patients. Weight Gain Weight gain has been observed with atypical antipsychotic use, including SECUADO. Monitor weight at baseline and frequently thereafter. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥7% of body weight from the placebo-controlled schizophrenia trial are presented in Table 3 . Table 3: Change in Body Weight in Adult Patients from Baseline in the 6-Week, Placebo-Controlled, Fixed Dose Schizophrenia Trial Placebo SECUADO 3.8 mg/24 hours 7.6 mg/24 hours N * = Number of subjects with data at Endpoint. Mean Change from Baseline (kg) (N*) 0.62 (167) 2.10 (168) 2.02 (164) Proportion of Patients with a ≥7% Increase in Body Weight % with ≥7% increase in body weight (n/N*) 3.9% (8/203) 18.3% (37/202) 14.3% (29/203) In the sublingual asenapine 52-week, double-blind, comparator-controlled adult trial that included primarily patients with schizophrenia, 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 4 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 4: Weight Change Results Categorized by BMI at Baseline: Comparator-Controlled 52-Week Study with Sublingual Asenapine in Adults with Schizophrenia BMI <23 Sublingual Asenapine N=295 BMI 23 - ≤27 Sublingual Asenapine N=290 BMI >27 Sublingual Asenapine N=302 Mean Change from Baseline (kg) 1.7 1 0 % with ≥7% increase in body weight 22% 13% 9% 5.6 Hypersensitivity Reactions Hypersensitivity reactions have been observed in patients treated with asenapine, including SECUADO. 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 the placebo-controlled trial, orthostatic hypotension was reported in 1.5% (3/204) of patients treated with SECUADO 3.8 mg/24 hours and 0% (0/204) of patients treated with SECUADO 7.6 mg/24 hours, compared to <1% (1/206) of patients treated with placebo. There were no reports of syncope for both doses of SECUADO in the placebo-controlled trial. During adult pre-marketing clinical trials with sublingual asenapine, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with sublingual asenapine. 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. SECUADO 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 SECUADO 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 trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including asenapine. Agranulocytosis (including fatal cases) has also 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 pre-existing low WBC or ANC or 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 SECUADO 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 SECUADO in patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) and follow their WBC until recovery. 5.10 QT Prolongation The effects of sublingual asenapine on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved sublingual 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 schizophrenia, with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, sublingual asenapine was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with sublingual 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 SECUADO clinical trial (3.8 mg/24 hours and 7.6 mg/24 hours doses). In the placebo-controlled trial, there were no reports of QT prolongations exceeding 500 msec for SECUADO and placebo. There were no reports of Torsades de Pointes or any other adverse reactions associated with delayed ventricular repolarization with sublingual asenapine or with SECUADO. The use of SECUADO 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). SECUADO 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, SECUADO 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 the SECUADO placebo-controlled trial, galactorrhea, amenorrhea, gynecomastia, and impotence were not reported for patients treated with SECUADO or placebo [ see Adverse Reactions (6.1) ]. In sublingual asenapine adult pre-marketing clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo. 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 In the SECUADO placebo-controlled trial, there were no reports of seizures in adult patients treated with doses of 3.8 mg/24 hours and 7.6 mg/24 hours of SECUADO. During adult pre-marketing clinical trials with sublingual asenapine, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1953) of patients treated with sublingual asenapine. As with other antipsychotic drugs, SECUADO 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 SECUADO, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that SECUADO therapy does not affect them adversely. Somnolence was reported in patients treated with SECUADO. In the short-term, fixed-dose, placebo-controlled schizophrenia adult trial, somnolence was reported in 4.4% (9/204) of patients on SECUADO 3.8 mg/24 hours and in 3.4% (7/204) of patients on SECUADO 7.6 mg/24 hours compared to 1.5% (3/206) of placebo patients. There were no reports of somnolence that led to discontinuation in the placebo-controlled trial. During adult pre-marketing clinical trials with sublingual asenapine, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with sublingual asenapine. 5.14 Body Temperature Regulation 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 SECUADO with caution in patients who may experience these conditions. 5.15 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. There were no reports of dysphagia with SECUADO; however, dysphagia has been reported with sublingual asenapine. SECUADO and other antipsychotic drugs should be used cautiously in patients at risk for aspiration. 5.16 External Heat When heat is applied to SECUADO after application, both the rate and extent of absorption are increased. After application of a heating pad, asenapine exposure (partial AUC 0-8 ) was about 3.9 times greater than without heating pad application [ see Clinical Pharmacology (12.3) ]. Advise patients to avoid exposing SECUADO to direct external heat sources such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing SECUADO. 5.17 Application Site Reactions Local skin reactions, such as irritation, were reported with SECUADO. During wear time or immediately after removal of SECUADO, the skin at the site of application may develop erythema, pruritus, papules, discomfort, pain, edema, or irritation. In the short-term, fixed-dose, placebo-controlled schizophrenia adult trial, application site reactions were reported in 15.2% (31/204) of patients on SECUADO 3.8 mg/24 hours and in 13.7% (28/204) of patients on SECUADO 7.6 mg/24 hours compared to 3.9% (8/206) of placebo patients. The most common application site reaction was erythema, which was reported in 9.3% (19/204) of patients on SECUADO 3.8 mg/24 hours and in 9.8% (20/204) of patients on SECUADO 7.6 mg/24 hours compared to 1.5% (3/206) of placebo patients. Another common application site reaction was pruritus, which was reported in 4.9% (10/204) of patients on SECUADO 3.8 mg/24 hours and in 3.9% (8/204) of patients on SECUADO 7.6 mg/24 hours compared to 1.9% (4/206) of placebo patients. One patient developed application site discoloration (hyperpigmentation) at multiple application sites that persisted for at least several weeks after discontinuing SECUADO treatment. Application site reactions occurred more frequently in Black or African American patients compared to Caucasians. Inform patients of these potential reactions and that increased skin irritation may occur with SECUADO if applied for a longer period than instructed or if the same application site is used repeatedly. Instruct patients to select a different application site each day to minimize skin reactions.