SECUADO is indicated for the treatment of adults with schizophrenia [see Clinical Studies (14)].

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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)].

SECUADO (asenapine) transdermal system is a translucent rounded square product available in three dosage strengths:

{ "type": "p", "children": [], "text": "SECUADO (asenapine) transdermal system is a translucent rounded square product available in three dosage strengths:" }

{ "type": "ul", "children": [ "3.8 mg asenapine / 24 hours ", "5.7 mg asenapine / 24 hours", "7.6 mg asenapine / 24 hours" ], "text": "" }

SECUADO is contraindicated in patients with:

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{ "type": "ul", "children": [ "Severe hepatic impairment (Child-Pugh C) [see Specific Populations (8.7),\n\t\t\t\t\t\t\t\tClinical Pharmacology (12.3)].", "A history of hypersensitivity reactions to asenapine or any components of the transdermal system. Reactions with asenapine have included\n\t\t\t\t\t\t\t\tanaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash \n\t\t\t\t\t\t\t\t[see Warnings and Precautions (5.6), \n\t\t\t\t\t\t\t\t\tAdverse Reactions (6)].\n" ], "text": "" }

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.

<div class="scrollingtable"><table class="Noautorules" width="700"> <caption> <span>Table 1: Changes in Fasting Glucose in Adult Patients in the 6-Week, Placebo-Controlled, Fixed Dose Schizophrenia Trial</span> </caption> <col align="center" width="25%"/> <col align="center" width="25%"/> <col align="center" width="25%"/> <col align="center" width="25%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2">Placebo</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2">SECUADO</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule">3.8 mg/24 hours</th><th align="center" class="Botrule Lrule Rrule Toprule">7.6 mg/24 hours</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4">N<span class="Sup">*</span> = Number of patients who had assessments at both Baseline and Endpoint.</td> </tr> </tfoot> <tbody> <tr class="Bold"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4">Mean Change from Baseline in Fasting Glucose at Endpoint</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Change from Baseline</span> <br/> <span>(mg/dL) (N*)</span></td><td align="center" class="Botrule Lrule Rrule Toprule">0.03<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">3.28<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">3.72<br/>(172)</td> </tr> <tr class="Bold"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4">Proportion of Patients with Shifts from Baseline to Endpoint</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Normal to High<br/> </span><span class="Bold">&lt;100 to ≥ 126 mg/dL</span>(n/N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">0%<br/>(0/198)</td><td align="center" class="Botrule Lrule Rrule Toprule">3.1%<br/>(6/196)</td><td align="center" class="Botrule Lrule Rrule Toprule">3.0%<br/>(6/199)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Borderline to High<br/> </span><span class="Bold">≥100 and<br/>&lt; 126 to ≥126 mg/dL</span> <br/>(n/N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">2.0%<br/>(4/198)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.0%<br/>(2/196)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.0%<br/>(2/199)</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 2: Changes in Lipids in Adult Patients in the 6-Week, Placebo-Controlled, Fixed Dose Schizophrenia Trial</span> </caption> <col align="center" width="40%"/> <col align="center" width="20%"/> <col align="center" width="20%"/> <col align="center" width="20%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2">Placebo</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2">SECUADO</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule">3.8 mg/24 hours</th><th align="center" class="Botrule Lrule Rrule Toprule">7.6 mg/24 hours</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4">N<span class="Sup">*</span> = Number of patients who had assessments at both Baseline and Endpoint.</td> </tr> </tfoot> <tbody> <tr class="Bold"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4">Mean Change from Baseline</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Total Cholesterol</span> <br/>(mg/dL) (N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">0.7<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">5.1<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">4.5<br/>(172)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">LDL</span> <br/>(mg/dL) (N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.6<br/>(172)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.4<br/>(170)</td><td align="center" class="Botrule Lrule Rrule Toprule">4.2<br/>(169)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">HDL</span> <br/>(mg/dL) (N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">-0.8<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">0.2<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">-0.7<br/>(172)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Fasting triglycerides</span> <br/>(mg/dL) (N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">-2.6<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">17.3<br/>(174)</td><td align="center" class="Botrule Lrule Rrule Toprule">6.7<br/>(172)</td> </tr> <tr class="Bold"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4">Proportion of Patients with Shifts from Baseline to Endpoint(n/N*)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Total Cholesterol Normal to High<br/> </span><span class="Bold">&lt;200 to ≥240 mg/dL</span> <br/>(n/N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.0%<br/>(2/197)</td><td align="center" class="Botrule Lrule Rrule Toprule">2.6%<br/>(5/196)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.0%<br/>(2/199)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">LDL Normal to High<br/> </span><span class="Bold">&lt;100 to ≥160 mg/dL</span> <br/>(n/N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">0.5%<br/>(1/195)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.0%<br/>(2/194)</td><td align="center" class="Botrule Lrule Rrule Toprule">0%<br/>(0/197)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">HDL Normal to High<br/> </span><span class="Bold">≥40 to &lt;40 mg/dL</span> <br/>(n/N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">8.1%<br/>(16/197)</td><td align="center" class="Botrule Lrule Rrule Toprule">10.7%<br/>(21/196)</td><td align="center" class="Botrule Lrule Rrule Toprule">12.1%<br/>(24/199)</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Fasting Triglycerides Normal to High<br/> </span><span class="Bold">&lt;150 to ≥200 mg/dL</span> <br/>(n/N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.1%<br/>(2/185)</td><td align="center" class="Botrule Lrule Rrule Toprule">7.0%<br/>(13/185)</td><td align="center" class="Botrule Lrule Rrule Toprule">3.2%<br/>(6/186)</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 3: Change in Body Weight in Adult Patients from Baseline in the 6-Week, Placebo-Controlled, Fixed Dose Schizophrenia Trial </span> </caption> <col align="center" width="30%"/> <col align="center" width="20%"/> <col align="center" width="25%"/> <col align="center" width="25%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"></th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2">Placebo</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2">SECUADO</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule">3.8 mg/24 hours</th><th align="center" class="Botrule Lrule Rrule Toprule">7.6 mg/24 hours</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4">N<span class="Sup">*</span> = Number of subjects with data at Endpoint.</td> </tr> </tfoot> <tbody> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Mean Change from<br/> Baseline</span> <br/>(kg) (N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">0.62<br/>(167)</td><td align="center" class="Botrule Lrule Rrule Toprule">2.10<br/>(168)</td><td align="center" class="Botrule Lrule Rrule Toprule">2.02<br/>(164)</td> </tr> <tr class="Bold"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4">Proportion of Patients with a ≥7% Increase in Body Weight </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">% with ≥7% increase in<br/> body weight</span> <br/>(n/N*)</td><td align="center" class="Botrule Lrule Rrule Toprule">3.9%<br/>(8/203)</td><td align="center" class="Botrule Lrule Rrule Toprule">18.3%<br/>(37/202)</td><td align="center" class="Botrule Lrule Rrule Toprule">14.3%<br/>(29/203)</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table class="Noautorules" width="750"> <caption> <span>Table 4: Weight Change Results Categorized by BMI at Baseline: Comparator-Controlled 52-Week Study with Sublingual Asenapine in Adults with Schizophrenia</span> </caption> <col align="center" width="25%"/> <col align="center" width="25%"/> <col align="center" width="25%"/> <col align="center" width="25%"/> <thead> <tr> <th align="center" class="Botrule Lrule Rrule Toprule"></th><th align="center" class="Botrule Lrule Rrule Toprule">BMI &lt;23<br/>Sublingual Asenapine<br/>N=295</th><th align="center" class="Botrule Lrule Rrule Toprule">BMI 23 - ≤27<br/>Sublingual Asenapine<br/>N=290</th><th align="center" class="Botrule Lrule Rrule Toprule">BMI &gt;27<br/>Sublingual Asenapine<br/>N=302</th> </tr> </thead> <tbody> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">Mean Change from<br/> Baseline</span> <br/>(kg)</td><td align="center" class="Botrule Lrule Rrule Toprule">1.7</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">0</td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold Italics">% with ≥7% increase<br/> in body weight<br/> </span></td><td align="center" class="Botrule Lrule Rrule Toprule">22%</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td> </tr> </tbody> </table></div>

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/mm3) 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 D2 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.

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 AUC0-8) 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of SECUADO was evaluated in a total of 315 adult patients diagnosed with schizophrenia who were exposed to SECUADO for up to 6 weeks in a placebo-controlled trial.

Adverse Reactions Leading to Discontinuation of Treatment

A total of 4.9% (10/204) patients treated with SECUADO 3.8 mg/24 hours, 7.8% (16/204) patients treated with SECUADO 7.6 mg/24 hours, and 6.8% (14/206) patients on placebo discontinued due to adverse reactions in the placebo-controlled trial. The adverse reaction that most commonly led to discontinuation among SECUADO-treated patients in this trial was akathisia, which led to discontinuation in no (0/204) patients treated with SECUADO 3.8 mg/24 hours, 1.5% (3/204) patients treated with SECUADO 7.6 mg/24 hours, and 0.5% (1/206) patients on placebo.

Commonly Observed Adverse Reactions

The most common adverse reactions (≥5% and at least twice the rate of placebo) reported in adult patients with schizophrenia treated with SECUADO in the placebo-controlled trial were extrapyramidal disorder, application site reaction and weight gain.

Adverse Reactions Occurring at an Incidence of 2% or More in SECUADO-Treated Patients.

Adverse reactions associated with the use of SECUADO (incidence of ≥2%, rounded to the nearest percent, and SECUADO incidence greater than placebo) that occurred during the placebo-controlled trial are shown in Table 5.

<div class="scrollingtable"><table width="750"> <caption> <span>Table 5: Adverse Reactions in ≥2% of Patients in Any SECUADO Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials</span> </caption> <colgroup> <col align="left" width="40%"/> <col align="center" width="20%"/> <col align="center" width="20%"/> <col align="center" width="20%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="4"><span class="Sup">*</span> The following terms were combined: <br/> <span class="Bold">Application site reactions</span> includes application site dermatitis, discoloration, discomfort, dryness, edema, erythema, exfoliation, induration, irritation, pain, papules, pruritus, and reaction. <br/> <span class="Bold">Blood glucose increased</span> includes blood glucose increased, blood insulin increased, glycosylated hemoglobin increased, hyperglycemia, Type 2 diabetes mellitus, diabetes mellitus, and hyperinsulinemia. <br/> <span class="Bold">Hepatic enzyme increased</span> includes hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased. <br/> <span class="Bold">Extrapyramidal symptoms</span> includes dyskinesia, dystonia, extrapyramidal disorder, parkinsonism. tardive dyskinesia, muscle spasm, and musculoskeletal stiffness. <br/> <span class="Bold">Somnolence</span> includes somnolence, sedation, lethargy, and hypersomnia. <br/> <span class="Bold">Hypertension</span> includes hypertension, blood pressure increased, diastolic hypertension, and hypertensive crisis.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2">System Organ Class/<br/> Preferred Term</th><th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2">Placebo<br/>N = 206<br/>(%)</th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2">SECUADO</th> </tr> <tr> <th align="center" class="Botrule Lrule Rrule Toprule">3.8 mg/24 hours<br/>N = 204<br/>(%)</th><th align="center" class="Botrule Lrule Rrule Toprule">7.6 mg/24 hours<br/>N = 204<br/>(%)</th> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Gastrointestinal disorders</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Constipation</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td><td align="center" class="Botrule Lrule Rrule Toprule">5</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Dyspepsia</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Diarrhea</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">General Disorders</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Application Site Reactions*</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td><td align="center" class="Botrule Lrule Rrule Toprule">15</td><td align="center" class="Botrule Lrule Rrule Toprule">14</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Investigations</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Blood glucose increased*</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Weight Increased</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td><td align="center" class="Botrule Lrule Rrule Toprule">6</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Hepatic enzyme increased*</td><td align="center" class="Botrule Lrule Rrule Toprule">0</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Infections and Infestations</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Nasopharyngitis</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Upper respiratory tract infection</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Metabolism and nutrition disorders</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Increased appetite</td><td align="center" class="Botrule Lrule Rrule Toprule">0</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Nervous System Disorders</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Headache</td><td align="center" class="Botrule Lrule Rrule Toprule">6</td><td align="center" class="Botrule Lrule Rrule Toprule">9</td><td align="center" class="Botrule Lrule Rrule Toprule">9</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Extrapyramidal symptoms*</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">8</td><td align="center" class="Botrule Lrule Rrule Toprule">13</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Akathisia</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Somnolence*</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">4</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Dystonia</td><td align="center" class="Botrule Lrule Rrule Toprule">0</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">3</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Vascular Disorders</span></td> </tr> <tr class="Last" valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule">      Hypertension*</td><td align="center" class="Botrule Lrule Rrule Toprule">1</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td><td align="center" class="Botrule Lrule Rrule Toprule">2</td> </tr> </tbody> </table></div>

Dose-Related Adverse Reactions: In the placebo-controlled schizophrenia trial, the incidence of an extrapyramidal disorder and weight increased appear to be dose-related (see Table 5).

Dystonia:

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups [Clinical Pharmacology (12.3)].

Extrapyramidal Symptoms:

In the short-term, placebo-controlled schizophrenia adult trial, data were objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Assessments of Involuntary Movement Scales (for dyskinesias). The mean change from baseline for the SECUADO 3.8 mg/24 hours or 7.6 mg/24 hours treated group was similar to placebo in each of the rating scale scores.

In the short-term, placebo-controlled schizophrenia adult trial, the incidence of reported extrapyramidal disorder events, excluding events related to akathisia, was 7.8% for patients treated with SECUADO 3.8 mg/24 hours, 12.8% for patients treated with SECUADO 7.6 mg/24 hours and 2.4% for placebo-treated patients; and the incidence of akathisia-related events was 3.9% for patients treated with SECUADO 3.8 mg/24 hours, 4.4% for patients treated with SECUADO 7.6 mg/24 hours and 2.4% for placebo-treated patients.

Laboratory Test Abnormalities:

Transaminases: Transient elevations in serum transaminases (primarily ALT) were more common in SECUADO-treated patients. The mean increase in ALT levels for SECUADO-treated patients was 6.0 units/L and 3.8 units/L for the SECUADO 3.8 mg/24 hours and 7.6 mg/24 hours treated groups, respectively, compared to a decrease of 1.1 units/L for placebo-treated patients. The proportion of patients with ALT elevations ≥3 times upper limit of normal (ULN) (at any time) was 1.6% and 3.1% for patients treated with SECUADO 3.8 mg/24 hours and 7.6 mg/24 hours, respectively, and 0% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial that included primarily adult patients with schizophrenia, the mean increase from baseline of ALT was 1.7 units/L for sublingual asenapine.

Prolactin: The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 0.0% and 1.3% for patients treated with SECUADO 3.8 mg/24 hours and 7.6 mg/24 hours, respectively, as compared to 2.4% for placebo-treated patients in the short-term placebo-controlled trial.

In a long-term (52-week), double-blind, comparator-controlled adult trial that included primarily patients with schizophrenia, the mean decrease in prolactin from baseline for sublingual asenapine-treated patients was 26.9 ng/mL.

Creatine Kinase (CK): The proportion of adult patients with CK elevations ≥3 times ULN at any time were 1.6% and 2.1% for patients treated with SECUADO 3.8 mg/24 hours and 7.6 mg/24 hours, respectively, as compared to 1.5% for placebo-treated patients in the short-term, placebo-controlled trial. The clinical relevance of this finding is unknown.

Other Adverse Reactions Observed During the Premarketing Evaluation of SECUADO

Other adverse reactions (<2% frequency) within the 6-week placebo-controlled trial in patients with schizophrenia are listed below. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the SECUADO label are not included.

Gastrointestinal disorders: vomiting, dry mouth

General disorders and administration site conditions: asthenia

Musculoskeletal and connective tissue disorders: myalgia

Other Adverse Reactions Reported in Clinical Trials with Sublingual Asenapine

Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual asenapine at multiple doses of ≥5 mg twice daily during any phase of a trial within the database of adult patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions already listed for adult patients in other parts of Adverse Reactions (6), or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) are not included. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).

Blood and lymphatic disorders: infrequent: anemia; rare: thrombocytopenia

Cardiac disorders: infrequent: temporary bundle branch block

Eye disorders: infrequent: accommodation disorder

Gastrointestinal disorders: infrequent: swollen tongue

General disorders: rare: idiosyncratic drug reaction

Investigations: infrequent: hyponatremia

Nervous system disorders: infrequent: dysarthria

The following adverse reactions have been identified during post-approval use of sublingual asenapine and are possible with SECUADO treatment. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure.

<div class="scrollingtable"><table class="Noautorules" width="900"> <caption> <span>Table 6: Clinically Important Drug Interactions with SECUADO</span> </caption> <col align="left" width="25%"/> <col align="left" width="75%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Antihypertensive Drugs</span></td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Implication</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Because of its α<span class="Sub">1</span>-adrenergic antagonism with potential for inducing hypotension, SECUADO may enhance the effects of certain antihypertensive agents <span class="Italics">[see <a href="#s_0507">Warnings and Precautions (5.7)</a>]</span>.</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Prevention or Management:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Monitor blood pressure and adjust dosage of antihypertensive drug accordingly.</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Diuretics, ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers, Alpha-blockers </td> </tr> <tr class="Bold"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">Strong CYP1A2 Inhibitors</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Implication</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Asenapine is metabolized by CYP1A2. Concomitant use of SECUADO with a CYP1A2 inhibitor increases AUC and C<span class="Sub">max</span> of asenapine <span class="Italics">[see <a href="#s_1203">Clinical Pharmacology (12.3)</a>]</span>. </td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Prevention or Management:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Dosage reduction for SECUADO based on clinical response may be necessary.</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Fluvoxamine, ciprofloxacin, enoxacin</td> </tr> <tr class="Bold"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2">CYP2D6 substrates and inhibitors</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Clinical Implication</span></td><td align="left" class="Botrule Lrule Rrule Toprule">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<span class="Sub">max</span><span class="Italics">[see <a href="#s_1203">Clinical Pharmacology (12.3)</a>]</span>. </td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Prevention or Management:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Reduce paroxetine dose by half when paroxetine is used in combination with SECUADO.</td> </tr> <tr valign="top"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Lrule Rrule Toprule">Paroxetine</td> </tr> </tbody> </table></div>

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/m2 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)].

SECUADO is not a controlled substance.

SECUADO has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance or physical dependence. Thus, it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs that they are misusing or abusing SECUADO (e.g., drug-seeking behavior, increases in dose).

Human Experience: In the placebo-controlled trial in adults for SECUADO, there were no reports of accidental or intentional acute overdosage of SECUADO.

{ "type": "p", "children": [], "text": "\nHuman Experience: In the placebo-controlled trial in adults for SECUADO, there were no reports of accidental or intentional acute overdosage of SECUADO." }

In adult clinical studies involving more than 3350 patients and/or healthy subjects for sublingual asenapine, accidental or intentional acute overdosage of sublingual asenapine was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of sublingual asenapine was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion.

{ "type": "p", "children": [], "text": "In adult clinical studies involving more than 3350 patients and/or healthy subjects for sublingual asenapine, accidental or intentional acute overdosage of sublingual asenapine was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of sublingual asenapine was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion." }

Management of Overdosage: There is no specific antidote to SECUADO. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Consult a Certified Poison Control Center at 1 800-222-1222 for up to date information on the management of overdosage.

{ "type": "p", "children": [], "text": "\nManagement of Overdosage: There is no specific antidote to SECUADO. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Consult a Certified Poison Control Center at 1 800-222-1222 for up to date information on the management of overdosage." }

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of SECUADO-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

{ "type": "p", "children": [], "text": "Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of SECUADO-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers." }

SECUADO transdermal system contains asenapine, an atypical antipsychotic.

{ "type": "p", "children": [], "text": "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 C17H16Cl NO and its molecular weight is 285.8 g/mol. The chemical structure is:

{ "type": "p", "children": [], "text": "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 C17H16Cl 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.

{ "type": "p", "children": [], "text": "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." }

<div class="scrollingtable"><table class="Noautorules" width="700"> <caption> <span>Table 7: SECUADO (asenapine) transdermal system</span> </caption> <col align="center" width="33.33%"/> <col align="center" width="33.33%"/> <col align="center" width="33.33%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Dosage Strength (Asenapine)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Total Asenapine Content per Transdermal System</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Transdermal System Size</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">3.8 mg/24 hours</td><td align="center" class="Botrule Lrule Rrule Toprule">6.4 mg</td><td align="center" class="Botrule Lrule Rrule Toprule">20 cm<span class="Sup">2</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">5.7 mg/24 hours</td><td align="center" class="Botrule Lrule Rrule Toprule">9.6 mg</td><td align="center" class="Botrule Lrule Rrule Toprule">30 cm<span class="Sup">2</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">7.6 mg/24 hours</td><td align="center" class="Botrule Lrule Rrule Toprule">12.8 mg</td><td align="center" class="Botrule Lrule Rrule Toprule">40 cm<span class="Sup">2</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"700\">\n<caption>\n<span>Table 7: SECUADO (asenapine) transdermal system</span>\n</caption>\n<col align=\"center\" width=\"33.33%\"/>\n<col align=\"center\" width=\"33.33%\"/>\n<col align=\"center\" width=\"33.33%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Dosage Strength (Asenapine)</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Total Asenapine Content per Transdermal System</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Transdermal System Size</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">3.8 mg/24 hours</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">6.4 mg</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">20 cm<span class=\"Sup\">2</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">5.7 mg/24 hours</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">9.6 mg</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">30 cm<span class=\"Sup\">2</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">7.6 mg/24 hours</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">12.8 mg</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\">40 cm<span class=\"Sup\">2</span></td>\n</tr>\n</tbody>\n</table></div>" }

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 D2 and 5-HT2A receptors.

Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7 receptors (Ki values of 2.5, 2.7, 0.07, 0.18, 0.03, 1.6, 0.25, and 0.11nM, respectively), dopamine D2A, D2B, D3, D4, and D1 receptors (Ki values of 1.3, 1.4, 0.42, 1.1, and 1.4 nM, respectively), adrenergic α1A, α2A, α2B, and α2C receptors (Ki values of 1.2, 1.2, 0.33 and 1.2 nM, respectively), and histamine H1 receptors (Ki value 1.0 nM), and moderate affinity for H2 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 M1).

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 Cmax,ss, Cmin,ss, and AUC0-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 tmax about 8 hours) as compared with SECUADO without a heating pad (median tmax about 16 hours). Mean asenapine exposure, calculated as partial AUC0-8, 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 α1-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 [14C]-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)].

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/m2 basis and 16.6 times the MRHD of 12.8 mg daily asenapine given transdermally on a mg/m2 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/m2 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/m2 basis).

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.

{ "type": "p", "children": [], "text": "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:

{ "type": "p", "children": [], "text": "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:" }

{ "type": "ul", "children": [ "PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), \n\t\t\t\t\t\t\t\tand 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." ], "text": "" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex or race." }

<div class="scrollingtable"><table class="Noautorules" width="800"> <caption> <span>Table 8: Primary Efficacy Results for Change from Baseline in PANSS Total Score Week 6 (Study 1)</span> </caption> <col width="35%"/> <col align="center" width="20%"/> <col align="center" width="25%"/> <col align="center" width="20%"/> <tfoot> <tr> <td colspan="4"> <p class="First">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. <br/> <span class="Sup">a </span>Difference (drug minus placebo) in least-squares mean change from baseline. A negative value for the placebo subtracted difference represents improvement. <br/>*: Statistically significant after multiplicity adjustments. </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <th align="left" class="Toprule" rowspan="2" valign="top">Treatment Group</th><th align="center" class="Botrule Toprule" colspan="3">Primary Efficacy Measure: PANSS Total Score</th> </tr> <tr class="Botrule"> <th>Mean Baseline Score <br/>(SD)</th><th align="center">LS Mean Change from <br/>Baseline (SE) to Week 6</th><th align="center">Placebo-subtracted Difference<span class="Sup">a</span> (95% CI)</th> </tr> <tr> <td class="Toprule">SECUADO 3.8 mg/24 hours*</td><td align="center">97.0 (9.78)</td><td align="center">-22.1 (1.2)</td><td align="center">-6.6 (-9.81, -3.40)</td> </tr> <tr> <td>SECUADO 7.6 mg/24 hours*</td><td align="center">95.6 (8.68)</td><td align="center">-20.4 (1.2)</td><td align="center">-4.8 (-8.06, -1.64)</td> </tr> <tr> <td>Placebo</td><td align="center">97.4 (10.07)</td><td align="center">-15.5 (1.2)</td><td align="center">--</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"800\">\n<caption>\n<span>Table 8:\tPrimary Efficacy Results for Change from Baseline in PANSS Total Score Week 6 (Study 1)</span>\n</caption>\n<col width=\"35%\"/>\n<col align=\"center\" width=\"20%\"/>\n<col align=\"center\" width=\"25%\"/>\n<col align=\"center\" width=\"20%\"/>\n<tfoot>\n<tr>\n<td colspan=\"4\">\n<p class=\"First\">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.\n\t\t\t\t\t\t\t\t\t\t\t<br/>\n<span class=\"Sup\">a </span>Difference (drug minus placebo) in least-squares mean change from baseline. A negative value for the placebo subtracted difference represents improvement. \n\t\t\t\t\t\t\t\t\t\t\t<br/>*: Statistically significant after multiplicity adjustments.\n\t\t\t\t\t\t\t\t\t\t</p>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr>\n<th align=\"left\" class=\"Toprule\" rowspan=\"2\" valign=\"top\">Treatment Group</th><th align=\"center\" class=\"Botrule Toprule\" colspan=\"3\">Primary Efficacy Measure: PANSS Total Score</th>\n</tr>\n<tr class=\"Botrule\">\n<th>Mean Baseline Score <br/>(SD)</th><th align=\"center\">LS Mean Change from <br/>Baseline (SE) to Week 6</th><th align=\"center\">Placebo-subtracted Difference<span class=\"Sup\">a</span> (95% CI)</th>\n</tr>\n<tr>\n<td class=\"Toprule\">SECUADO 3.8 mg/24 hours*</td><td align=\"center\">97.0 (9.78)</td><td align=\"center\">-22.1 (1.2)</td><td align=\"center\">-6.6 (-9.81, -3.40)</td>\n</tr>\n<tr>\n<td>SECUADO 7.6 mg/24 hours*</td><td align=\"center\">95.6 (8.68)</td><td align=\"center\">-20.4 (1.2)</td><td align=\"center\">-4.8 (-8.06, -1.64)</td>\n</tr>\n<tr>\n<td>Placebo</td><td align=\"center\">97.4 (10.07)</td><td align=\"center\">-15.5 (1.2)</td><td align=\"center\">--</td>\n</tr>\n</tbody>\n</table></div>" }

Figure 4: Change from Baseline in PANSS Total Score Over Time (Weeks) in Patients with Schizophrenia (Study 1)

{ "type": "p", "children": [], "text": "\nFigure 4:\tChange from Baseline in PANSS Total Score Over Time (Weeks) in Patients with Schizophrenia (Study 1)\n" }

Maintenance of Efficacy with Sublingual Asenapine

{ "type": "p", "children": [], "text": "\nMaintenance of Efficacy with Sublingual Asenapine\n" }

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.

{ "type": "p", "children": [], "text": "Maintenance of efficacy has been demonstrated in a placebo-controlled, double-blind, multicenter, flexible dose with sublingual \n\t\t\t\t\t\t\tasenapine (5 mg or 10 mg twice daily based on tolerability) clinical trial with a randomized withdrawal design. All patients were \n\t\t\t\t\t\t\tinitially 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\n\t\t\t\t\t\t\ttreatment with sublingual asenapine for a period of 26 weeks. Of these, a total of 386 patients who met pre-specified criteria for \n\t\t\t\t\t\t\tcontinued stability (mean length of stabilization was 22 weeks) were randomized to a double-blind, placebo-controlled, randomized \n\t\t\t\t\t\t\twithdrawal phase. Sublingual asenapine was statistically superior to placebo in time to relapse or impending relapse defined as \n\t\t\t\t\t\t\tincrease in PANSS ≥20% from baseline and a Clinical Global Impression–Severity of Illness (CGI-S) score ≥4 (at least 2 days\n\t\t\t\t\t\t\twithin 1 week) or PANSS score ≥5 on \"hostility\" or \"uncooperativeness\" items and CGI-S score ≥4 (≥2 days within a week),\n\t\t\t\t\t\t\tor PANSS score ≥5 on any two of the following items: \"unusual thought content,\" \"conceptual disorganization,\" or \n\t\t\t\t\t\t\t\"hallucinatory behavior\" items, and CGI-S score ≥4 (≥2 days within 1 week) or investigator judgment of worsening symptoms or\n\t\t\t\t\t\t\tincreased 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

{ "type": "p", "children": [], "text": "\nFigure 5: Kaplan-Meier Estimation of Percent Relapse for Sublingual Asenapine and Placebo\n" }

Adhesion

{ "type": "p", "children": [], "text": "\nAdhesion\n" }

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.

{ "type": "p", "children": [], "text": "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." }

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:

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] .

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Instructions for Use)." }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions\n" }

Counsel patients on the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.) and to seek immediate emergency assistance if they develop any of these signs and symptoms [see Contraindications (4),Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.) and to seek immediate emergency assistance if they develop any of these signs and symptoms [see Contraindications (4),Warnings and Precautions (5.6)]." }

Neuroleptic Malignant Syndrome

{ "type": "p", "children": [], "text": "\nNeuroleptic Malignant Syndrome\n" }

Counsel patients about a potentially fatal adverse reaction referred to as NMS that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Counsel patients about a potentially fatal adverse reaction referred to as NMS that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)]." }

Tardive Dyskinesia

{ "type": "p", "children": [], "text": "\nTardive Dyskinesia\n" }

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.4)]." }

Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)

{ "type": "p", "children": [], "text": "\nMetabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)\n" }

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)]." }

Orthostatic Hypotension

{ "type": "p", "children": [], "text": "\nOrthostatic Hypotension\n" }

Counsel patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and at times of re-initiating treatment or increases in dose [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Counsel patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and at times of re-initiating treatment or increases in dose [see Warnings and Precautions (5.7)]." }

Leukopenia/Neutropenia

{ "type": "p", "children": [], "text": "\nLeukopenia/Neutropenia \n" }

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking SECUADO [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking SECUADO [see Warnings and Precautions (5.9)]." }

Hyperprolactinemia

{ "type": "p", "children": [], "text": "\nHyperprolactinemia\n" }

Counsel patients on the signs and symptoms of hyperprolactinemia and to contact their health care provider if these abnormalities occur [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of hyperprolactinemia and to contact their health care provider if these abnormalities occur [see Warnings and Precautions (5.11)]." }

Interference with Cognitive and Motor Performance

{ "type": "p", "children": [], "text": "\nInterference with Cognitive and Motor Performance\n" }

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SECUADO therapy does not affect them adversely [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SECUADO therapy does not affect them adversely [see Warnings and Precautions (5.13)]." }

Heat Exposure and Dehydration

{ "type": "p", "children": [], "text": "\nHeat Exposure and Dehydration \n" }

Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14)].

{ "type": "p", "children": [], "text": "Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14)]." }

External Heat

{ "type": "p", "children": [], "text": "\nExternal Heat\n" }

Inform patients to avoid exposing SECUADO to external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., [see Warnings and Precautions (5.16)].

{ "type": "p", "children": [], "text": "Inform patients to avoid exposing SECUADO to external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., [see Warnings and Precautions (5.16)]." }

Application Site Reactions

{ "type": "p", "children": [], "text": "\nApplication Site Reactions\n" }

Inform patients that application site reactions, including erythema, pruritus, papules, discomfort, pain, edema or irritation, have been reported with use of SECUADO. Inform patients that increased skin irritation may occur 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. Patients should monitor for these reactions while wearing or immediately after removal of SECUADO [see Warnings and Precautions (5.17)].

{ "type": "p", "children": [], "text": "Inform patients that application site reactions, including erythema, pruritus, papules, discomfort, pain, edema or irritation, have been reported with use of SECUADO. Inform patients that increased skin irritation may occur 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. Patients should monitor for these reactions while wearing or immediately after removal of SECUADO [see Warnings and Precautions (5.17)]." }

Concomitant Medications

{ "type": "p", "children": [], "text": "\nConcomitant Medications\n" }

Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)].

{ "type": "p", "children": [], "text": "Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)]." }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Advise patients that SECUADO may cause fetal harm as well as extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise patients that SECUADO may cause fetal harm as well as extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]." }

Pregnancy Registry

{ "type": "p", "children": [], "text": "\nPregnancy Registry\n" }

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SECUADO during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SECUADO during pregnancy [see Use in Specific Populations (8.1)]." }

Manufactured by: Hisamitsu Pharmaceutical Co. Inc., 408, Tashirodaikan-machi, Tosu, Saga, Japan

{ "type": "p", "children": [], "text": "Manufactured by: Hisamitsu Pharmaceutical Co. Inc., 408, Tashirodaikan-machi, Tosu, Saga, Japan" }

Distributed by: Noven Therapeutics, LLC, Miami, Florida USA.

{ "type": "p", "children": [], "text": "Distributed by: Noven Therapeutics, LLC, Miami, Florida USA." }

For more information, call 1-800-455-8070 or visit www.secuado.com

{ "type": "p", "children": [], "text": "For more information, call 1-800-455-8070 or visit www.secuado.com" }

SECUADO is a registered trademark of Hisamitsu Pharmaceutical Co., Inc.

{ "type": "p", "children": [], "text": "SECUADO is a registered trademark of Hisamitsu Pharmaceutical Co., Inc." }

©2019-2025 Hisamitsu Pharmaceutical Co., Inc. All rights reserved.

{ "type": "p", "children": [], "text": "©2019-2025 Hisamitsu Pharmaceutical Co., Inc. All rights reserved." }

5O134A-0

{ "type": "p", "children": [], "text": "5O134A-0" }

Instructions for Use

{ "type": "p", "children": [], "text": "\nInstructions for Use\n" }

SECUADO® (seh kue a’ doe)

{ "type": "p", "children": [], "text": "\nSECUADO® (seh kue a’ doe)\n" }

(asenapine) transdermal system

{ "type": "p", "children": [], "text": "\n(asenapine) transdermal system\n" }

Read this Instructions for Use before you start using the SECUADO transdermal system (patch) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

{ "type": "p", "children": [], "text": "Read this Instructions for Use before you start using the SECUADO transdermal system (patch) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment." }

Important Information:

{ "type": "p", "children": [], "text": "\nImportant Information:\n" }

{ "type": "ul", "children": [ "The SECUADO transdermal system (patch) is for use on the skin only (transdermal).", "Do not cut the pouch open until you are ready to apply the patch.", "You should apply only 1 SECUADO patch to 1 application site every 24 hours. The patch should only be worn for 24 hours. Do not wear the patch longer than 24 hours.", "Avoid bathing or swimming while wearing the patch. Swimming or bathing may cause the patch to fall off. You may shower.", "Avoid exposing the patch application site to direct heat sources such as hair dryers, heating pads, electric blankets, or heated water beds.", "If your skin feels irritated or feels like it is burning after you apply the patch, remove the patch and apply a new patch to a new application site." ], "text": "" }

Applying your SECUADO patch:

{ "type": "p", "children": [], "text": "\nApplying your SECUADO patch:\n" }

{ "type": "ul", "children": [ "Change (rotate) your patch application site every time you apply a new patch. Changing your application site every time you apply a patch will help to lessen your chances of developing skin irritation at the application site. Do not use the same application site 2 times in a row.", "The application site you choose should be clean, dry, and intact. Do not apply the patch on skin that has cuts, scrapes, burns, rashes, redness, or other skin problems.", "The application site you choose should be hairless or nearly hairless. If there is a lot of hair, use scissors to clip the hair as close to the skin as possible. Do not shave the application site.\n", "Do not apply the patch on skin that has oils, lotions, or powders on it.", "Do not apply the patch to areas of your skin where you wear tight clothing, such as waistbands, bras, or tank top straps." ], "text": "" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="50%"/> <col align="center" valign="middle" width="50%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule"><span class="Bold">Step 1. </span></td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="7"><img alt="step 1" src="/dailymed/image.cfm?name=secuado-07.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Disc"> <li> <span class="Bold">Always remove the used patch before applying a new one.</span> You should only wear 1 patch at a time.</li> <li> <span class="Bold">Choose 1 application site to apply 1 patch.</span> </li> <li> <span class="Bold">The application site you may choose should be one of the approved sites listed. Apply the patch to the left or right:</span> <ul class="Circle"> <li>upper arm</li> <li>upper back</li> <li>stomach area (abdomen)</li> <li>hip</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"><span class="Bold">Step 2. </span> <br/>When you are ready to apply your patch, use scissors and carefully cut the protective pouch along the dashed line to open the pouch and remove the patch. <span class="Bold">Do not cut the SECUADO patch.</span></td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3"><img alt="step 2" src="/dailymed/image.cfm?name=secuado-08.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Disc"> <li>Do not use the patch if it is cut or damaged or if the seal on the pouch is broken. Throw it away and get a new one.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> <ul class="Disc"> <li>Apply the patch right away after removing it from the pouch.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"><span class="Bold">Step 3. </span> <br/>Hold the patch with the protective liner facing you. Bend the patch along the wave-shaped line in the middle of the protective liner. Slowly peel <span class="Bold">half</span> of the protective liner off your patch.</td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"><img alt="step 3" src="/dailymed/image.cfm?name=secuado-09.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> <ul class="Disc"> <li> <span class="Bold">Do not</span> touch the sticky side of the patch.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Step 4. <br/>Holding the other half of the protective liner,</span> apply the sticky half of the patch to the application site you chose and <span class="Bold">smooth it down </span> with your fingers.</td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="step 4" src="/dailymed/image.cfm?name=secuado-10.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"><span class="Bold">Step 5. </span> <br/>Hold the edge of the remaining half of the protective liner, then slowly peel it away and <span class="Bold">smooth the patch down</span> onto your skin with your fingers.</td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"><img alt="step 5" src="/dailymed/image.cfm?name=secuado-11.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"><span class="Bold">Step 6. <br/>Press and hold</span> the patch firmly with the palm of your hand to make sure the patch and edges are sticking to your skin.</td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="4"><img alt="step 6" src="/dailymed/image.cfm?name=secuado-12.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Disc"> <li>Check the patch regularly during the day to make sure the patch is still firmly attached to your skin, especially after showering, using the bathroom, undressing, changing clothes, sleeping, or sweating.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Disc"> <li>If the patch edges lift off your skin, you should smooth down edges with your fingers, <span class="Bold">press and hold</span> the patch firmly with the palm of your hand.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> <ul class="Disc"> <li> <span class="Bold">If your patch falls off, do not reapply the same patch.</span> Choose a new application site, and repeat Steps 1 through 7 to apply a new SECUADO patch. Then, follow your normal schedule for changing the patch.</li> </ul> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Step 7. </span> <br/>Wash your hands with soap and water after applying the patch.</td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="step 7" src="/dailymed/image.cfm?name=secuado-13.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"center\" valign=\"middle\" width=\"50%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Step 1. </span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"7\"><img alt=\"step 1\" src=\"/dailymed/image.cfm?name=secuado-07.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Always remove the used patch before applying a new one.</span> You should only wear 1 patch at a time.</li>\n<li>\n<span class=\"Bold\">Choose 1 application site to apply 1 patch.</span>\n</li>\n<li>\n<span class=\"Bold\">The application site you may choose should be one of the approved sites listed. Apply the patch to the left or right:</span>\n<ul class=\"Circle\">\n<li>upper arm</li>\n<li>upper back</li>\n<li>stomach area (abdomen)</li>\n<li>hip</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Step 2. </span>\n<br/>When you are ready to apply your patch, use scissors and carefully cut the protective pouch along the dashed line to open the pouch and remove the patch. <span class=\"Bold\">Do not cut the SECUADO patch.</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"3\"><img alt=\"step 2\" src=\"/dailymed/image.cfm?name=secuado-08.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\">\n<ul class=\"Disc\">\n<li>Do not use the patch if it is cut or damaged or if the seal on the pouch is broken. Throw it away and get a new one.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\">\n<ul class=\"Disc\">\n<li>Apply the patch right away after removing it from the pouch.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Step 3. </span>\n<br/>Hold the patch with the protective liner facing you. Bend the patch along the wave-shaped line in the middle of the protective liner. Slowly peel <span class=\"Bold\">half</span> of the protective liner off your patch.</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\"><img alt=\"step 3\" src=\"/dailymed/image.cfm?name=secuado-09.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not</span> touch the sticky side of the patch.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Step 4. <br/>Holding the other half of the protective liner,</span> apply the sticky half of the patch to the application site you chose and <span class=\"Bold\">smooth it down </span> with your fingers.</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"step 4\" src=\"/dailymed/image.cfm?name=secuado-10.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Step 5. </span>\n<br/>Hold the edge of the remaining half of the protective liner, then slowly peel it away and <span class=\"Bold\">smooth the patch down</span> onto your skin with your fingers.</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\"><img alt=\"step 5\" src=\"/dailymed/image.cfm?name=secuado-11.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Step 6. <br/>Press and hold</span> the patch firmly with the palm of your hand to make sure the patch and edges are sticking to your skin.</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"4\"><img alt=\"step 6\" src=\"/dailymed/image.cfm?name=secuado-12.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\">\n<ul class=\"Disc\">\n<li>Check the patch regularly during the day to make sure the patch is still firmly attached to your skin, especially after showering, using the bathroom, undressing, changing clothes, sleeping, or sweating.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\">\n<ul class=\"Disc\">\n<li>If the patch edges lift off your skin, you should smooth down edges with your fingers, <span class=\"Bold\">press and hold</span> the patch firmly with the palm of your hand.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">If your patch falls off, do not reapply the same patch.</span> Choose a new application site, and repeat Steps 1 through 7 to apply a new SECUADO patch. Then, follow your normal schedule for changing the patch.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Step 7. </span>\n<br/>Wash your hands with soap and water after applying the patch.</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"step 7\" src=\"/dailymed/image.cfm?name=secuado-13.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n</tbody>\n</table></div>" }

Removing and disposing of your used SECUADO patch:

{ "type": "p", "children": [], "text": "\nRemoving and disposing of your used SECUADO patch:\n" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="50%"/> <col align="center" valign="middle" width="50%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule"><span class="Bold">Step 8.</span> <br/>After you have worn the patch for 24 hours, remove the used patch from your skin and <span class="Bold">fold it in half so that the sticky sides stick together.</span></td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="4"><img alt="step 8" src="/dailymed/image.cfm?name=secuado-14.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Disc"> <li>Your used patch still has some medicine and should be <span class="Bold">folded</span>.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Disc"> <li>If the patch is hard to remove from the skin, gently apply an oil-based product (petroleum jelly, olive oil, or mineral oil) to the patch edges.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule"> <ul class="Disc"> <li>If any adhesive (glue) remains on the skin after you remove the patch, apply an oil-based product or lotion to help with the removal.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"><span class="Bold">Step 9.</span> <br/>Safely throw away the used <span class="Bold">folded</span> patch in the trash right away so that children and pets cannot reach it</td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="step 9" src="/dailymed/image.cfm?name=secuado-15.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule"><span class="Bold">Step 10.</span> <br/>Wash your hands with soap and water after removing the patch.</td><td align="center" class="Botrule Lrule Rrule Toprule"><img alt="step 10" src="/dailymed/image.cfm?name=secuado-16.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"center\" valign=\"middle\" width=\"50%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Step 8.</span>\n<br/>After you have worn the patch for 24 hours, remove the used patch from your skin and <span class=\"Bold\">fold it in half so that the sticky sides stick together.</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"4\"><img alt=\"step 8\" src=\"/dailymed/image.cfm?name=secuado-14.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\">\n<ul class=\"Disc\">\n<li>Your used patch still has some medicine and should be <span class=\"Bold\">folded</span>.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\">\n<ul class=\"Disc\">\n<li>If the patch is hard to remove from the skin, gently apply an oil-based product (petroleum jelly, olive oil, or mineral oil) to the patch edges.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\">\n<ul class=\"Disc\">\n<li>If any adhesive (glue) remains on the skin after you remove the patch, apply an oil-based product or lotion to help with the removal.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Step 9.</span>\n<br/>Safely throw away the used <span class=\"Bold\">folded</span> patch in the trash right away so that children and pets cannot reach it</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"step 9\" src=\"/dailymed/image.cfm?name=secuado-15.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Step 10.</span>\n<br/>Wash your hands with soap and water after removing the patch.</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"><img alt=\"step 10\" src=\"/dailymed/image.cfm?name=secuado-16.jpg&amp;setid=685eaf44-5944-4f38-afba-0a4fc0b3462b\"/></td>\n</tr>\n</tbody>\n</table></div>" }

How should I store SECUADO patch?

{ "type": "p", "children": [], "text": "\nHow should I store SECUADO patch?\n" }

{ "type": "ul", "children": [ "Store SECUADO patches at room temperature between 68°F to 77°F (20°C to 25°C).", "\nKeep SECUADO patches and all medicines out of the reach of children.\n" ], "text": "" }

Manufactured by: Hisamitsu Pharmaceutical Co., Inc., 408, Tashirodaikan-machi, Tosu, Saga, Japan ©2019-2023, Hisamitsu Pharmaceutical Co., Inc. All rights reserved.

{ "type": "p", "children": [], "text": "Manufactured by: Hisamitsu Pharmaceutical Co., Inc., 408, Tashirodaikan-machi, Tosu, Saga, Japan ©2019-2023, Hisamitsu Pharmaceutical Co., Inc. All rights reserved." }

Distributed by: Noven Therapeutics, LLC, Miami, Florida USA

{ "type": "p", "children": [], "text": "Distributed by: Noven Therapeutics, LLC, Miami, Florida USA" }

SECUADO is a registered trademark of Hisamitsu Pharmaceutical Co., Inc.

{ "type": "p", "children": [], "text": "SECUADO is a registered trademark of Hisamitsu Pharmaceutical Co., Inc." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

4O134A-0

{ "type": "p", "children": [], "text": "4O134A-0" }

Revised: 12/2023

{ "type": "p", "children": [], "text": "Revised: 12/2023" }

NDC 68968-0172-3

{ "type": "p", "children": [], "text": "NDC 68968-0172-3" }

PUSH IN

{ "type": "p", "children": [], "text": "PUSH IN" }

PULL UP

{ "type": "p", "children": [], "text": "PULL UP" }

Secuado®

{ "type": "p", "children": [], "text": "Secuado®\n" }

(asenapien)

{ "type": "p", "children": [], "text": "(asenapien)" }

transdermal system

{ "type": "p", "children": [], "text": "transdermal system" }

3.8 mg/24 hours

{ "type": "p", "children": [], "text": "\n3.8 mg/24 hours\n" }

For Transdermal Use Only

{ "type": "p", "children": [], "text": "\nFor Transdermal Use Only\n" }

30 Transdermal Systems

{ "type": "p", "children": [], "text": "30 Transdermal Systems" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Each 20cm2 system contains 6.4mg asenapine.

{ "type": "p", "children": [], "text": "Each 20cm2 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.

{ "type": "p", "children": [], "text": "\nInactive 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.

{ "type": "p", "children": [], "text": "\nDosage 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.

{ "type": "p", "children": [], "text": "\nImportant: 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).

{ "type": "p", "children": [], "text": "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

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1M418T-0

{ "type": "p", "children": [], "text": "1M418T-0" }

Manufactured by

{ "type": "p", "children": [], "text": "Manufactured by" }

Hisamitsu Pharmaceutical Co., Inc.

{ "type": "p", "children": [], "text": "\nHisamitsu Pharmaceutical Co., Inc.\n" }

408, Tashirodaikan-machi, Tosu, Saga, Japan

{ "type": "p", "children": [], "text": "408, Tashirodaikan-machi, Tosu, Saga, Japan" }

Distributed by

{ "type": "p", "children": [], "text": "Distributed by" }

Noven Therapeutics, LLC

{ "type": "p", "children": [], "text": "\nNoven Therapeutics, LLC\n" }

Miami, FL 33186

{ "type": "p", "children": [], "text": "Miami, FL 33186" }

NDC 68968-0173-3

{ "type": "p", "children": [], "text": "NDC 68968-0173-3" }

PUSH IN

{ "type": "p", "children": [], "text": "PUSH IN" }

PULL UP

{ "type": "p", "children": [], "text": "PULL UP" }

Secuado®

{ "type": "p", "children": [], "text": "Secuado®\n" }

(asenapien)

{ "type": "p", "children": [], "text": "(asenapien)" }

transdermal system

{ "type": "p", "children": [], "text": "transdermal system" }

5.7 mg/24 hours

{ "type": "p", "children": [], "text": "\n5.7 mg/24 hours\n" }

For Transdermal Use Only

{ "type": "p", "children": [], "text": "\nFor Transdermal Use Only\n" }

30 Transdermal Systems

{ "type": "p", "children": [], "text": "30 Transdermal Systems" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Each 30cm2 system contains 9.6mg asenapine.

{ "type": "p", "children": [], "text": "Each 30cm2 system contains 9.6mg 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.

{ "type": "p", "children": [], "text": "\nInactive 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.

{ "type": "p", "children": [], "text": "\nDosage 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.

{ "type": "p", "children": [], "text": "\nImportant: 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).

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "Find out more at www.secuado.com" }

1M419T-0

{ "type": "p", "children": [], "text": "1M419T-0" }

Manufactured by

{ "type": "p", "children": [], "text": "Manufactured by" }

Hisamitsu Pharmaceutical Co., Inc.

{ "type": "p", "children": [], "text": "Hisamitsu Pharmaceutical Co., Inc." }

408, Tashirodaikan-machi, Tosu, Saga, Japan

{ "type": "p", "children": [], "text": "408, Tashirodaikan-machi, Tosu, Saga, Japan" }

Distributed by

{ "type": "p", "children": [], "text": "Distributed by" }

Noven Therapeutics, LLC

{ "type": "p", "children": [], "text": "Noven Therapeutics, LLC" }

Miami, FL 33186

{ "type": "p", "children": [], "text": "Miami, FL 33186" }

NDC 68968-0174-3

{ "type": "p", "children": [], "text": "NDC 68968-0174-3" }

PUSH IN

{ "type": "p", "children": [], "text": "PUSH IN" }

PULL UP

{ "type": "p", "children": [], "text": "PULL UP" }

Secuado®

{ "type": "p", "children": [], "text": "Secuado®\n" }

(asenapien)

{ "type": "p", "children": [], "text": "(asenapien)" }

transdermal system

{ "type": "p", "children": [], "text": "transdermal system" }

7.6 mg/24 hours

{ "type": "p", "children": [], "text": "\n7.6 mg/24 hours\n" }

For Transdermal Use Only

{ "type": "p", "children": [], "text": "\nFor Transdermal Use Only\n" }

30 Transdermal Systems

{ "type": "p", "children": [], "text": "30 Transdermal Systems" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Each 40cm2 system contains 12.8mg asenapine.

{ "type": "p", "children": [], "text": "Each 40cm2 system contains 12.8mg 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.

{ "type": "p", "children": [], "text": "\nInactive 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.

{ "type": "p", "children": [], "text": "\nDosage 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.

{ "type": "p", "children": [], "text": "\nImportant: 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. 

{ "type": "p", "children": [], "text": "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).

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "Find out more at www.secuado.com" }

1M420T-0

{ "type": "p", "children": [], "text": "1M420T-0" }

Manufactured by

{ "type": "p", "children": [], "text": "Manufactured by" }

Hisamitsu Pharmaceutical Co., Inc.

{ "type": "p", "children": [], "text": "\nHisamitsu Pharmaceutical Co., Inc.\n" }

408, Tashirodaikan-machi, Tosu, Saga, Japan

{ "type": "p", "children": [], "text": "408, Tashirodaikan-machi, Tosu, Saga, Japan" }

Distributed by

{ "type": "p", "children": [], "text": "Distributed by" }

Noven Therapeutics, LLC

{ "type": "p", "children": [], "text": "\nNoven Therapeutics, LLC\n" }

Miami, FL 33186

{ "type": "p", "children": [], "text": "Miami, FL 33186" }

Asenapine is indicated for: • Bipolar I disorder [see Clinical Studies (14.2)] • Acute monotherapy of manic or mixed episodes, in pediatric patients 10 to 17 years of age • Adjunctive treatment to lithium or valproate in adults

{ "type": "p", "children": [], "text": "Asenapine is indicated for: • Bipolar I disorder [see Clinical Studies (14.2)] \n • Acute monotherapy of manic or mixed episodes, in pediatric patients 10 to 17 years of age • Adjunctive treatment to lithium or valproate in adults" }

 Asenapine is a sublingual tablet. To ensure optimal absorption, patients should be instructed to place the tablet under the tongue and allow it to dissolve completely. The tablet will dissolve in saliva within seconds. Asenapine sublingual tablets should not be split, crushed, chewed, or swallowed [see Clinical Pharmacology (12.3)]. Patients should be instructed to not eat or drink for 10 minutes after administration [see Clinical Pharmacology (12.3)].

Acute Treatment of Manic or Mixed Episodes:

Monotherapy in Pediatric Patients:The recommended dose of asenapine is 2.5 mg to 10 mg twice daily in pediatric patients 10 to 17 years of age, and dose may be adjusted for individual response and tolerability. The starting dose of asenapine is 2.5 mg twice daily. After 3 days, the dose can be increased to 5 mg twice daily, and from 5 mg to 10 mg twice daily after 3 additional days. Pediatric patients aged 10 to 17 years appear to be more sensitive to dystonia with initial dosing with asenapine when the recommended escalation schedule is not followed [see Use in Specific Populations (8.4)]. The safety of doses greater than 10 mg twice daily has not been evaluated in clinical trials [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

Adjunctive Therapy in Adults: The recommended starting dose of asenapine is 5 mg twice daily when administered as adjunctive therapy with either lithium or valproate. Depending on the clinical response and tolerability in the individual patient, the dose can be increased to 10 mg twice daily. The safety of doses above 10 mg twice daily as adjunctive therapy with lithium or valproate has not been evaluated in clinical trials.

For patients on asenapine, used as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients continue treatment beyond the acute episode.

2.5 mg: White to off white, round tablets debossed with ‘L’ on one side and ‘70’ on the other side.

{ "type": "p", "children": [], "text": "\n2.5 mg: White to off white, round tablets debossed with ‘L’ on one side and ‘70’ on the other side." }

5 mg: White to off white, round tablets debossed with “464” on one side and plain on other side. 10 mg: White to off white round tablets debossed with “465” on one side and plain on other side.

{ "type": "p", "children": [], "text": "\n5 mg: White to off white, round tablets debossed with “464” on one side and plain on other side.\n10 mg: White to off white round tablets debossed with “465” on one side and plain on other side.\n" }

Asenapine is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Asenapine is contraindicated in patients with: " }

{ "type": "ul", "children": [ "Severe hepatic impairment (Child-Pugh C) [see Specific Populations (8.7), Clinical Pharmacology (12.3)]. ", "A history of hypersensitivity reactions to asenapine. Reactions have included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash [see Warnings and Precautions (5.6), Adverse Reactions (6)]. " ], "text": "" }

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)].

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)].

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. 

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.

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 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="599.4975"> <colgroup> <col width="29.8169717138103%"/> <col width="18.3250138657793%"/> <col width="16.1397670549085%"/> <col width="16.6389351081531%"/> <col width="19.0793122573489%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="4" valign="top"> <span class="Bold">Bipolar I Disorder (3-weeks)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="2" valign="middle"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"> <span class="Bold">Asenapine</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <span class="Bold">5 mg twice daily</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">10 mg twice daily</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">5 mg or 10 mg twice daily</span><span class="Bold"><span class="Sup">†</span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Mean Change from Baseline in Fasting Glucose at Endpoint<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Change from Baseline <br/> (mg/dL) (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="middle"> 0 <br/> (174)<br/> </td><td align="center" class="Rrule" valign="middle"> 4.1 <br/> (84)<br/> </td><td align="center" class="Rrule" valign="middle"> 3.5 <br/> (81)<br/> </td><td align="center" class="Rrule" valign="middle"> 1.7 <br/> (321)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Proportion of Patients with Shifts from Baseline to Endpoint <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Normal to High<br/> &lt;100 to ≥126 mg/dL <br/> (n/N<span class="Sup">**</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 2.4%<br/> (3/126)<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> (0/53)<br/> </td><td align="center" class="Rrule" valign="top"> 1.7%<br/> (1/60)<br/> </td><td align="center" class="Rrule" valign="top"> 1.8%<br/> (4/224)<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> Borderline to High<br/> ≥100 and &lt;126 to ≥126<br/> mg/dL (n/N<span class="Sup">**</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> (0/39)<br/> </td><td align="center" class="Rrule" valign="top"> 12.5%<br/> (3/24)<br/> </td><td align="center" class="Rrule" valign="top"> 15.8%<br/> (3/19)<br/> </td><td align="center" class="Rrule" valign="top"> 12.8%<br/> (10/78)<br/> </td> </tr> </tbody> </table></div>

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 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="609.8715"> <colgroup> <col width="20.3031294297241%"/> <col width="18.9837531348817%"/> <col width="20.2377058117981%"/> <col width="20.2377058117981%"/> <col width="20.2377058117981%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="4" valign="top"> <span class="Bold">Bipolar I Disorder (3-weeks)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">Asenapine2.5 mg   twice daily</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">Asenapine5 mg   twice daily</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">Asenapine10 mg   twice daily</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Mean Change from Baseline in Fasting Glucose at Endpoint<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Change from Baseline (mg/dL) (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> -2.24<br/> (56)<br/> </td><td align="center" class="Rrule" valign="top"> 1.43<br/> (51)<br/> </td><td align="center" class="Rrule" valign="top"> -0.45<br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 0.34<br/> (52)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Proportion of Subjects with Shifts from Baseline to Endpoint<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Normal to High &gt;45 &amp; &lt;100 to ≥126 mg/dL<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td><td align="center" class="Rrule" valign="top"> 1.8%<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> (0/56)<br/> </td><td align="center" class="Rrule" valign="top"> (0/51)<br/> </td><td align="center" class="Rrule" valign="top"> (1/57)<br/> </td><td align="center" class="Rrule" valign="top"> (0/52)<br/> </td> </tr> </tbody> </table></div>

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 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="599.4975"> <colgroup> <col width="26.1009428729895%"/> <col width="17.3821408763173%"/> <col width="18.8352745424293%"/> <col width="18.8352745424293%"/> <col width="18.8463671658347%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="4" valign="top"> <span class="Bold">Bipolar I Disorder (3-weeks)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="2" valign="middle"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"> <span class="Bold">Asenapine</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <span class="Bold">5 mg twice daily</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">10 mg twice daily</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">5 mg or 10 mg twice daily</span><span class="Bold"><span class="Sup">†</span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Mean Change from Baseline (mg/dL)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Total cholesterol (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="middle"> -1.6 <br/> (278)<br/> </td><td align="center" class="Rrule" valign="middle"> -1.6 <br/> (108)<br/> </td><td align="center" class="Rrule" valign="middle"> -4.7 <br/> (95)<br/> </td><td align="center" class="Rrule" valign="middle"> -0.5 <br/> (525)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> LDL (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="middle"> 1.4 <br/> (271)<br/> </td><td align="center" class="Rrule" valign="middle"> -2.5 <br/> (101)<br/> </td><td align="center" class="Rrule" valign="middle"> -4.1 <br/> (94)<br/> </td><td align="center" class="Rrule" valign="middle"> -0.3 <br/> (499)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> HDL (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="middle"> 0.2<br/> (278)<br/> </td><td align="center" class="Rrule" valign="middle"> 0.1 <br/> (108)<br/> </td><td align="center" class="Rrule" valign="middle"> 0.7 <br/> (95)<br/> </td><td align="center" class="Rrule" valign="middle"> 0.7 <br/> (525)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Fasting triglycerides (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="middle"> -16.9 <br/> (222)<br/> </td><td align="center" class="Rrule" valign="middle"> 3.9 <br/> (89)<br/> </td><td align="center" class="Rrule" valign="middle"> -8.5 <br/> (85)<br/> </td><td align="center" class="Rrule" valign="middle"> -3 <br/> (411)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Proportion of Patients with Shifts from Baseline to Endpoint<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Total cholesterol<br/> Normal to High<br/> &lt;200 to ≥240<br/> (mg/dL) (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 1.2%<br/> (2/174)<br/> </td><td align="center" class="Rrule" valign="top"> 3%<br/> (2/66)<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> (0/63)<br/> </td><td align="center" class="Rrule" valign="top"> 2.1%<br/> (7/333)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> LDL<br/> Normal to High<br/> &lt;100 to ≥160<br/> (mg/dL) (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 1.9%<br/> (2/108)<br/> </td><td align="center" class="Rrule" valign="top"> 2.4%<br/> (1/41)<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> (0/41)<br/> </td><td align="center" class="Rrule" valign="top"> 0.5%<br/> (1/223)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> HDL<br/> Normal to Low<br/> ≥40 to &lt;40<br/> (mg/dL) (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 7.4%<br/> (16/215)<br/> </td><td align="center" class="Rrule" valign="top"> 4.1%<br/> (4/97)<br/> </td><td align="center" class="Rrule" valign="top"> 5.1%<br/> (4/78)<br/> </td><td align="center" class="Rrule" valign="top"> 7%<br/> (29/417)<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> Fasting triglycerides<br/> Normal to High<br/> &lt;150 to ≥200<br/> (mg/dL) (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 4.6%<br/> (7/153)<br/> </td><td align="center" class="Rrule" valign="top"> 8.2%<br/> (5/61)<br/> </td><td align="center" class="Rrule" valign="top"> 1.6%<br/> (1/64)<br/> </td><td align="center" class="Rrule" valign="top"> 6.2%<br/> (17/273)<br/> </td> </tr> </tbody> </table></div>

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 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="609.8715"> <colgroup> <col width="28.2411950714208%"/> <col width="16.5848871442591%"/> <col width="18.5475956820412%"/> <col width="18.5475956820412%"/> <col width="18.0787264202377%"/> </colgroup> <thead> <tr class="First"> <th align="justify" class="Lrule Rrule Toprule" rowspan="2">  <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="4"> <span class="Bold">Bipolar I Disorder (3-weeks)</span> <br/> </th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Asenapine2.5 <span class="Bold">mg twice </span>daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Asenapine5 <span class="Bold">mg twice </span>daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Asenapine10 <span class="Bold">mg twice </span>daily</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Mean Change from Baseline (mg/dL)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Total Fasting <br/> cholesterol (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> -2.3 <br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 3.7 <br/> (50)<br/> </td><td align="center" class="Rrule" valign="top"> 7.2 <br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 9.3 <br/> (52)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Fasting LDL <br/> (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> -2.5<br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> -0.2<br/> (50)<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 4.9<br/> (51)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Fasting HDL <br/> (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 1.6<br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 2.3<br/> (50)<br/> </td><td align="center" class="Rrule" valign="top"> 1.5<br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 1.7<br/> (52)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Fasting triglycerides<br/> (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> -6.6<br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 8.7<br/> (50)<br/> </td><td align="center" class="Rrule" valign="top"> 13.4<br/> (57)<br/> </td><td align="center" class="Rrule" valign="top"> 14.7<br/> (52)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Proportion of Subjects with Shifts from Baseline to Endpoint<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Total Fasting cholesterol<br/> Normal to High <br/> &lt;170 to &gt; = 200 (mg/dL)<br/> (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 1.8%<br/> (1/57)<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> (0/50)<br/> </td><td align="center" class="Rrule" valign="top"> 1.8%<br/> (1/57)<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> (0/52)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Fasting LDL<br/> Normal to High <br/> &lt;110 to &gt; = 130 <br/> (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 1.8%<br/> (1/57)<br/> </td><td align="center" class="Rrule" valign="top"> 2%<br/> (1/50)<br/> </td><td align="center" class="Rrule" valign="top"> 1.8%<br/> (1/57)<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> (0/51)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Fasting HDL<br/> Normal to Low<br/> ≥40 to &lt;40 (mg/dL)<br/> (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 3.5%<br/> (2/57)<br/> </td><td align="center" class="Rrule" valign="top"> 6%<br/> (3/50)<br/> </td><td align="center" class="Rrule" valign="top"> 3.5%<br/> (2/57)<br/> </td><td align="center" class="Rrule" valign="top"> 9.6%<br/> (5/52)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"> Fasting triglycerides<br/> Normal to High<br/> &lt;150 to ≥200 (mg/dL)<br/> (n/N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 0%<br/> (0/57)<br/> </td><td align="center" class="Rrule" valign="top"> 4%<br/> (2/50)<br/> </td><td align="center" class="Rrule" valign="top"> 3.5%<br/> (2/57)<br/> </td><td align="center" class="Rrule" valign="top"> 1.9%<br/> (1/52)<br/> </td> </tr> </tbody> </table></div>

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 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="609.8715"> <colgroup> <col width="26.561988877985%"/> <col width="19.8124522952786%"/> <col width="17.0101406607785%"/> <col width="17.1736997055937%"/> <col width="19.4417184603642%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="4" valign="top"> <span class="Bold">Bipolar I Disorder (3-weeks)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="2" valign="middle"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"> <span class="Bold">Asenapine</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <span class="Bold">5 mg twice daily</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">10 mg twice daily</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">5 mg or 10 mg twice daily</span><span class="Bold"><span class="Sup">†</span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Change from Baseline (kg) (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="middle"> 0.2<br/> (288)<br/> </td><td align="center" class="Rrule" valign="middle"> 1.4<br/> (110)<br/> </td><td align="center" class="Rrule" valign="middle"> 1.3<br/> (98)<br/> </td><td align="center" class="Rrule" valign="middle"> 1.3<br/> (544)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Proportion of Patients with a ≥7% Increase in Body Weight<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> % with ≥7% increase in body weight<br/> </td><td align="center" class="Rrule" valign="top"> 0.4%<br/> </td><td align="center" class="Rrule" valign="top"> 6.4%<br/> </td><td align="center" class="Rrule" valign="top"> 1%<br/> </td><td align="center" class="Rrule" valign="top"> 5.5%<br/> </td> </tr> </tbody> </table></div>

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  

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="595.5075"> <colgroup> <col width="37.7889447236181%"/> <col width="20.7370184254606%"/> <col width="20.7370184254606%"/> <col width="20.7370184254606%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">BMI &lt;23 </span> <br/> <span class="Bold">Asenapine </span> <br/> <span class="Bold">N=295 </span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">BMI 23 - ≤27</span> <br/> <span class="Bold">Asenapine</span> <br/> <span class="Bold">N=290 </span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">BMI &gt;27 </span> <br/> <span class="Bold">Asenapine </span> <br/> <span class="Bold">N=302 </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Mean change from Baseline (kg)<br/> </td><td align="center" class="Rrule" valign="top"> 1.7<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"> % with ≥7% increase in body weight<br/> </td><td align="center" class="Rrule" valign="top"> 22%<br/> </td><td align="center" class="Rrule" valign="top"> 13%<br/> </td><td align="center" class="Rrule" valign="top"> 9%<br/> </td> </tr> </tbody> </table></div>

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 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="609.8715"> <colgroup> <col width="20.7610947552066%"/> <col width="18.5257878093992%"/> <col width="20.2377058117981%"/> <col width="20.2377058117981%"/> <col width="20.2377058117981%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="4" valign="top"> <span class="Bold">Bipolar I Disorder (3-weeks)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">Asenapine</span> <br/> <span class="Bold">2.5 mg </span> <br/> <span class="Bold">twice daily</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">Asenapine</span> <br/> <span class="Bold">5 mg </span> <br/> <span class="Bold">twice daily</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">Asenapine</span> <br/> <span class="Bold">10 mg </span> <br/> <span class="Bold">twice daily</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> Change from Baseline (kg) <br/> (N<span class="Sup">*</span>)<br/> </td><td align="center" class="Rrule" valign="top"> 0.5<br/>  <br/> (89)<br/> </td><td align="center" class="Rrule" valign="top"> 1.7<br/>  <br/> (92)<br/> </td><td align="center" class="Rrule" valign="top"> 1.6<br/>  <br/> (90)<br/> </td><td align="center" class="Rrule" valign="top"> 1.4<br/>  <br/> (87)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> Proportion of Subjects with a ≥7% Increase in Body Weight<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> % with ≥7% increase in body weight<br/> </td><td align="center" class="Rrule" valign="top"> 1.1%<br/> </td><td align="center" class="Rrule" valign="top"> 12%<br/> </td><td align="center" class="Rrule" valign="top"> 8.9%<br/> </td><td align="center" class="Rrule" valign="top"> 8%<br/> </td> </tr> </tbody> </table></div>

N* = Number of subjects who had assessments at both Baseline and Endpoint.

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.

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.

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.

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/mm3) and follow their WBC until recovery.

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.

Like other drugs that antagonize dopamine D2 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.

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.

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.

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.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Monotherapy in Pediatric Patients with Bipolar Mania: The following findings are based on a 3-week , placebo-controlled trial for bipolar mania in which asenapine was administered at doses of 2.5 mg, 5 mg, or 10 mg twice daily.

Adverse Reactions Leading to Discontinuation of Treatment: A total of 6.7% (7/104) of patients treated with asenapine 2.5 mg twice daily, 5.1% (5/99) of patients treated with asenapine 5 mg twice daily, and 5.1% (5/99) of patients treated with asenapine 10 mg twice daily discontinued treatment due to adverse reactions compared to 4% (4/101) on placebo. The most common adverse reactions that led to discontinuation in pediatric patients treated with asenapine (rates at least 2% in any asenapine arm and at least twice the placebo rate) were somnolence (3% in the 2.5 mg twice daily group, 1% in the 5 mg twice daily group, and 2% in the 10 mg twice daily group), abdominal pain (2% in the 10 mg twice daily group), and nausea (2% in the 10 mg twice daily group) No placebo-treated patients dropped out for these events.

Adverse Reactions Occurring with Asenapine at an Incidence of 2% or More in Asenapine-treated Bipolar I Patients: Adverse reactions associated with the use of asenapine (incidence of ≥2% in any asenapine dose group and greater than placebo) that occurred during acute therapy are shown in Table 10.

Table 10: Adverse Reactions Reported in 2% or More of Pediatric Patients (Ages 10 to 17 Years) in Any Asenapine Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="603.288"> <colgroup> <col width="25%"/> <col width="14.6604938271605%"/> <col width="15.4320987654321%"/> <col width="15.4210758377425%"/> <col width="14.8148148148148%"/> <col width="14.6715167548501%"/> </colgroup> <thead> <tr class="First"> <th align="center" class="Lrule Rrule Toprule" rowspan="2"> <span class="Bold">System Organ Class / AE Preferred Term</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo </span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Asenapine </span> <br/> <span class="Bold">2.5 mg </span> <br/> <span class="Bold">twice daily </span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Asenapine </span> <br/> <span class="Bold">5 mg </span> <br/> <span class="Bold">twice daily </span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Asenapine </span> <br/> <span class="Bold">10 mg </span> <br/> <span class="Bold">twice daily </span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">All Asenapine</span> <br/> <span class="Bold">2.5, 5, and 10 mg</span> <br/> </th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">N=101 </span> <br/> <span class="Bold">%</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">N=104 </span> <br/> <span class="Bold">%</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">N=99 </span> <br/> <span class="Bold">%</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">N=99 </span> <br/> <span class="Bold">%</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">N=302 </span> <br/> <span class="Bold">%</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" colspan="6" valign="top"> <span class="Bold">Cardiac Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Tachycardia<span class="Sup">1</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="6" valign="top"> <span class="Bold">Gastrointestinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Oral hypoesthesia<span class="Sup">2</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 25 <br/> </td><td align="center" class="Rrule" valign="bottom"> 25 <br/> </td><td align="center" class="Rrule" valign="bottom"> 30 <br/> </td><td align="center" class="Rrule" valign="bottom"> 27 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Nausea <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Vomiting <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Abdominal pain<span class="Sup">3</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 7 <br/> </td><td align="center" class="Rrule" valign="bottom"> 9 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 5 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Glossodynia <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="6" valign="top"> <span class="Bold">General Disorders and Administrative Site Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Fatigue<span class="Sup">4</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 5 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 8 <br/> </td><td align="center" class="Rrule" valign="bottom"> 14 <br/> </td><td align="center" class="Rrule" valign="bottom"> 9 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Irritability <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="6" valign="top"> <span class="Bold">Injury, Poisoning, and Procedural Complications</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Muscle strain <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="6" valign="top"> <span class="Bold">Investigations</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Increased weight <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Hyperinsulinemia<span class="Sup">5</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> ALT increased <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> AST increased <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="bottom"> <span class="Bold">Metabolism and Nutrition Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Increased appetite <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 10 <br/> </td><td align="center" class="Rrule" valign="bottom"> 9 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td><td align="center" class="Rrule" valign="bottom"> 8 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Dehydration <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="bottom"> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Myalgia <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="bottom"> <span class="Bold">Nervous System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Somnolence<span class="Sup">6</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 12 <br/> </td><td align="center" class="Rrule" valign="bottom"> 46 <br/> </td><td align="center" class="Rrule" valign="bottom"> 53 <br/> </td><td align="center" class="Rrule" valign="bottom"> 49 <br/> </td><td align="center" class="Rrule" valign="bottom"> 49 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Headache <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td><td align="center" class="Rrule" valign="bottom"> 8 <br/> </td><td align="center" class="Rrule" valign="bottom"> 11 <br/> </td><td align="center" class="Rrule" valign="bottom"> 9 <br/> </td><td align="center" class="Rrule" valign="bottom"> 9 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Dizziness <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td><td align="center" class="Rrule" valign="bottom"> 10 <br/> </td><td align="center" class="Rrule" valign="bottom"> 5 <br/> </td><td align="center" class="Rrule" valign="bottom"> 7 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Dysgeusia <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 5 <br/> </td><td align="center" class="Rrule" valign="bottom"> 9 <br/> </td><td align="center" class="Rrule" valign="bottom"> 6 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Akathisia <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Parkinsonism <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="bottom"> <span class="Bold">Psychiatric Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Insomnia <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Suicidal ideation <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Anger <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="bottom"> <span class="Bold">Reproductive System and Breast Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Dysmenorrhea <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="bottom"> <span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Oropharyngeal pain <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Nasal congestion <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Dyspnea <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="bottom"> <span class="Bold">Skin and Subcutaneous Tissue Disorders </span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="bottom"> Rash <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 1 <br/> </td> </tr> </tbody> </table></div>

1 Includes the preferred terms tachycardia and heart rate increased.

2 Includes the preferred terms oral hypoesthesia, oral paresthesia, and oral dysesthesia.

3 Includes the preferred terms abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

4 Includes the preferred terms fatigue and lethargy.

5 Includes the preferred terms hyperinsulinemia and blood insulin increased.

6 Includes the preferred terms somnolence, sedation, and hypersomnia.

Dose-Related Adverse Reactions: In the short term pediatric bipolar I trial the incidence of fatigue appeared to be dose-related (see Table 10).

Adjunctive Therapy in Adult Patients with Bipolar Mania: The following findings are based on a 12 week placebo-controlled trial (with a 3 week efficacy endpoint) in adult patients with bipolar mania in which sublingual asenapine was administered in doses of 5 mg or 10 mg twice daily as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment: Approximately 16% (25/158) of asenapine-treated patients discontinued treatment due to an adverse reaction, compared with about 11% (18/166) on placebo. The most common adverse reactions associated with discontinuation in subjects treated with asenapine (rates at least 1% and at least twice the placebo rate) were depression (2.5%), suicidal ideation (2.5%), bipolar I disorder (1.9%), insomnia (1.9%) and depressive symptoms (1.3%).

Adverse Reactions Occurring at an Incidence of 2% or More Among Asenapine-Treated (Adjunctive) Bipolar I Patients: Adverse reactions associated with the use of asenapine (incidence of 2% or greater, rounded to the nearest percent, and asenapine incidence greater than placebo) that occurred during acute adjunctive therapy at 3 weeks, a time when most of the patients were still participating in the trial, are shown in Table 11.

Table 11: Adverse Reactions Reported in 2% or More of Adult Patients In Any Asenapine-Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="794.01"> <colgroup> <col width="45.5611390284757%"/> <col width="17.0854271356784%"/> <col width="0.16750418760469%"/> <col width="37.1859296482412%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">System Organ Class/Preferred Term</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/> <span class="Bold">N=166</span> <br/> <span class="Bold">%</span> <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="2"> <span class="Bold">Asenapine </span> <br/> <span class="Bold">5 mg or 10 mg twice daily<span class="Sup">*</span></span> <br/> <span class="Bold">N=158</span> <br/> <span class="Bold">%</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" colspan="4" valign="bottom"> <span class="Bold">Gastrointestinal disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Dyspepsia <br/> </td><td align="center" class="Rrule" colspan="2" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Oral hypoesthesia <br/> </td><td align="center" class="Rrule" colspan="2" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 5 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> <span class="Bold">General disorders </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Fatigue <br/> </td><td align="center" class="Rrule" colspan="2" valign="bottom"> 2 <br/> </td><td align="center" class="Rrule" valign="bottom"> 4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Edema peripheral <br/> </td><td align="center" class="Rrule" colspan="2" valign="bottom"> &lt;1 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> <span class="Bold">Investigations </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Increased weight<br/> </td><td align="center" class="Rrule" colspan="2" valign="bottom"> 0 <br/> </td><td align="center" class="Rrule" valign="bottom"> 3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> <span class="Bold">Nervous system disorders </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Dizziness <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Other extrapyramidal symptoms (excluding akathisia)<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Somnolence<span class="Sup">‡ </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"> 10<br/> </td><td align="center" class="Rrule" valign="top"> 22<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> <span class="Bold">Psychiatric disorders </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> Insomnia <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> <span class="Bold">Vascular disorders </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule Last"> <td class="Lrule Rrule" valign="bottom"> Hypertension <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> </tbody> </table></div>

* Asenapine 5 mg to 10 mg twice daily with flexible dosing.

† Extrapyramidal symptoms included: dystonia, parkinsonism, oculogyration, and tremor (excluding akathisia).

‡ Somnolence includes the following events: somnolence and sedation.

Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups [see Dosage and Administration (2.3), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)].

Extrapyramidal Symptoms: In the short-term, placebo-controlled bipolar mania adult trials, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Assessments of Involuntary Movement Scales (for dyskinesias). The mean change from baseline for the all-asenapine 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores.

In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for asenapine-treated patients was 8% versus 4% for placebo; and the incidence of akathisia-related events for asenapine-treated patients was 7% versus 3% for placebo. The incidence rates of all EPS events (including akathisia) were lower at the 5 mg twice daily dose (11% of N=122) than the 10 mg twice daily dose (25% of N=119) in another study.

In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the incidences of EPS-related events, excluding events related to akathisia, were 4%, 3%, and 5% for patients treated with asenapine 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 3% for placebo-treated patients. EPS-related events include: bradykinesia, dyskinesia, dystonia, oromandibular dystonia, muscle contractions involuntary, muscle twitching, musculoskeletal stiffness, parkinsonism, protrusion tongue, resting tremor, and tremor.

For events of akathisia, incidences were 2%, 2%, and 1% for pediatric patients treated with asenapine 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 0% for placebo-treated patients.

Other Findings: Oral hypoesthesia and/or oral paresthesia may occur directly after administration of asenapine and usually resolves within 1 hour.

Laboratory Test Abnormalities:

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term bipolar mania adult trials were more common in treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in transaminase levels for asenapine-treated patients was 6.1 units/L compared to a decrease of 3.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times upper limit of normal (ULN) (at Endpoint) was 2.1% for asenapine-treated patients versus 0.7% for placebo-treated patients. The incidence rate of transaminase elevations ≥3 times ULN is 3% of N=95 for 10 mg twice daily dose, and 0% of N=108 for the 5 mg twice daily dose and 0% of N=115 for placebo in another study. 

In a 52-week, double-blind, comparator-controlled trial that included primarily adult patients, the mean increase from baseline of ALT was 1.7 units/L.

In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, transient elevations in serum transaminases (primarily ALT) were more common in treated patients. The proportion of pediatric patients with ALT elevations ≥3 times upper limit of normal (ULN) was 2.4% for patients treated with asenapine 10 mg twice daily versus none for the other asenapine dose groups and placebo-treated patients.

Prolactin: In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 6.7 ng/mL for asenapine-treated patients compared to a decrease of 1 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2% for asenapine-treated patients versus 0.8% for placebo-treated patients.

In a long-term (52-week), double-blind, comparator-controlled adult trial, the mean decrease in prolactin from baseline for asenapine-treated patients was 26.9 ng/mL.

In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the mean increases (at Endpoint) in prolactin levels were 3.2 ng/mL for patients treated with asenapine 2.5 mg twice daily, 2.1 ng/mL for patients treated with asenapine 5 mg twice daily, and 6.4 ng/mL for patients treated with asenapine 10 mg twice daily compared to an increase of 2.5 ng/mL for placebo-treated patients. There were no reports of prolactin elevations ≥4 times ULN (at Endpoint) for patients treated with asenapine or placebo. Galactorrhea or dysmenorrhea were reported in 0% of patients treated with asenapine 2.5 mg twice daily, 2% of patients treated with asenapine 5 mg twice daily, and 1% of patients treated with asenapine 10 mg twice daily compared to 1% of placebo-treated patients. There were no reports of gynecomastia in this trial.

Creatine Kinase (CK): The proportion of adult patients with CK elevations >3 times ULN at any time were 6.4% and 11.1% for patients treated with asenapine 5 mg twice daily and 10 mg twice daily, respectively, as compared to 6.7% for placebo-treated patients in pre-marketing short-term, fixed-dose trials in bipolar mania and another indication. The clinical relevance of this finding is unknown.

The proportion of patients with CK elevations ≥3 times ULN during a 3-week trial in pediatric bipolar I disorder at any time were 1%, 0%, and 1% for patients treated with asenapine 2.5 mg, 5 mg, and 10 mg twice daily, respectively, versus 3% for placebo-treated patients.

Other Adverse Reactions Observed During the Premarketing Evaluation of Asenapine:

 Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual asenapine at multiple doses of ≥5 mg twice daily during any phase of a trial within the database of adult patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions already listed for adult patients in other parts of Adverse Reactions (6), or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) are not included. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).

Blood and lymphatic disorders: infrequent: anemia; rare: thrombocytopenia

Cardiac disorders: infrequent: temporary bundle branch block

Eye disorders: infrequent: accommodation disorder

Gastrointestinal disorders: infrequent: swollen tongue

General disorders: rare: idiosyncratic drug reaction

Investigations: infrequent: hyponatremia

Nervous system disorders: infrequent: dysarthria

Following is a list of MedDRA terms not already listed either for adults or pediatric patients in other parts of Adverse Reactions (6), or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) that reflect adverse reactions reported by pediatric patients (Ages 10 to 17 years) treated with sublingual asenapine at doses of 2.5 mg, 5 mg, or 10 mg twice daily during any phase of a trial within the database of pediatric patients.

Eye disorders: infrequent: diplopia, vision blurred

Gastrointestinal disorders: infrequent: gastroesophageal reflux disease

Injury, Poisoning, and Procedural Complications: infrequent: fall

Skin and subcutaneous tissue disorders: infrequent: photosensitivity reaction

Renal and urinary disorders: infrequent: enuresis 

The following adverse reactions have been identified during post-approval use of asenapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure. In many cases, the occurrence of these adverse reactions led to discontinuation of therapy.

Table 12: Clinically Important Drug Interactions with Asenapine

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Concomitant Drug Name or Drug Class</span> </td><td class="Rrule" valign="middle"> <span class="Bold">Clinical Rationale</span></td><td class="Rrule" valign="middle"> <span class="Bold">Clinical Recommendation</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"> Antihypertensive Drugs </td><td class="Rrule" valign="middle"> Because of its α<span class="Sub">1</span>-adrenergic antagonism with potential for inducing hypotension, asenapine may enhance the effects of certain antihypertensive agents <span class="Italics">[see Warnings and Precautions (5.7)]</span>. </td><td align="justify" class="Rrule" valign="middle">Monitor blood pressure and adjust dosage of antihypertensive drug accordingly. <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Strong CYP1A2 Inhibitors (e.g., Fluvoxamine) </td><td class="Rrule" valign="middle"> Asenapine is metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when asenapine is used with fluvoxamine at 25 mg administered twice daily <span class="Italics">[see Clinical Pharmacology (12.3)]</span>. However, the tested fluvoxamine dose was suboptimal. Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure. </td><td class="Rrule" valign="middle">Dosage reduction for asenapine based on clinical response may be necessary. </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">CYP2D6 substrates and inhibitors (e.g., paroxetine) </td><td class="Rrule" valign="middle"> Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with asenapine increased the paroxetine exposure by 2-fold as compared to use paroxetine alone <span class="Italics">[see Clinical Pharmacology (12.3)]. </span></td><td class="Rrule" valign="middle"> Reduce paroxetine dose by half when paroxetine is used in combination with asenapine. </td> </tr> </tbody> </table></div>

No dosage adjustment of asenapine is necessary when administered concomitantly with paroxetine (see Table 12 in Drug Interactions (7.1) for paroxetine dosage adjustment), imipramine, cimetidine, valporate, lithium, or a CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin).

In addition, valproic acid and lithium pre-dose serum concentrations collected from an adjunctive therapy study were comparable between asenapine-treated patients and placebo-treated patients indicating a lack of effect of asenapine on valproic and lithium plasma levels.

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine 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 asenapine 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 to 4% and of miscarriage is 15 to 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 sublingually twice daily. In a pre-and post-natal study in rats, intravenous administration of asenapine at doses up to 0.7 times the MRHD produced increases in post-implantation loss and early pup deaths, and decreases in subsequent pup survival and weight gain [see Data]. 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, the maximum recommended human dose (MRHD) of 10 mg twice daily given sublingually on a mg/m2 basis. 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.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, 0.4, and 0.7 times the MRHD of 10 mg twice daily given sublingually on a mg/m2 basis), 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 asenapine and any potential adverse effects on the breastfed infant from asenapine or from the underlying maternal condition.

Safety and efficacy of asenapine in pediatric patients below the age of 10 years of age have not been evaluated.

Bipolar I Disorder

The safety and efficacy of asenapine as monotherapy in the treatment of bipolar I disorder were established in a 3week, placebo-controlled, double-blind trial of 403 pediatric patients 10 to 17 years of age, of whom 302 patients received asenapine at fixed doses ranging from 2.5 mg to 10 mg twice daily [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. In a Phase 1 study, pediatric patients aged 10 to 17 years appeared to be more sensitive to dystonia with initial dosing with asenapine when the recommended dose escalation schedule was not followed. Similar safety findings were reported from a 50-week, open-label, uncontrolled safety trial in pediatric patients with bipolar I disorder treated with asenapine monotherapy. The safety and efficacy of asenapine as adjunctive therapy in the treatment of bipolar I disorder have not been established in the pediatric population. In general, the pharmacokinetics of asenapine in pediatric patients (10 to 17 years) and adults are similar [see Clinical Pharmacology (12.3)].

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/m2 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).

Clinical studies of asenapine in the treatment of bipolar mania and another indication 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 2250 patients in pre-marketing clinical studies of asenapine, 1.1% (25) were 65 years of age or over. Multiple factors that might increase the pharmacodynamic response to asenapine, 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, dosage adjustments are not recommended based on age alone [see Clinical Pharmacology (12.3)].

Elderly patients with dementia-related psychosis treated with asenapine are at an increased risk of death compared to placebo. Asenapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

No dosage adjustment for asenapine 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. 

Asenapine 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 asenapine 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)].

No dosage adjustment for asenapine is required on the basis of a patient’s sex, race (Caucasian and Japanese), or smoking status [see Clinical Pharmacology (12.3)].

Asenapine is not a controlled substance.

Asenapine has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance or physical dependence. Thus, it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs that they are misusing or abusing asenapine (e.g., drug-seeking behavior, increases in dose).

Human Experience: In adult pre-marketing clinical studies involving more than 3350 patients and/or healthy subjects, accidental or intentional acute over dosage of asenapine was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of asenapine was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion.

{ "type": "p", "children": [], "text": "\nHuman Experience: In adult pre-marketing clinical studies involving more than 3350 patients and/or healthy subjects, accidental or intentional acute over dosage of asenapine was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of asenapine was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion." }

Management of Overdosage: There is no specific antidote to asenapine. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Consult with a Certified Poison Control Center for up-to-date guidance and advice on the management of overdosage (1-800-222-1222.) 

{ "type": "p", "children": [], "text": "\nManagement of Overdosage: There is no specific antidote to asenapine. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Consult with a Certified Poison Control Center for up-to-date guidance and advice on the management of overdosage (1-800-222-1222.) " }

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of asenapine-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

{ "type": "p", "children": [], "text": "Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of asenapine-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers." }

Asenapine sublingual tablet contains asenapine maleate which is an atypical antipsychotic that   is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2 butenedioate (1:1). Its molecular formula is C17H16ClNO⋅C4H4O4 and its molecular weight is 401.84 (free base: 285.8). The chemical structure is:

{ "type": "p", "children": [], "text": "Asenapine sublingual tablet contains asenapine maleate which is an atypical antipsychotic that   is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2 butenedioate (1:1). Its molecular formula is C17H16ClNO⋅C4H4O4 and its molecular weight is 401.84 (free base: 285.8). The chemical structure is:" }

Asenapine maleate is off-white to white powder.

{ "type": "p", "children": [], "text": "Asenapine maleate is off-white to white powder." }

Asenapine is supplied for sublingual administration in tablets containing 2.5-mg, 5-mg or 10-mg asenapine; inactive ingredients include butylated hydroxy anisole, butylated hydroxy toluene, low-substituted hydroxypropyl cellulose, mannitol, povidone, sodium stearyl fumarate.

{ "type": "p", "children": [], "text": "Asenapine is supplied for sublingual administration in tablets containing 2.5-mg, 5-mg or 10-mg asenapine; inactive ingredients include butylated hydroxy anisole, butylated hydroxy toluene, low-substituted hydroxypropyl cellulose, mannitol, povidone, sodium stearyl fumarate.\n" }

The mechanism of action of asenapine in bipolar I disorder is unknown.

Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C,      5-HT5A, 5-HT6, and 5-HT7 receptors (Ki values of 2.5, 2.7, 0.07, 0.18, 0.03, 1.6, 0.25, and 0.11 nM, respectively), dopamine D2A, D2B, D3, D4, and D1 receptors (Ki values of 1.3, 1.4, 0.42, 1.1, and 1.4 nM, respectively), α1A,  α2A,  α2B,  and α2C-adrenergic receptors (Ki values of 1.2, 1.2, 0.33 and 1.2 nM, respectively), and histamine H1 receptors (Ki value 1 nM), and moderate affinity for H2 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 M1).

Following a single 5 mg dose of asenapine, the mean Cmax was approximately 4 ng/mL and was observed at a mean tmax of 1 hour. Elimination of asenapine is primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). Following an initial more rapid distribution phase, the mean terminal half-life is approximately 24 hrs. With multiple-dose twice-daily dosing, steady-state is attained within 3 days. Overall, steady-state asenapine pharmacokinetics are similar to single-dose pharmacokinetics.

Absorption: Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations occurring within 0.5 to 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is 35%. Increasing the dose from 5 mg to 10 mg twice daily (a two-fold increase) results in less than linear (1.7 times) increases in both the extent of exposure and maximum concentration. The absolute bioavailability of asenapine when swallowed is low (<2% with an oral tablet formulation).

The intake of water several (2 or 5) minutes after asenapine administration resulted in decreased asenapine exposure. Therefore, eating and drinking should be avoided for 10 minutes after administration [see Dosage and Administration (2.1)].

Distribution: Asenapine is rapidly distributed and has a large volume of distribution (approximately 20 to 25 L/kg), indicating extensive extravascular distribution. Asenapine is highly bound (95%) to plasma proteins, including albumin and α1-acid glycoprotein.

Metabolism and Elimination: Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) are the primary metabolic pathways for asenapine.

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. Following an initial more rapid distribution phase, the terminal half-life of asenapine is approximately 24 hours. Steady-state concentrations of asenapine are reached within 3 days of twice daily dosing.

After administration of a single dose of [14C]-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. Asenapine activity is primarily due to the parent drug.

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)].

Food: A crossover study in 26 healthy adult male subjects was performed to evaluate the effect of food on the pharmacokinetics of a single 5 mg dose of asenapine. Consumption of food immediately prior to sublingual administration decreased asenapine exposure by 20%; consumption of food 4 hours after sublingual administration decreased asenapine exposure by about 10%. These effects are probably due to increased hepatic blood flow.

In clinical trials establishing the efficacy and safety of asenapine, patients were instructed to avoid eating for 10 minutes following sublingual dosing. There were no other restrictions with regard to the timing of meals in these trials [see Dosage and Administration (2.1)].

Water: In clinical trials establishing the efficacy and safety of asenapine, patients were instructed to avoid drinking for 10 minutes following sublingual dosing. The effect of water administration following 10 mg sublingual asenapine dosing was studied at different time points of 2, 5, 10, and 30 minutes in 15 healthy adult male subjects. The exposure of asenapine following administration of water 10 minutes after sublingual dosing was equivalent to that when water was administered 30 minutes after dosing. Reduced exposure to asenapine was observed following water administration at 2 minutes (19% decrease) and 5 minutes (10% decrease) [see Dosage and Administration (2.1)].

Drug Interaction Studies:  

Effects of other drugs on the exposure of asenapine are summarized in Figure 1. In addition, a population pharmacokinetic analysis indicated that the concomitant administration of lithium had no effect on the pharmacokinetics of asenapine. Figure 1: Effect of Other Drugs on Asenapine Pharmacokinetics

The effects of asenapine on the pharmacokinetics of other co-administered drugs are summarized in Figure 2. Coadministration of paroxetine with asenapine caused a two-fold increase in the maximum plasma concentrations and systemic exposure of paroxetine. Asenapine enhances the inhibitory effects of paroxetine on its own metabolism by CYP2D6.

Figure 2: Effect of Asenapine on Other Drug Pharmacokinetics

Studies in Special Populations:

Exposures of asenapine in special populations are summarized in Figure 3. Additionally, based on population pharmacokinetic analysis, no effects of sex, race, BMI, and smoking status on asenapine exposure were observed. Exposure in elderly patients is 30 to 40% higher as compared to adults.

Figure 3: Effect of Intrinsic Factors on Asenapine Pharmacokinetics

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 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.

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 the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/m2 basis.

Monotherapy

Pediatric patients: The efficacy of asenapine in the treatment of acute mania was established in a single, 3-week, placebo-controlled, double-blind trial of 403 pediatric patients 10 to 17 years of age, of whom 302 patients received asenapine at fixed doses of 2.5 mg, 5 mg and 10 mg twice daily. All patients were started on 2.5 mg twice daily. For those assigned to 5 mg twice daily, the dose was increased to 5 mg twice daily after 3 days. For those assigned to 10 mg twice daily, the dose was increased from 2.5 to 5 mg twice daily after 3 days, and then to 10 mg twice daily after 3 additional days.

Asenapine was statistically superior to placebo in improving YMRS total score and the CGI-BP Severity of Illness overall score as measured by the change from baseline to week 3 (Trial 3 Pediatric in Table 14). An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, and race.

Adjunctive Therapy: The efficacy of asenapine as an adjunctive therapy in acute mania was established in a 12-week, placebo-controlled trial with a 3-week primary efficacy endpoint involving 326 adult patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially responsive to lithium or valproate monotherapy after at least 2 weeks of treatment. All patients randomized to asenapine were initially administered 5 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. Asenapine was statistically superior to placebo in the reduction of manic symptoms (measured by the YMRS total score) as an adjunctive therapy to lithium or valproate monotherapy at week 3 (Trial 5 Adjunctive in Table 14).

 Table 14: Acute Bipolar I Trials Establishing Efficacy in Adults and Pediatric Patients 10 to 17 Years

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="610.071"> <colgroup> <col width="15.729234793983%"/> <col width="36.0039241334205%"/> <col width="13.4183562241116%"/> <col width="15.8709396119468%"/> <col width="18.977545236538%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="top"> <span class="Bold">Study Number </span> <br/> </td><td align="justify" class="Rrule" rowspan="2" valign="top"> <span class="Bold">Treatment Group </span> <br/>  <br/>  <br/> </td><td align="center" class="Rrule" colspan="3" valign="top"> <span class="Bold">Primary Efficacy Measure: YMRS Total Score</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <span class="Bold">Mean Baseline Score (SD)</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">LS Mean Change from Baseline (SE)</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <span class="Bold">Placebo-subtracted Difference<span class="Sup">a</span> (95% CI)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="4" valign="top"> Trial 4 (Pediatric 10 to 17 years) <br/> </td><td align="justify" class="Rrule" valign="top"> Asenapine 2.5 mg* twice daily<br/> </td><td align="center" class="Rrule" valign="top"> 29.5 (5.7)<br/> </td><td align="center" class="Rrule" valign="top"> -12.8 (0.8)<br/> </td><td align="center" class="Rrule" valign="top"> -3.2 (-5.6, -0.8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Asenapine 5 mg* twice daily<br/> </td><td align="center" class="Rrule" valign="top"> 30.4 (5.9)<br/> </td><td align="center" class="Rrule" valign="top"> -14.9 (0.8)<br/> </td><td align="center" class="Rrule" valign="top"> -5.3 (-7.7, -2.9)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Asenapine 10 mg* twice daily<br/> </td><td align="center" class="Rrule" valign="top"> 30.1 (5.7)<br/> </td><td align="center" class="Rrule" valign="top"> 15.8 (0.9)<br/> </td><td align="center" class="Rrule" valign="top"> -6.2 (-8.6, -3.8)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Placebo<br/> </td><td align="center" class="Rrule" valign="middle"> 30.1 (5.7)<br/> </td><td align="center" class="Rrule" valign="middle"> -9.6 (0.9)<br/> </td><td align="center" class="Rrule" valign="middle"> --<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="top"> Trial 5 (Adjunctive)<br/> </td><td align="justify" class="Rrule" valign="top"> Asenapine 5 to 10 mg<span class="Sup">*</span> twice daily + Lithium/Valproate<br/> </td><td align="center" class="Rrule" valign="top"> 28 (5.6)<br/> </td><td align="center" class="Rrule" valign="top"> -10.3 (0.8)<br/> </td><td align="center" class="Rrule" valign="top"> -2.4 (-4.4, -0.3)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> Lithium/Valproate<br/> </td><td align="center" class="Rrule" valign="top"> 28.2 (5.8)<br/> </td><td align="center" class="Rrule" valign="top"> -7.9 (0.8)<br/> </td><td align="center" class="Rrule" valign="top"> --<br/> </td> </tr> </tbody> </table></div>

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses that are demonstrated to be effective.

Asenapine sublingual tablets are supplied as:

{ "type": "p", "children": [], "text": "Asenapine sublingual tablets are supplied as:" }

2.5-mg Tablets: White to off white, round tablets debossed with ‘L’ on one side and ‘70’ on the other side.

{ "type": "p", "children": [], "text": "\n2.5-mg Tablets: White to off white, round tablets debossed with ‘L’ on one side and ‘70’ on the other side." }

Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-544-60

{ "type": "p", "children": [], "text": "Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-544-60" }

Cartons of 100 - 10 blister cards of 10 tablets each   NDC 62332-544-31

{ "type": "p", "children": [], "text": "Cartons of 100 - 10 blister cards of 10 tablets each   NDC 62332-544-31" }

5-mg Tablets: White to off white, round tablets debossed with “464” on one side and plain on other side.

{ "type": "p", "children": [], "text": "\n5-mg Tablets: White to off white, round tablets debossed with “464” on one side and plain on other side." }

Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-198-60

{ "type": "p", "children": [], "text": "Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-198-60" }

Cartons of 100 - 10 blister cards of 10 tablets each  NDC 62332-198-31

{ "type": "p", "children": [], "text": "Cartons of 100 - 10 blister cards of 10 tablets each  NDC 62332-198-31" }

10-mg Tablets: White to off white, round tablets debossed with “465” on one side and plain on other side.

{ "type": "p", "children": [], "text": "\n10-mg Tablets: White to off white, round tablets debossed with “465” on one side and plain on other side." }

Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-199-60

{ "type": "p", "children": [], "text": "Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-199-60" }

Cartons of 100 - 10 blister cards of 10 tablets each  NDC 62332-199-31

{ "type": "p", "children": [], "text": "Cartons of 100 - 10 blister cards of 10 tablets each  NDC 62332-199-31" }

  Storage

{ "type": "p", "children": [], "text": " \n\nStorage\n" }

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]." }

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

{ "type": "p", "children": [], "text": "\nAdvise the patient to read the FDA-approved patient labeling (Instructions for Use).\n" }

Dosage and Administration

{ "type": "p", "children": [], "text": "\n Dosage and Administration \n" }

Counsel patients on proper sublingual administration of asenapine and advise them to read the FDA-approved patient labeling (Instructions for Use). When initiating treatment with asenapine, provide dosage escalation instructions [see Dosage and Administration (2)].

{ "type": "p", "children": [], "text": "Counsel patients on proper sublingual administration of asenapine and advise them to read the FDA-approved patient labeling (Instructions for Use). When initiating treatment with asenapine, provide dosage escalation instructions [see Dosage and Administration (2)]. \n" }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions \n" }

Counsel patients on the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.) and to seek immediate emergency assistance if they develop any of these signs and symptoms [see Contraindications (4), Warnings and Precautions (5.6) and Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of a serious allergic reaction (e.g., difficulty breathing, itching, swelling of the face, tongue or throat, feeling lightheaded etc.) and to seek immediate emergency assistance if they develop any of these signs and symptoms [see Contraindications (4), Warnings and Precautions (5.6) and Adverse Reactions (6)]. " }

Application Site Reactions

{ "type": "p", "children": [], "text": "\nApplication Site Reactions \n" }

Inform patients that application site reactions, primarily in the sublingual area, including oral ulcers, blisters, peeling/sloughing and inflammation have been reported. Instruct patients to monitor for these reactions [see Adverse Reactions (6.2)]. Inform patients that numbness or tingling of the mouth or throat may occur directly after administration of asenapine and usually resolves within 1 hour [see Adverse Reactions (6.1)].

{ "type": "p", "children": [], "text": "Inform patients that application site reactions, primarily in the sublingual area, including oral ulcers, blisters, peeling/sloughing and inflammation have been reported. Instruct patients to monitor for these reactions [see Adverse Reactions (6.2)]. Inform patients that numbness or tingling of the mouth or throat may occur directly after administration of asenapine and usually resolves within 1 hour [see Adverse Reactions (6.1)]. " }

Neuroleptic Malignant Syndrome

{ "type": "p", "children": [], "text": "\nNeuroleptic Malignant Syndrome \n" }

Counsel patients about a potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Patients should contact their health care provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Counsel patients about a potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Patients should contact their health care provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)]. " }

Tardive Dyskinesia

{ "type": "p", "children": [], "text": "\nTardive Dyskinesia \n" }

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.4)]. \n" }

Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)

{ "type": "p", "children": [], "text": "\nMetabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) \n" }

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)]. Orthostatic Hypotension

{ "type": "p", "children": [], "text": "Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)].\n\nOrthostatic Hypotension \n" }

Educate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Educate patients about the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions (5.7)]. " }

Leukopenia/Neutropenia

{ "type": "p", "children": [], "text": "\nLeukopenia/Neutropenia \n" }

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking asenapine [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking asenapine [see Warnings and Precautions (5.9)]. " }

Hyperprolactinemia

{ "type": "p", "children": [], "text": "\nHyperprolactinemia \n" }

Counsel patients on the signs and symptoms of hyperprolactinemia and to contact their health care provider if these abnormalities occur [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of hyperprolactinemia and to contact their health care provider if these abnormalities occur [see Warnings and Precautions (5.11)].\n" }

Interference with Cognitive and Motor Performance

{ "type": "p", "children": [], "text": "\nInterference with Cognitive and Motor Performance \n" }

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that asenapine therapy does not affect them adversely [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that asenapine therapy does not affect them adversely [see Warnings and Precautions (5.13)]. " }

Heat Exposure and Dehydration

{ "type": "p", "children": [], "text": "\nHeat Exposure and Dehydration \n" }

Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14)].

{ "type": "p", "children": [], "text": "Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.14)]. " }

Concomitant Medications

{ "type": "p", "children": [], "text": "\nConcomitant Medications \n" }

Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)].

{ "type": "p", "children": [], "text": "Advise patients to inform their health care provider if they are taking, or plan to take, any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)]. " }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy \n" }

Advise patients that asenapine may cause fetal harm as well as extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise patients that asenapine may cause fetal harm as well as extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]. " }

Pregnancy Registry

{ "type": "p", "children": [], "text": "\nPregnancy Registry \n" }

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy [see Use in Specific Populations (8.1)]." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Alembic Pharmaceuticals Limited

{ "type": "p", "children": [], "text": "\nAlembic Pharmaceuticals Limited\n" }

(Formulation Division),

{ "type": "p", "children": [], "text": "(Formulation Division)," }

Panelav 389350, Gujarat, India

{ "type": "p", "children": [], "text": "Panelav 389350, Gujarat, India" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Alembic Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nAlembic Pharmaceuticals, Inc.\n" }

Bedminster, NJ 07921, USA

{ "type": "p", "children": [], "text": "Bedminster, NJ 07921, USA" }

Revised: 02/2025

{ "type": "p", "children": [], "text": "Revised: 02/2025" }

INSTRUCTIONS FOR USE Asenapine (a-SEN-a-peen) Sublingual Tablets

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE Asenapine (a-SEN-a-peen) Sublingual Tablets\n" }

Read these Instructions for Use before you start using asenapine sublingual tablets and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read these Instructions for Use before you start using asenapine sublingual tablets and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment." }

IMPORTANT:

{ "type": "p", "children": [], "text": "\nIMPORTANT:\n" }

•For sublingual (under your tongue) use only. •Do not remove tablet until ready to administer. •Use dry hands when handling tablet.

{ "type": "p", "children": [], "text": "\n•For sublingual (under your tongue) use only. •Do not remove tablet until ready to administer. •Use dry hands when handling tablet.\n" }

Your asenapine sublingual tablets

{ "type": "p", "children": [], "text": "\nYour asenapine sublingual tablets\n" }

Directions for Taking your Asenapine Sublingual Tablets: Step 1. Firmly press and hold thumb button, then pull out the tablet pack (see Figure A). Do not push tablet through the tablet pack. Do not cut or tear the tablet pack. Figure A Step 2. Peel off the lidding foil carefully. (see Figure B). Figure B Step 3. Gently remove the tablet (see Figure C). Do not split, cut or crush the tablet. Figure C Step 4. Place the whole tablet under tongue and allow it to dissolve completely (see Figure D). Figure D Do not chew or swallow the tablet. Do not eat or drink for 10 minutes (see Figure E). Figure E Step 5. Slide the tablet pack back into case until it clicks (see Figure F). Figure F Storing asenapine sublingual tablets: Store asenapine sublingual tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

{ "type": "p", "children": [], "text": "\n\n Directions for Taking your Asenapine Sublingual Tablets: Step 1. Firmly press and hold thumb button, then pull out the tablet pack (see Figure A). Do not push tablet through the tablet pack. Do not cut or tear the tablet pack.\n Figure A\nStep 2. Peel off the lidding foil carefully. (see Figure B).\n Figure B\nStep 3. Gently remove the tablet (see Figure C). Do not split, cut or crush the tablet.\n\nFigure C\nStep 4. Place the whole tablet under tongue and allow it to dissolve completely (see Figure D).\n Figure D\nDo not chew or swallow the tablet. Do not eat or drink for 10 minutes (see Figure E).\n Figure E\nStep 5. Slide the tablet pack back into case until it clicks (see Figure F).\n\nFigure F\n Storing asenapine sublingual tablets:\n Store asenapine sublingual tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). " }

These Instructions for Use have been approved by the U.S. Food and Drug Administration. For more information call 1-866-210-9797.

{ "type": "p", "children": [], "text": "These Instructions for Use have been approved by the U.S. Food and Drug Administration.\n For more information call 1-866-210-9797." }

Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India

{ "type": "p", "children": [], "text": "Manufactured by:\nAlembic Pharmaceuticals Limited\n(Formulation Division), Panelav 389350, Gujarat, India" }

Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA

{ "type": "p", "children": [], "text": "Manufactured for:\nAlembic Pharmaceuticals, Inc.\nBedminster, NJ 07921, USA" }

Revised: 02/2025

{ "type": "p", "children": [], "text": "Revised: 02/2025" }

NDC 62332-544-60 Asenapine Sublingual Tablets 2.5 mg For sublingual (under the tongue) use only. Do not split, cut or crush tablet. Do not chew or swallow tablet. Fragile: Do not push tablet through tablet pack.

{ "type": "p", "children": [], "text": "\nNDC 62332-544-60 Asenapine Sublingual Tablets 2.5 mg For sublingual (under the tongue) use only. Do not split, cut or crush tablet. Do not chew or swallow tablet. Fragile: Do not push tablet through tablet pack.\n" }

Rx only Alembic 60 Tablets - 6 blister cards of 10 tablets each

{ "type": "p", "children": [], "text": "\nRx only\nAlembic\n 60 Tablets - 6 blister cards of 10 tablets each\n" }

NDC 62332-198-60 Asenapine Sublingual Tablets 5 mg  For sublingual (under the tongue) use only. Do not split, cut or crush tablet. Do not chew or swallow tablet. Fragile: Do not push tablet through tablet pack Rx onlyAlembic 60 Tablets - 6 blister cards of 10 tablets each

{ "type": "p", "children": [], "text": "\nNDC 62332-198-60 Asenapine Sublingual Tablets 5 mg  For sublingual (under the tongue) use only. Do not split, cut or crush tablet. Do not chew or swallow tablet. Fragile: Do not push tablet through tablet pack Rx onlyAlembic 60 Tablets - 6 blister cards of 10 tablets each\n" }

NDC 62332-199-60 Asenapine Sublingual Tablets 10 mg  For sublingual (under the tongue) use only. Do not split, cut or crush tablet. Do not chew or swallow tablet. Fragile: Do not push tablet through tablet pack Rx onlyAlembic 60 Tablets - 6 blister cards of 10 tablets each

{ "type": "p", "children": [], "text": "\nNDC 62332-199-60 Asenapine Sublingual Tablets 10 mg  For sublingual (under the tongue) use only. Do not split, cut or crush tablet. Do not chew or swallow tablet. Fragile: Do not push tablet through tablet pack Rx onlyAlembic 60 Tablets - 6 blister cards of 10 tablets each\n" }