Document

DailyMed Label: SECUADO

Title
DailyMed Label: SECUADO
Date
2023
Document type
DailyMed Prescription
Name
SECUADO
Generic name
ASENAPINE
Manufacturer
Noven Therapeutics, LLC
Product information
NDC: 68968-0172
Product information
NDC: 68968-0173
Product information
NDC: 68968-0174
Product information
NDC: 68968-0172
Product information
NDC: 68968-0172
Product information
NDC: 68968-0173
Product information
NDC: 68968-0173
Product information
NDC: 68968-0174
Product information
NDC: 68968-0174
Description
SECUADO transdermal system contains asenapine, an atypical antipsychotic. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical name is trans -5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7] oxepino [4,5-c] pyrrole. Its molecular formula is C 17 H 16 Cl NO and its molecular weight is 285.8 g/mol. The chemical structure is: SECUADO is for transdermal administration and is provided in three strengths: 3.8 mg, 5.7 mg or 7.6 mg asenapine every 24 hours ( Table 7 ). The composition of the transdermal systems per unit area is identical. Inactive ingredients include alicyclic saturated hydrocarbon resin, butylated hydroxytoluene, isopropyl palmitate, maleate salts (monosodium maleate and disodium maleate), mineral oil, polyester film backing, polyisobutylene, silicone-treated polyester release liner, sodium acetate anhydrous, and styrene-isoprene-styrene block copolymer. Table 7: SECUADO (asenapine) transdermal system Dosage Strength (Asenapine) Total Asenapine Content per Transdermal System Transdermal System Size 3.8 mg/24 hours 6.4 mg 20 cm 2 5.7 mg/24 hours 9.6 mg 30 cm 2 7.6 mg/24 hours 12.8 mg 40 cm 2 chemical structure
Indications
SECUADO is indicated for the treatment of adults with schizophrenia [ see Clinical Studies (14) ]. SECUADO is an atypical antipsychotic indicated for the treatment of adults with schizophrenia. ( 1 )
Dosage
For transdermal use only. ( 2.2 ) Apply one SECUADO transdermal system every 24 hours. ( 2.2 ) Apply SECUADO to one of the following sites: the hip, abdomen, upper arm, or upper back area. ( 2.2 ) The recommended starting dose of SECUADO is 3.8 mg/24 hours. May increase dosage to 5.7 mg/24 hours or 7.6 mg/24 hours after one week. ( 2.1 ) Initiate SECUADO at a dosage of 3.8 mg/24 hours. In a short-term, placebo-controlled trial, there was no suggestion of added benefit at a dosage of 7.6 mg/24 hours, on average, but there was an increase in certain adverse reactions. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after one week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies [ see Clinical Studies (14) ]. Based on the average exposure (AUC) of asenapine, SECUADO 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine and SECUADO 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine [ see Clinical Pharmacology (12.3) ]. See the FDA-approved patient labeling ( Instructions for Use ). SECUADO transdermal system is applied once daily. Each SECUADO transdermal system should be worn for 24 hours only. Instruct patients to wear only one SECUADO transdermal system at any time. Apply SECUADO to clean, dry, and intact skin at the selected application site. Application sites include: the upper arm, upper back, abdomen, or hip. Apply the transdermal system to a different application site each time a new SECUADO transdermal system is applied. Do not cut open the pouch until ready to apply SECUADO and do not use the transdermal system if the individual pouch seal is broken or if it appears to be damaged. Do not cut SECUADO, the whole transdermal system should be applied. If the SECUADO transdermal system lifts at the edges, reattach SECUADO by pressing firmly and smoothing down the edges of the system. If SECUADO comes off completely, apply a new SECUADO transdermal system. Discard SECUADO by folding the used transdermal system so that the adhesive side sticks to itself and safely discard. If irritation or a burning sensation occurs while wearing SECUADO, remove the system and apply a new transdermal system to a new application site [ see Warnings and Precautions (5.17) ]. Showering is permitted, but the use of SECUADO during swimming or taking a bath has not been evaluated. Do not apply external heat sources (e.g., heating pad) over the SECUADO transdermal system [ see Warnings and Precautions (5.16) ]. Prolonged application of heat over a SECUADO transdermal system increases plasma concentrations of asenapine [ see Clinical Pharmacology (12.3) ].
Dosage forms
SECUADO (asenapine) transdermal system is a translucent rounded square product available in three dosage strengths: 3.8 mg asenapine / 24 hours 5.7 mg asenapine / 24 hours 7.6 mg asenapine / 24 hours Transdermal System: 3.8 mg/24 hours, 5.7 mg/24 hours and 7.6 mg/24 hours ( 3 )
Contraindications
SECUADO is contraindicated in patients with: Severe hepatic impairment (Child-Pugh C) [see Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . A history of hypersensitivity reactions to asenapine or any components of the transdermal system. Reactions with asenapine have included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash [see Warnings and Precautions (5.6) , Adverse Reactions (6) ]. Severe hepatic impairment (Child-Pugh C). ( 8.7 , 12.3 ) Known hypersensitivity to SECUADO or to any components in the transdermal system. ( 4 , 5.6 , 17 )
Warnings
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 ) 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) ]. 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) ]. 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. 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. 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% 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. 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. 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. 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. 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. 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. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive. 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. 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. 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. 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. 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. 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.
Adverse reactions
The following adverse reactions are discussed in more detail in other sections of the labeling:
Drug interactions
Antihypertensive drugs: SECUADO may enhance antihypertensive effects. Monitor blood pressure and adjust dosage of antihypertensive drug accordingly. ( 7.1 ) Strong CYP1A2 Inhibitors: Consider dose reduction for SECUADO based on clinical response. ( 7.1 ) Paroxetine (CYP2D6 substrate and inhibitor): Reduce paroxetine dose by half. ( 7.1 ) Table 6: Clinically Important Drug Interactions with SECUADO Antihypertensive Drugs Clinical Implication Because of its α 1 -adrenergic antagonism with potential for inducing hypotension, SECUADO may enhance the effects of certain antihypertensive agents [see Warnings and Precautions (5.7) ] . Prevention or Management: Monitor blood pressure and adjust dosage of antihypertensive drug accordingly. Examples: Diuretics, ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers, Alpha-blockers Strong CYP1A2 Inhibitors Clinical Implication Asenapine is metabolized by CYP1A2. Concomitant use of SECUADO with a CYP1A2 inhibitor increases AUC and C max of asenapine [see Clinical Pharmacology (12.3) ] . Prevention or Management: Dosage reduction for SECUADO based on clinical response may be necessary. Examples: Fluvoxamine, ciprofloxacin, enoxacin CYP2D6 substrates and inhibitors Clinical Implication Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism by CYP2D6. Concomitant use of SECUADO with paroxetine increases paroxetine AUC and C max [see Clinical Pharmacology (12.3) ] . Prevention or Management: Reduce paroxetine dose by half when paroxetine is used in combination with SECUADO. Examples: Paroxetine
Use in_specific_populations
Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including SECUADO, during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Studies have not been conducted with SECUADO in pregnant women. There are no available human data informing the drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. No teratogenicity was observed in animal reproduction studies with intravenous administration of asenapine to rats and rabbits during organogenesis at doses 0.7 and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 10 mg of sublingual asenapine twice daily and 1.1 and 0.66 times, respectively, the MRHD of 12.8 mg of transdermal asenapine daily. In a pre-and post-natal study in rats, intravenous administration of asenapine at doses up to 0.7 times the MRHD of 10 mg of sublingual asenapine twice daily produced increases in post-implantation loss and early pup deaths, and decreases in subsequent pup survival and weight gain [ see Data ]. These doses are up to 1.1 times the MRHD of 12.8 mg transdermal asenapine daily. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions 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 during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data In animal studies, asenapine increased post-implantation loss and decreased pup weight and survival at doses similar to or less than recommended clinical doses. In these studies, there was no increase in the incidence of structural abnormalities caused by asenapine. Asenapine was not teratogenic in reproduction studies in rats and rabbits at intravenous doses up to 1.5 mg/kg in rats and 0.44 mg/kg in rabbits administered during organogenesis. These doses are 0.7 and 0.4 times, respectively, MRHD of 10 mg of sublingual asenapine twice daily and 1.1 and 0.66 times, respectively, the MRHD of 12.8 mg transdermal asenapine daily. Plasma levels of asenapine were measured in the rabbit study, and the area under the curve (AUC) at the highest dose tested was 2 times that in humans receiving the MRHD of 10 mg of sublingual asenapine twice daily. In a study in which rats were treated from day 6 of gestation through day 21 postpartum with intravenous doses of asenapine of 0.3, 0.9, and 1.5 mg/kg/day (0.15, 0.44, and 0.7 times the MRHD of 10 mg of sublingual asenapine twice daily and 0.22, 0.68 and 1.13 times the MRHD of 12.8 mg transdermal asenapine daily), increases in post-implantation loss and early pup deaths were seen at all doses, and decreases in subsequent pup survival and weight gain were seen at the two higher doses. A cross-fostering study indicated that the decreases in pup survival were largely due to prenatal drug effects. Increases in post-implantation loss and decreases in pup weight and survival were also seen when pregnant rats were dosed orally with asenapine. Risk Summary Lactation studies have not been conducted to assess the presence of asenapine in human milk, the effects of asenapine on the breastfed infant, or the effects of asenapine on milk production. Asenapine is excreted in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for SECUADO and any potential adverse effects on the breastfed infant from SECUADO or from the underlying maternal condition. Safety and effectiveness of SECUADO in pediatric patients have not been established. Efficacy of sublingual asenapine was not demonstrated in an 8-week, placebo-controlled, double-blind trial, in 306 adolescent patients aged 12 to 17 years with schizophrenia at doses of 2.5 and 5 mg twice daily. The most common adverse reactions (proportion of patients equal or greater than 5% and at least twice placebo) reported were somnolence, akathisia, dizziness, and oral hypoesthesia or paresthesia. The proportion of patients with an equal or greater than 7% increase in body weight at endpoint compared to baseline for placebo, sublingual asenapine 2.5 mg twice daily, and sublingual asenapine 5 mg twice daily was 3%, 10%, and 10%, respectively. No new major safety findings were reported from a 26-week, open-label, uncontrolled safety trial in pediatric patients with schizophrenia treated with sublingual asenapine. Juvenile Animal Data Subcutaneous administration of asenapine to juvenile rats for 56 days from day 14 of age to day 69 of age at 0.4, 1.2, and 3.2 mg/kg/day (0.2, 0.6 and 1.5 times the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/m 2 basis) resulted in significant reduction in body weight gain in animals of both sexes at all dose levels from the start of dosing until weaning. Body weight gain remained reduced in males to the end of treatment, however, recovery was observed once treatment ended. Neurobehavioral assessment indicated increased motor activity in animals at all dose levels following the completion of treatment, with the evidence of recovery in males. There was no recovery after the end of treatment in female activity pattern as late as day 30 following the completion of treatment (last retesting). Therefore, a No Observed Adverse Effect Level (NOAEL) for the juvenile animal toxicity of asenapine could not be determined. There were no treatment-related effects on the startle response, learning/memory, organ weights, microscopic evaluations of the brain and, reproductive performance (except for minimally reduced conception rate and fertility index in males and females administered 1.2 and 3.2 mg/kg/day). The SECUADO placebo-controlled trial for the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Of the approximately 614 patients in placebo-controlled study of SECUADO, 1.6% (10) were 65 years of age or over. Multiple factors that might increase the pharmacodynamic response to SECUADO, causing poorer tolerance or orthostasis, could be present in elderly patients, and these patients should be monitored carefully. Based on a pharmacokinetic study in elderly patients with sublingual asenapine, dosage adjustments are not recommended based on age alone [ see Clinical Pharmacology (12.3) ]. Elderly patients with dementia-related psychosis treated with SECUADO are at an increased risk of death compared to placebo. SECUADO is not approved for the treatment of patients with dementia-related psychosis [ see Warning and Precautions (5.1 , 5.2) ]. No dosage adjustment for SECUADO is required on the basis of a patient’s renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute). The exposure of asenapine was similar among subjects with varying degrees of renal impairment and subjects with normal renal function [ see Clinical Pharmacology (12.3) ]. The effect of renal function on the excretion of other metabolites and the effect of dialysis on the pharmacokinetics of asenapine has not been studied. SECUADO is contraindicated in patients with severe hepatic impairment (Child-Pugh C) because asenapine exposure is 7-fold higher in subjects with severe hepatic impairment than the exposure observed in subjects with normal hepatic function. No dosage adjustment for SECUADO is required in patients with mild to moderate hepatic impairment (Child-Pugh A and B) because asenapine exposure is similar to that in subjects with normal hepatic function [see Contraindications (4) and Clinical Pharmacology (12.3) ].
How supplied
SECUADO (asenapine) transdermal system is a translucent rounded square product with a printed backing on one side and a release liner on the other supplied as: 3.8 mg/24 hours transdermal system (system size: 20 cm 2 ) Carton of 30 transdermal systems, each transdermal system is packaged in an individual pouch NDC 68968-0172-3 5.7 mg/24 hours transdermal system (system size: 30 cm 2 ) Carton of 30 systems, each system is packaged into an individual pouch NDC 68968-0173-3 7.6 mg/24 hours transdermal system (system size: 40 cm 2 ) Carton of 30 transdermal systems, each transdermal system is packaged in an individual pouch NDC 68968-0174-3 Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (between 59°F and 86°F) [see USP Controlled Room Temperature] .
Clinical pharmacology
The mechanism of action of asenapine in schizophrenia is unclear. However, it’s efficacy in schizophrenia could be mediated through a combination of antagonist activity at D 2 and 5-HT 2A receptors. Asenapine exhibits high affinity for serotonin 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5A , 5-H T6 and 5-HT 7 receptors (Ki values of 2.5, 2.7, 0.07, 0.18, 0.03, 1.6, 0.25, and 0.11nM, respectively), dopamine D 2A , D 2B , D 3 , D 4 , and D 1 receptors (Ki values of 1.3, 1.4, 0.42, 1.1, and 1.4 nM, respectively), adrenergic α 1A , α 2A , α 2B , and α 2C receptors (Ki values of 1.2, 1.2, 0.33 and 1.2 nM, respectively), and histamine H 1 receptors (Ki value 1.0 nM), and moderate affinity for H 2 receptors (Ki value of 6.2 nM). In in vitro assays asenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors (e.g., Ki value of 8128 nM for M 1 ). SECUADO has a different pharmacokinetic profile compared to sublingual asenapine. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during wear time (24 hours). Following SECUADO removal, the apparent elimination half-life is approximately 30 hours. Absorption On average, approximately 60% of the asenapine is released from the transdermal system over 24 hours. Inter-individual variability for SECUADO as coefficient of variation (%CV) for the steady-state asenapine C max,ss , C min,ss , and AUC 0-tau,ss was generally about 20% to 30%. Asenapine PK at steady-state is dose-proportional in the dose range of 3.8 mg/24 hours to 7.6 mg/24 hours following application of SECUADO. Steady-state plasma concentrations are achieved in about 72 hours after the first application of SECUADO. Peak to trough ratio is 1.5. Based on relative bioavailability and established dose proportionality, AUC for 3.8 mg/24 hours and 7.6 mg/24 hours was considered to be similar to that for sublingual asenapine 5 mg twice daily and 10 mg twice daily, respectively. There is no effect on asenapine PK with regards to the application site (upper arm, upper back, abdomen, and hip area). Application of a heating pad on SECUADO for 8 hours led to a faster absorption rate (median t max about 8 hours) as compared with SECUADO without a heating pad (median t max about 16 hours). Mean asenapine exposure, calculated as partial AUC 0-8 , following SECUADO application, was about 3.9 times greater than that without a heating pad, indicating the apparent heat effect in absorption during the time period of heating pad application. Distribution Asenapine is rapidly distributed and has a large volume of distribution (approximately 20-25 L/kg), indicating extensive extravascular distribution. Asenapine is highly bound (95%) to plasma proteins, including albumin and α 1 -acid glycoprotein. Elimination Asenapine is a high clearance drug with a clearance after intravenous administration of 52 L/h. In this circumstance, hepatic clearance is influenced primarily by changes in liver blood flow rather than by changes in the intrinsic clearance, i.e., the metabolizing enzymatic activity Metabolism Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) are the primary metabolic pathways for asenapine. Excretion After administration of a single dose of [ 14 C]-labeled asenapine, about 90% of the dose was recovered; approximately 50% was recovered in urine, and 40% recovered in feces. About 50% of the circulating species in plasma have been identified. The predominant species was asenapine N -glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. Pharmacological activity is primarily due to the parent drug. Special Populations Exposures of asenapine in special populations for sublingual asenapine are summarized in Figure 1 . Based on population pharmacokinetic analysis for sublingual asenapine, no effects of sex, race, ethnicity (Japanese versus Caucasian), BMI, and smoking status on asenapine exposure were observed. Exposure in elderly patients is 30-40% higher as compared to adults. Figure 1: Effect of Intrinsic Factors on Sublingual Asenapine Pharmacokinetics Drug Interaction Studies Effects of other drugs on the exposure of asenapine are summarized in Figure 2 . Marginal increase of asenapine exposure was observed when sublingual asenapine is used with fluvoxamine at 25 mg administered twice daily. However, the tested fluvoxamine dose was suboptimal. Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure. Figure 2: Effect of Other Drugs on Asenapine Pharmacokinetics The effects of asenapine on the pharmacokinetics of other co-administered drugs are summarized in Figure 3 . Figure 3: Effect of Asenapine on Other Drug Pharmacokinetics In vitro studies indicate that asenapine is a substrate for UGT1A4, CYP1A2 and to a lesser extent CYP3A4 and CYP2D6. Asenapine is a weak inhibitor of CYP2D6. Asenapine does not cause induction of CYP1A2 or CYP3A4 activities in cultured human hepatocytes. Coadministration of asenapine with known inhibitors, inducers or substrates of these metabolic pathways has been studied in a number of drug-drug interaction studies [see Drug Interactions ( 7.1 )] . fig1 fig2 fig3
Nonclinical toxicology
Carcinogenesis: In a lifetime carcinogenicity study in CD-1 mice asenapine was administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD of 10.0 mg twice daily. The incidence of malignant lymphomas was increased in female mice, with a no-effect dose resulting in plasma levels estimated to be 1.5 times those in humans receiving the MRHD. The mouse strain used has a high and variable incidence of malignant lymphomas, and the significance of these results to humans is unknown. There were no increases in other tumor types in female mice. In male mice, there were no increases in any tumor type. In a lifetime carcinogenicity study in Sprague-Dawley rats, asenapine did not cause any increases in tumors when administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD. In a 39-week study in minipigs, the asenapine transdermal system was administered at doses of 0.43 to 3.84 mg/kg asenapine, once every 24 hours. No significant dermal findings occurred at doses up to 17 times the MRHD of 12.8 mg transdermal asenapine daily for schizophrenia. Mutagenesis: No evidence for genotoxic potential of asenapine was found in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assays in human lymphocytes, the in vitro sister chromatid exchange assay in rabbit lymphocytes, or the in vivo micronucleus assay in rats. Impairment of Fertility: Asenapine did not impair fertility in rats when tested at doses up to 11 mg/kg twice daily given orally. This dose is 10 times MRHD of 10 mg twice daily asenapine given sublingually on a mg/m 2 basis and 16.6 times the MRHD of 12.8 mg daily asenapine given transdermally on a mg/m 2 basis. Transdermal administration of asenapine to rats, dogs and minipigs did not demonstrate any significant dermal findings when applied daily for 24 hours. Rats were treated for 26-weeks with percutaneous doses of asenapine (as free base) up to 1.42 mg/kg (1.3 times the MRHD of 12.8 mg transdermal asenapine as free base daily on a mg/kg basis), dogs were treated for 13-weeks with percutaneous doses of asenapine (as free base) up to 5.6 mg/kg (14.2 times the MRHD of 12.8 mg transdermal asenapine daily on mg/m 2 basis) and minipigs were treated for 39-weeks with percutaneous doses of asenapine (as free base) up to 3.84 mg/kg (17 times the MRHD of 12.8 mg transdermal asenapine [as free base] daily on mg/m 2 basis).
Clinical studies
The efficacy of SECUADO in the treatment of adult patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the sublingual formulation of asenapine. In addition, the efficacy of SECUADO was evaluated in a 6-week, fixed-dose, randomized, double-blind, and placebo-controlled trial (Study 1; NCT 02876900) of adult patients who met DSM-IV criteria for schizophrenia. In Study 1, the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) rating scales were used as the primary and key secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. CGI-S is a validated clinician-rated scale that measures the patient’s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale, based on the rater’s total clinical experience with this population. The primary endpoint was change from baseline in PANSS total score to Week 6. The change from baseline for SECUADO was compared to that for placebo. The results of the trial are shown in Table 8 . The time course of efficacy is shown in Figure 4 . In the 6-week trial (n=607) comparing two fixed doses of SECUADO (3.8 mg/24 hours and 7.6 mg/24 hours) to placebo, both doses were statistically superior to placebo for both PANSS total score and CGI-S. An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex or race. Table 8: Primary Efficacy Results for Change from Baseline in PANSS Total Score Week 6 (Study 1) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. a  Difference (drug minus placebo) in least-squares mean change from baseline. A negative value for the placebo subtracted difference represents improvement. *: Statistically significant after multiplicity adjustments. Treatment Group Primary Efficacy Measure: PANSS Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) to Week 6 Placebo-subtracted Difference a (95% CI) SECUADO 3.8 mg/24 hours* 97.0 (9.78) -22.1 (1.2) -6.6 (-9.81, -3.40) SECUADO 7.6 mg/24 hours* 95.6 (8.68) -20.4 (1.2) -4.8 (-8.06, -1.64) Placebo 97.4 (10.07) -15.5 (1.2) -- Figure 4: Change from Baseline in PANSS Total Score Over Time (Weeks) in Patients with Schizophrenia (Study 1) Maintenance of Efficacy with Sublingual Asenapine Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose with sublingual asenapine (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. All patients were initially administered 5 mg twice daily for 1 week and then titrated up to 10 mg twice daily. A total of 700 patients entered open label treatment with sublingual asenapine for a period of 26 weeks. Of these, a total of 386 patients who met pre-specified criteria for continued stability (mean length of stabilization was 22 weeks) were randomized to a double-blind, placebo-controlled, randomized withdrawal phase. Sublingual asenapine was statistically superior to placebo in time to relapse or impending relapse defined as increase in PANSS ≥20% from baseline and a Clinical Global Impression–Severity of Illness (CGI-S) score ≥4 (at least 2 days within 1 week) or PANSS score ≥5 on "hostility" or "uncooperativeness" items and CGI-S score ≥4 (≥2 days within a week), or PANSS score ≥5 on any two of the following items: "unusual thought content," "conceptual disorganization," or "hallucinatory behavior" items, and CGI-S score ≥4 (≥2 days within 1 week) or investigator judgment of worsening symptoms or increased risk of violence to self (including suicide) or other persons.The Kaplan-Meier curves of the time to relapse or impending relapse during the randomized, double-blind, placebo-controlled withdrawal phase of this trial for asenapine and placebo are shown in Figure 5 . Figure 5: Kaplan-Meier Estimation of Percent Relapse for Sublingual Asenapine and Placebo Adhesion Based on a clinical study in 40 subjects, each wearing one SECUADO 3.8 mg/24 hours, 40 transdermal systems (100%) exhibited 75% or greater surface area adhesion at all timepoints evaluated (every 4 hours) throughout the 24-hour wear period. Based on a clinical study in 39 subjects, each wearing one SECUADO 7.6 mg/24 hours, 36 transdermal systems (92%) exhibited 75% or greater surface area adhesion at all timepoints evaluated (every 4 hours) throughout the 24-hour wear period. One SECUADO 7.6 mg/24 hours transdermal system worn on the hip fully detached. fig4 fig5
Package label
NDC 68968-0172-3 PUSH IN PULL UP Secuado ® (asenapien) transdermal system 3.8 mg/24 hours For Transdermal Use Only 30 Transdermal Systems Rx only Each 20cm 2 system contains 6.4mg asenapine. Inactive ingredients: Alicylic saturated hydrocarbon resin, butylated hydroxytoluene, isopropyl palmitate, maleate salts (monosodium maleate and disodium maleate), mineral oil, polyester film backing, polyisobutylene, silicone-treated polyester release liner, sodium acetate anhydrous, and styrene-isoprene-styrene block copolymer. Dosage and Administration: See package insert. Important: Read Instructions for Use for application and proper use. Do not wear more than one Secuado transdermal system at a time. Apply immediately upon removal from pouch. To dispose, fold used transdermal system in half (sticky sides together) and place in trash right away. Keep out of the reach of children. Do not store unpouched. Store at room temperature at 20°C to 25°C (68°F to 77°F). Find out more at www.secuado.com 1M418T-0 Manufactured by Hisamitsu Pharmaceutical Co., Inc. 408, Tashirodaikan-machi, Tosu, Saga, Japan Distributed by Noven Therapeutics, LLC Miami, FL 33186 Carton Label - 3.8 mg

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asenapine