Asenapine (asenapine (asenapine maleate) tablet) Dailymed

Asenapine sublingual tablets are indicated for:

• Schizophrenia in adults [see Clinical Studies (14.1)]
• Bipolar I disorder [see Clinical Studies (14.2)]
  • Acute monotherapy of manic or mixed episodes, in adults and pediatric patients 10 to 17 years of age
  • Adjunctive treatment to lithium or valproate in adults
  • Maintenance monotherapy treatment in adults

Asenapine sublingual tablets are an atypical antipsychotic indicated for (1):

• Schizophrenia in adults
• Bipolar I disorder
  • Acute monotherapy treatment of manic or mixed episodes, in adults and pediatric patients 10 to 17 years of age
  • Adjunctive treatment to lithium or valproate in adults
  • Maintenance monotherapy treatment in adults

2 Dosage And Administration

	Starting Dose	Recommended Dose	Maximum Dose
Schizophrenia – acute treatment in adults (2.2)	5 mg sublingually twice daily	5 mg sublingually twice daily	10 mg sublingually twice daily
Schizophrenia – maintenance treatment in adults (2.2)	5 mg sublingually twice daily	5-10 mg sublingually twice daily	10 mg sublingually twice daily
Bipolar mania-adults: acute and maintenance monotherapy (2.3)	5-10 mg sublingually twice daily	5-10 mg sublingually twice daily	10 mg sublingually twice daily
Bipolar mania – pediatric patients (10 to 17 years): monotherapy (2.3)	2.5 mg sublingually twice daily	2.5-10 mg sublingually twice daily	10 mg sublingually twice daily
Bipolar mania – adults: as an adjunct to lithium or valproate (2.3)	5 mg sublingually twice daily	5-10 mg sublingually twice daily	10 mg sublingually twice daily

• Do not swallow tablet. Asenapine sublingual tablets should be placed under the tongue and left to dissolve completely. The tablet will dissolve in saliva within seconds. Eating and drinking should be avoided for 10 minutes after administration. (2.1, 17)

2.1 Administration Instructions

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)].

2.2 Schizophrenia

The recommended dose of asenapine sublingual tablets is 5 mg given twice daily. In short-term controlled trials, there was no suggestion of added benefit with a 10 mg twice daily dose, but there was a clear increase in certain adverse reactions. If tolerated, daily dosage can be increased to 10 mg twice daily after one week. The safety of doses above 10 mg twice daily has not been evaluated in clinical studies [see Clinical Studies (14.1)].

2.3 Bipolar I Disorder

Acute Treatment of Manic or Mixed Episodes:

Monotherapy in Adults: The recommended starting and treatment dose of asenapine sublingual tablets is 5 mg to 10 mg twice daily. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials [see Clinical Studies (14.2)].

Monotherapy in Pediatric Patients: The recommended dose of asenapine sublingual tablets are 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets, whether used as monotherapy or as adjunctive therapy with lithium or valproate, it is generally recommended that responding patients continue treatment beyond the acute episode.

Maintenance Treatment of Bipolar I Disorder:

Monotherapy in Adults: Continue on the asenapine sublingual tablets dose that the patient received during stabilization (5 mg to 10 mg twice daily). Depending on the clinical response and tolerability in the individual patient, a dose of 10 mg twice daily can be decreased to 5 mg twice daily. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials [see Clinical Studies (14.2)].

Asenapine sublingual tablets are contraindicated in patients with:

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

• Severe hepatic impairment (Child-Pugh C). (8.7, 12.3)
• Known hypersensitivity to asenapine sublingual tablets, or to any components in the formulation. (4, 5.6, 17)

5 Warnings And Precautions

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack). (5.2)
• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3)
• Tardive Dyskinesia: Discontinue if clinically appropriate. (5.4)
• Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. (5.5)
• Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. (5.7)
• Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing asenapine sublingual tablets if a clinically significant decline in WBC occurs in absence of other causative factors. (5.9)
• QT Prolongation: Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. (5.10)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.12)
• Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.13)

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Asenapine sublingual tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

5.2 Cerebrovascular Adverse Events, Including Stroke, In Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Asenapine sublingual tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue asenapine sublingual tablets and provide intensive symptomatic treatment and monitoring.

5.4 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including asenapine sublingual tablets. 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 sublingual tablets 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 sublingual tablets, drug discontinuation should be considered. However, some patients may require treatment with asenapine sublingual tablets despite the presence of the syndrome.

5.5 Metabolic Changes

Atypical antipsychotic drugs, including asenapine sublingual tablets, 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 sublingual tablets. 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 schizophrenia and bipolar mania trials are presented in Table 1.

TABLE 1: Changes in Fasting Glucose in Adult Patients

Â	Schizophrenia (6-weeks)				Bipolar I Disorder (3-weeks)
	Placebo	Asenapine sublingual tablets			Placebo	Asenapine sublingual tablets
		5 mg twice daily	10 mg twice daily	5 or 10 mg twice dailyIncludes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=90)		5 mg twice daily	10 mg twice daily	5 or 10 mg twice dailyIncludes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379).
Mean Change from Baseline in Fasting Glucose at Endpoint
Â
Change from Baseline (mg/dL) (N= Number of patients who had assessments at both Baseline and Endpoint.)	-0.2(232)	3.8(158)	1.1(153)	3.2(377)	0 (174)	4.1(84)	3.5(81)	1.7(321)
Proportion of Patients with Shifts from Baseline to Endpoint
Normal to High <100 to ≥126 mg/dL (n/N= Number of patients at risk at Baseline with assessments at both Baseline and Endpoint.)	4.1%(7/170)	4.5%(5/111)	4.5%(5/111)	5.0%(13/262)	2.4%(3/126)	0%(0/53)	1.7%(1/60)	1.8%(4/224)
Borderline to High ≥100 and <126 to ≥126 mg/dL (n/N)	5.9%(3/51)	6.8%(3/44)	6.3%(2/32)	10.5%(10/95)	0%(0/39)	12.5%(3/24)	15.8%(3/19)	12.8%(10/78)

In a 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.

Pediatric Patients: Data from the short-term, placebo-controlled trial in pediatric patients with bipolar I disorder are shown in Table 2.

TABLE 2: Changes in Fasting Glucose in Pediatric Subjects

	Bipolar I Disorder (3-weeks)
	Placebo	Asenapine sublingual tablets 2.5 mg twice daily	Asenapine sublingual tablets 5 mg twice daily	Asenapine sublingual tablets 10 mg twice daily
	Mean Change from Baseline in Fasting Glucose at Endpoint
Change from Baseline (mg/dL) (N= Number of subjects who had assessments at both Baseline and Endpoint.)	-2.24(56)	1.43(51)	-0.45(57)	0.34(52)
	Proportion of Subjects with Shifts from Baseline to Endpoint
Normal to High>45 & < 100 to ≥126 mg/dL (n/N)	0%(0/56)	0%(0/51)	1.8%(1/57)	0%(0/52)

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 schizophrenia and bipolar mania trials are presented in Table 3.

TABLE 3: Changes in Lipids in Adult Patients

Â	Schizophrenia (6-weeks)				Bipolar I Disorder (3-weeks)
	Placebo	Asenapine sublingual tablets			Placebo	Asenapine sublingual tablets
		5 mg twice daily	10 mg twice daily	5 or 10 mg twice dailyIncludes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=90)		5 mg twice daily	10 mg twice daily	5 or 10 mg twice dailyIncludes patients treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily (N=379)
Mean Change from Baseline (mg/dL)
Total cholesterol (N= Number of subjects who had assessments at both Baseline and Endpoint)	-2.2(351)	-2.4(258)	3.3(199)	0.4(539)	-1.6(278)	-1.6(108)	-4.7(95)	-0.5(525)
LDL (N)	0.1(285)	-0.2(195)	2.6(195)	1.3(465)	1.4(271)	-2.5(101)	-4.1(94)	-0.3(499)
HDL (N)	0.5(290)	0.4(199)	1.0(199)	0.5(480)	0.2(278)	0.1(108)	0.7(95)	0.7(525)
Fasting triglycerides (N)	-7.6(233)	-1.9(159)	0.1(154)	3.8(380)	-16.9(222)	3.9(89)	-8.5(85)	-3.0(411)
Proportion of Patients with Shifts from Baseline to Endpoint
Total cholesterolNormal to High <200 to ≥240 (mg/dL) (n/N)	1.3% (3/225)	0.6%(1/161)	2.2%(3/134)	1.7% (6/343)	1.2(2/174)	3.0(2/66)	0(0/63)	2.1(7/333)
LDLNormal to High <100 to ≥160 (mg/dL) (n/N)	1.7% (2/117)	0.0%(0/80)	1.2%(1/86)	1.0% (2/196)	1.9(2/108)	2.4(1/41)	0(0/41)	0.5(1/223)
HDLNormal to Low ≥40 to <40 (mg/dL) (n/N)	10.7%(21/196)	13.3%(18/135)	14.7%(20/136)	14.0%(45/322)	7.4(16/215)	4.1 (4/97)	5.1 (4/78)	7.0(29/417)
Fasting triglyceridesNormal to High <150 to ≥200 (mg/dL) (n/N)	2.4% (4/167)	7.0%(8/115)	8.3%(9/108)	7.7% (20/260)	4.6(7/153)	8.2(5/61)	1.6(1/64)	6.2(17/273)

In short-term schizophrenia trials, the proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 8.3% for asenapine sublingual tablets-treated patients versus 7% for placebo-treated patients. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 13.2% for asenapine sublingual tablets-treated patients versus 10.5% for placebo-treated patients. 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 sublingual tablets-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 sublingual tablets-treated patients versus 8.6% for placebo-treated patients.

Pediatric Patients: Data from the short-term, placebo-controlled bipolar mania trial are presented in Table 4

TABLE 4: Changes in Fasting Lipids in Pediatric Subjects

	Bipolar I Disorder (3-weeks)
	Placebo	Asenapine sublingual tablets2.5 mg twice daily	Asenapine sublingual tablets5 mg twice daily	Asenapine sublingual tablets10 mg twice daily
Mean Change from Baseline (mg/dL)
Total fasting cholesterol (N= Number of patients who had assessments at both Baseline and Endpoint)	-2.3(57)	3.7(50)	7.2(57)	9.3(52)
Fasting LDL (N)	-2.5(57)	-0.2(50)	3.0(57)	4.9(51)
Fasting HDL (N)	1.6 (57)	2.3 (50)	1.5(57)	1.7(52)
Fasting triglycerides (N)	-6.6(57)	8.7(50)	13.4(57)	14.7(52)
Proportion of Subjects with Shifts from Baseline to Endpoint
Total fasting cholesterol Normal to High <170 to >=200 (mg/dL) (n/N)	1.8% (1/57)	0% (0/50)	1.8%(1/57)	0%(0/52)
Fasting LDL Normal to High <110 to >=130 (n/N)	1.8% (1/57)	2.0% (1/50)	1.8%(1/57)	0%(0/51)
Fasting HDL Normal to Low ≥40 to <40 (mg/dL) (n/N)	3.5% (2/57)	6.0% (3/50)	3.5%(2/57)	9.6%(5/52)
Fasting triglycerides Normal to High <150 to ≥200 (mg/dL) (n/N)	0% (0/57)	4.0% (2/50)	3.5%(2/57)	1.9%(1/52)

Weight Gain

Weight gain has been observed in patients treated with atypical antipsychotics, including asenapine sublingual tabelts. 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 schizophrenia and bipolar mania trials are presented in Table 5.

Table 5: Change in Body Weight in Adult Patients from Baseline

Â	Schizophrenia (6-weeks)				Bipolar I Disorder (3-weeks)
	Placebo	Asenapine sublingual tablets			Placebo	Asenapine sublingual tablets
		5 mg twice daily	10 mg twice daily	5 or 10 mg twice dailyIncludes subjects treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily (N=90)		5 mg twice daily	10 mg twice daily	5 or 10 mg twice dailyIncludes patients treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily (N=379).
Change from Baseline (kg) (N= Number of subjects who had assessments at both Baseline and Endpoint.)	0.0(348)	1.0(251)	0.9(200)	1.1(532)	0.2(288)	1.4(110)	1.3(98)	1.3(544)
Proportion of Patients with a ≥ 7% Increase in Body weight
% with ≥7% increase in body weight	1.6%	4.4%	4.8%.	4.9%	0.4%	6.4%	1.0%	5.5%

Adult Patients: In a 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 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 Adults with Schizophrenia

	BMI <23Asenapine sublingual tablets N=295	BMI 23 - ≤27Asenapine sublingual tabletsN=290	BMI >27Asenapine sublingual tablets N=302
Mean change from Baseline (kg)	1.7	1	0
% with ≥7% increase in body weight	22%	13%	9%

Pediatric Patients: Data on mean changes in body weight and the proportion of pediatric patients meeting a weight gain criterion of ≥7% of body weight from the short-term, placebo-controlled bipolar mania trial are presented in Table 7. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients by comparisons to age-and sex-matched population standards.

The distance of a z-score from 0 represents the distance of a percentile from the median, measured in standard deviations (SD). After adjusting for age and sex, the mean change from baseline to endpoint in weight z-score for asenapine sublingual tablets 2.5 mg, 5 mg, and 10 mg twice daily, was 0.11, 0.08 and 0.09 SD versus 0.02 SD for placebo, respectively.

When treating pediatric patients, weight gain should be monitored and assessed against that expected for normal growth.

Table 7: Change in Body Weight in Pediatric Subjects from Baseline

	Bipolar I Disorder (3-weeks)
	Placebo	Asenapine sublingual tablets2.5 mgtwice daily	Asenapine sublingual tablets5 mgtwice daily	Asenapine sublingual tablets10 mgtwice daily
Change from Baseline (kg) (N= Number of subjects who had assessments at both Baseline and Endpoint.)	0.5(89)	1.7(92)	1.6(90)	1.4(87)
	Proportion of Subjects with a ≥7% Increase in Body Weight
% with ≥7% increase in body weight	1.1%	12.0%	8.9%	8.0%

5.6 Hypersensitivity Reactions

Hypersensitivity reactions have been observed in patients treated with asenapine sublingual tablets. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.

5.7 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects

Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In short-term schizophrenia adult trials, syncope was reported in 0.2% (1/572) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of asenapine sublingual tablets, compared to 0.3% (1/378) of patients treated with placebo. 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 sublingual tablets, compared to 0% (0/329) of patients treated with placebo. During adult pre-marketing clinical trials with asenapine sublingual tablets, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1,953) of patients treated with asenapine sublingual tablets. In a 3-week, bipolar mania pediatric trial, syncope was reported in 1% (1/104) of patients treated with asenapine sublingual tablets 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 sublingual tablets 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 sublingual tablets should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7.1)]. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.

5.8 Falls

Asenapine sublingual tablets may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including asenapine sublingual tablets. 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 sublingual tablets 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 sublingual tablets in patients with severe neutropenia (absolute neutrophil count <1000/mm³) and follow their WBC until recovery.

5.10 QT Prolongation

The effects of asenapine sublingual tablets on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved asenapine sublingual tablets 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, asenapine sublingual tablets was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with asenapine sublingual tablets 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval.

5.11 Hyperprolactinemia

Like other drugs that antagonize dopamine D₂ receptors, asenapine sublingual tablets 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 sublingual tablets 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 sublingual tablets 2.5 mg twice daily treatment group, 2% in the asenapine sublingual tablets 5 mg twice daily treatment group, and 1% in the asenapine sublingual tablets 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. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

5.12 Seizures

Seizures were reported in 0% and 0.3% (0/572,1/379) of adult patients treated with doses of 5 mg and 10 mg twice daily of asenapine sublingual tablets, respectively, compared to 0% (0/503, 0/203) of patients treated with placebo in pre-marketing short-term schizophrenia and bipolar mania trials, respectively. During adult pre-marketing clinical trials with asenapine sublingual tablets, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1,953) of patients treated with asenapine sublingual tablets. There were no reports of seizures in pediatric patients treated with asenapine sublingual tablets in a 3-week-term, bipolar mania trial.

As with other antipsychotic drugs, asenapine sublingual tablets should be used with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

5.13 Potential for Cognitive and Motor Impairment

Somnolence was reported in patients treated with asenapine sublingual tablets. It was usually transient with the highest incidence reported during the first week of treatment. In short-term, fixed-dose, placebo-controlled schizophrenia adult trials, somnolence was reported in 15% (41/274) of patients on asenapine sublingual tablets 5 mg twice daily and in 13% (26/208) of patients on asenapine sublingual tablets 10 mg twice daily compared to 7% (26/378) of placebo patients. In short-term, placebo-controlled bipolar mania adult trials of therapeutic doses (5-10 mg twice daily), somnolence was reported in 23% (145/620) of patients on asenapine sublingual tablets compared to 5% (18/329) of placebo patients. In the 3-week fixed-dose study, somnolence occurred at a lower rate in the 5mg twice daily dose 20% (24/122) versus the 10mg twice daily dose 26% (31/119) compared to 4% (5/126) in placebo patients. During adult pre-marketing clinical trials with asenapine sublingual tablets, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1,953) of patients treated with asenapine sublingual tablets. Somnolence led to discontinuation in 0.6% (12/1,953) 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets therapy does not affect them adversely.

5.14 Body Temperature Regulation

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. In the pre-marketing short-term placebo-controlled trials for both schizophrenia and acute bipolar I disorder, 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 sublingual tablets, 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 sublingual tablets with caution in patient who may experience these conditions.

5.15 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with asenapine sublingual tablets. Asenapine sublingual tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.

5.16 Risks in Patients with Phenylketonuria

Phenylketonurics: Contains Phenylalanine 0.17 mg per tablet.

Phenylalanine can be harmful to patients with phenylketonuria (PKU). Asenapine sublingual tablets contain phenylalanine, a component of aspartame. Each 2.5 mg, 5 mg and 10 mg tablets contains 0.17 mg of phenylalanine. Before prescribing asenapine sublingual tablets in a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including asenapine sublingual tablets.

6 Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1 and 5.2)]
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)]
• Tardive Dyskinesia [see Warnings and Precautions (5.4)]
• Metabolic Changes [see Warnings and Precautions (5.5)]
• Hypersensitivity Reactions [see Contraindications, Warnings and Precautions (5.6)]
• Orthostatic Hypotension, Syncope, and other Hemodynamic Effects [see Warnings and Precautions (5.7)]
• Falls [see Warnings and Precautions (5.8)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.9)]
• QT Interval Prolongation [see Warnings and Precautions (5.10)]
• Hyperprolactinemia [see Warnings and Precautions (5.11)]
• Seizures [see Warnings and Precautions (5.12)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)]
• Body Temperature Regulation [see Warnings and Precautions (5.14)]
• Dysphagia [see Warnings and Precautions (5.15)]

The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with acute treatment in adults with schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of asenapine sublingual tablets in the maintenance treatment of schizophrenia in adults was similar to that seen with acute treatment.

The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with acute monotherapy treatment of manic or mixed episodes associated with bipolar I disorder in adults were somnolence, oral hypoesthesia dizziness, extrapyramidal symptoms (excluding akathisia) and akathisia; and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia. The rates were lower at the 5mg twice daily dose than the 10mg twice daily dose for all of these most common adverse reactions. The safety profile of asenapine sublingual tablets in the maintenance treatment of manic or mixed episodes associated with bipolar I disorder in adults was similar to that seen with acute treatment.

The adult information below is derived from a clinical trial database for asenapine sublingual tablets consisting of over 5,355 patients and/or healthy subjects exposed to one or more sublingual doses of asenapine sublingual tablets. A total of 1,427 asenapine-treated patients were treated for at least 24 weeks and 785 asenapine sublingual tablets-treated patients had at least 52 weeks of exposure at therapeutic doses.

In a 3-week monotherapy trial, the most common adverse reactions (≥5% and at least twice the rate of placebo) reported in pediatric patients with bipolar I disorder treated with asenapine sublingual tablets were somnolence, dizziness, dysgeusia, oral hypoesthesia, nausea, increased appetite, fatigue, and increased weight. No new major safety findings were reported from a 50-week, open-label, uncontrolled safety trial.

A total of 651 pediatric patients were treated with asenapine sublingual tablets. Of these patients, 352 pediatric patients were treated with asenapine sublingual tablets for at least 180 days and 58 pediatric patients treated with asenapine sublingual tablets had at least 1 year of exposure. The safety of asenapine sublingual tablets was evaluated in 403 pediatric patients with bipolar I disorder who participated in a 3-week, placebo-controlled, double-blind trial, of whom 302 patients received asenapine sublingual tablets at fixed doses ranging from 2.5 mg to 10 mg twice daily.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment- emergent adverse event of the type uled. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.


The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were (6.1):

• Schizophrenia Adults: akathisia, oral hypoesthesia, somnolence.
• Bipolar I Disorder Adults (Monotherapy): somnolence, oral hypoesthesia, dizziness, extrapyramidal symptoms (excluding akathisia) and akathisia.
• Bipolar I Disorder Pediatric Patients (Monotherapy): somnolence, dizziness, dysgeusia, oral paresthesia, nausea, increased appetite, fatigue, increased weight.
• Bipolar I Disorder Adults (Adjunctive): somnolence, oral hypoesthesia.

To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

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.

Adult Patients with Schizophrenia: The following findings are based on the short-term placebo-controlled pre-marketing trials for schizophrenia (a pool of three 6-week fixed-dose trials and one 6-week flexible-dose trial) in which sublingual asenapine sublingual tablets was administered in doses ranging from 5 to 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9% of asenapine sublingual tablets-treated patients and 10% of placebo-treated patients discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in patients treated with asenapine sublingual tablets at the rate of at least 1% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in asenapine sublingual tablets -Treated Patients with Schizophrenia: Adverse reactions associated with the use of asenapine sublingual tablets (incidence of 2% or greater, rounded to the nearest percent, and asenapine sublingual tablets incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 8.

Table 8: Adverse Reactions Reported in 2% or More of Adult Patients in Any Asenapine Sublingual Tablets Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials

System Organ Class/ Preferred Term	PlaceboN=378%	Asenapine Sublingual Tablets5 mg twice dailyN=274%	Asenapine Sublingual Tablets10mg twice dailyN=208%	All Asenapine Sublingual TabletsAlso includes the Flexible-dose trial (N=90). 5mg or 10 mg twice dailyN=572%
Gastrointestinal disorders
Constipation	6	7	4	5
Dry mouth	1	3	1	2
Oral hypoesthesia	1	6	7	5
Salivary hypersecretion	0	<1	4	2
Stomach discomfort	1	<1	3	2
Vomiting	5	4	7	5
General disorders
Fatigue	3	4	3	3
Irritability	<1	2	1	2
Investigations
Increased weight	<1	2	2	3
Metabolism disorders
Increased appetite	<1	3	0	2
Nervous system disorders
AkathisiaAkathisia includes: akathisia and hyperkinesia.	3	4	11	6
Dizziness	4	7	3	5
Extrapyramidal symptoms (excluding akathisia)Extrapyramidal symptoms included dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor, and extrapyramidal disorder (excluding akathisia).	7	9	12	10
SomnolenceSomnolence includes the following events: somnolence, sedation, and hypersomnia.	7	15	13	13
Psychiatric disorders
Insomnia	13	16	15	15
Vascular disorders
Hypertension	2	2	3	2

Dose-Related Adverse Reactions: In the short term schizophrenia trials the incidence of akathisia appeared to be dose-related (see Table 8).

Monotherapy in Adult Patients with Bipolar Mania: The following findings are based on the short-term placebo-controlled trials for bipolar mania (a pool of two 3-week flexible-dose trials and one 3-week fixed-dose trial) in which sublingual asenapine sublingual tablets was administered in doses of 5 mg or 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: Approximately 10% (61/620) of asenapine sublingual tablets-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 7% (22/329) on placebo. There were no adverse reactions associated with discontinuation in patients treated with asenapine sublingual tablets at the rate of at least 1% and at least twice the placebo rate

Adverse Reactions Occurring at an Incidence of 2% or More Among asenapine sublingual tablets -Treated (Monotherapy) patients with Bipolar I Disorder: Adverse reactions associated with the use of asenapine sublingual tablets (incidence of 2% or greater, rounded to the nearest percent, and asenapine sublingual tablets incidence greater than placebo) that occurred during acute monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 9.

Table 9: Adverse Reactions Reported in 2% or More of Adult Patients in Any Asenapine Sublingual Tablets Dose Group and Which Occurred at Greater Incidence Than in the Respective Placebo Group in 3-Week Bipolar Mania Fixed and Flexible Dose Trials

	(Fixed Dose Study)			All PlaceboIncludes fixed and flexible dose trials	All Asenapine Sublingual Tablets 5 mg or 10 mg twice dailyAsenapine sublingual tablets 5 mg to 10 mg twice daily with fixed and flexible dosing.
System Organ Class/Preferred Term	Placebo	Asenapine Sublingual Tablets 5 mg twice daily	Asenapine Sublingual Tablets 10 mg twice daily
	N=126 %	N=122 %	N=119 %	N=329 %	N=620 %
Gastrointestinal disorders
Oral HypoesthesiaOral Hypoesthesia includes the preferred terms: oral hypoesthesia, oral paresthesia, and oral dysaesthesia.	2	13	24	1	10
Nausea	3	4	5	5	5
Constipation	2	4	3	4	4
DyspepsiaDyspepsia includes the preferred terms: dyspepsia and gastrooesophageal reflux disease.	6	4	5	4	4
Vomiting	2	1	3	3	3
Abdominal PainAbdominal pain includes the preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.	0	2	3	3	3
Dry Mouth	5	3	1	2	3
Toothache	1	2	2	2	3
General disorders
FatigueFatigue includes the preferred terms: fatigue and lethargy.	2	2	5	2	4
Infections and Infestations
NasopharyngitisNasopharyngitis includes the preferred terms: nasopharyngitis and upper respiratory tract infection.	2	1	5	2	3
Investigations
Weight Increase	1	0	1	1	3
Alanine Aminotransferase Increase	0	0	3	0	1
Metabolism disorders
Increased appetite	2	1	6	2	4
Musculoskeletal and connective tissue disorders
Arthralgia	1	1	2	1	2
Nervous system disorders
SomnolenceSomnolence includes the preferred terms: somnolence, sedation, and hypersomnia.	4	20	26	5	23
Dizziness	5	3	5	4	8
Extrapyramidal symptoms (excluding akathisia)Extrapyramidal symptoms (excluding akathisia) includes the preferred terms: dyskinesia, dystonia, resting tremor, tremor, oromandibular dystonia, myoclonus, muscle spasms, muscle rigidity, musculoskeletal stiffness, muscle contractions involuntary, blepharospasm, tongue disorder, and Parkinsonism.	7	7	11	4	8
Akathisia	1	4	15	2	6
Dysgeusia	0	3	9	<1	4
Psychiatric Disorders
Bipolar Disorder/ManiaBipolar Disorder/Mania includes the preferred terms: bipolar disorder, bipolar I disorder and mania.	3	8	3	5	6
Agitation	1	4	3	3	4
Anxiety	3	0	3	2	3

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 sublingual tablets 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 sublingual tablets 2.5 mg twice daily, 5.1% (5/99) of patients treated with asenapine sublingual tablets 5 mg twice daily, and 5.1% (5/99) of patients treated with asenapine sublingual tablets 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 sublingual tablets (rates at least 2% in any asenapine sublingual tablets arm and at least twice the placebo rate) were somnolence (3% in the 2.5mg twice daily group, 1% in the 5mg twice daily group, and 2% in the 10mg twice daily group), abdominal pain (2% in the 10mg 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 Sublingual Tablets at an Incidence of 2% or More in Asenapine Sublingual Tablets-treated Bipolar I Patients: Adverse reactions associated with the use of asenapine sublingual tablets (incidence of ≥2% in any asenapine sublingual tablets 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 Sublingual Tablets Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial

System Organ Class/ AE Preferred Term	Placebo	Asenapine sublingual tablets 2.5 mg twice daily	Asenapine sublingual tablets 5 mg twice daily	Asenapine sublingual tablets 10 mg twice daily	All Asenapine sublingual tablets 2.5, 5, and 10 mg
	N=101%	N=104%	N=99%	N=99%	N=302%
Cardiac Disorders
TachycardiaIncludes the preferred terms tachycardia and heart rate increased.	0	3	0	1	1
Gastrointestinal Disorders
Oral hypoesthesiaIncludes the preferred terms oral hypoesthesia, oral paresthesia, and oral dysesthesia.	4	25	25	30	27
Nausea	3	6	6	6	6
Vomiting	3	4	4	4	4
Abdominal painIncludes the preferred terms abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.	7	9	3	5	6
Glossodynia	0	0	2	0	1
General Disorders and Administrative Site Disorders
FatigueIncludes the preferred terms fatigue and lethargy.	5	4	8	14	9
Irritability	1	1	1	2	1
Injury, Poisoning, and Procedural Complications
Muscle strain	0	0	0	2	1
Investigations
Increased weight	0	6	2	2	3
HyperinsulinemiaIncludes the preferred terms hyperinsulinemia and blood insulin increased.	0	1	3	1	2
ALT increased	0	0	0	2	1
AST increased	0	0	0	2	1
Metabolism and Nutrition Disorders
Increased appetite	2	10	9	6	8
Dehydration	1	0	2	0	1
Musculoskeletal and Connective Tissue Disorders
Myalgia	0	0	2	1	1
Nervous System Disorders
SomnolenceIncludes the preferred terms somnolence, sedation, and hypersomnia.	12	46	53	49	49
Headache	6	8	11	9	9
Dizziness	3	6	10	5	7
Dysgeusia	2	4	5	9	6
Akathisia	0	2	2	1	2
Parkinsonism	0	1	0	2	1
Psychiatric Disorders
Insomnia	3	3	4	3	3
Suicidal ideation	1	4	1	3	3
Anger	0	0	0	2	1
Reproductive System and Breast Disorders
Dysmenorrhea	1	0	2	0	1
Respiratory, Thoracic, and Mediastinal Disorders
Oropharyngeal pain	2	0	3	1	1
Nasal congestion	1	0	2	0	1
Dyspnea	0	0	2	0	1
Skin and Subcutaneous Tissue Disorders
Rash	1	0	1	2	1

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 asenapine sublingual tablets 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 sublingual tablets-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 sublingual tablets (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 Sublingual Tablets -Treated (Adjunctive) Bipolar I Patients: Adverse reactions associated with the use of asenapine sublingual tablets (incidence of 2% or greater, rounded to the nearest percent, and asenapine sublingual tablets 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 Sublingual Tablets -Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials

System Organ Class/Preferred Term	Placebo N=166%	Asenapine Sublingual Tablets 5 mg or 10 mg twice dailyAsenapine sublingual tablets 5 mg to 10 mg twice daily with flexible dosing. N=158%
Gastrointestinal disorders
  Dyspepsia	2	3
  Oral hypoesthesia	0	5
General disorders
  Fatigue	2	4
  Edema peripheral	<1	3
Investigations
  Increased weight	0	3
Nervous system disorders
  Dizziness	2	4
  Other extrapyramidal symptoms (excluding akathisia)Extrapyramidal symptoms included: dystonia, parkinsonism, oculogyration, and tremor (excluding akathisia).	5	6
  SomnolenceSomnolence includes the following events: somnolence and sedation.	10	22
Psychiatric disorders
  Insomnia	8	10
Vascular disorders
  Hypertension	<1	3

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 schizophrenia and 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 the short-term, placebo-controlled schizophrenia adult trials, the incidence of reported EPS-related events, excluding events related to akathisia, for asenapine sublingual tablets -treated patients was 10% versus 7% for placebo; and the incidence of akathisia-related events for asenapine sublingual tablets-treated patients was 6% versus 3% for placebo. In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for asenapine sublingual tablets-treated patients was 8% versus 4% for placebo; and the incidence of akathisia-related events for asenapine sublingual tablets-treated patients was 7% versus 3% for placebo. The incidence rates of all EPS events (including akathisia) were lower at the 5mg twice daily dose (11% of N=122) than the 10mg twice daily dose (25% of N=119) in a fixed-dose 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 sublingual tablets 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 sublingual tablets 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 sublingual tablets and usually resolves within 1 hour.

Laboratory Test Abnormalities:

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania adult trials were more common in treated patients. In short-term, placebo-controlled schizophrenia adult trials, the mean increase in transaminase levels for asenapine sublingual tablets-treated patients was 1.6 units/L compared to a decrease of 0.4 units/L for placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times ULN (at Endpoint) was 0.9% for asenapine sublingual tablets-treated patients versus 1.3% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in transaminase levels for asenapine sublingual tablets-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 sublingual tablets-treated patients versus 0.7% for placebo-treated patients. The incidence rate of transaminase elevations ≥3 times ULN is 3% of N=95 for 10mg twice daily dose, and 0% of N=108 for the 5mg twice daily dose and 0% of N=115 for placebo in a fixed-dose study.

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.

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 sublingual tablets 10 mg twice daily versus none for the other asenapine sublingual tablets dose groups and placebo-treated patients.

Prolactin: In short-term, placebo-controlled adult schizophrenia trials, the mean decreases in prolactin levels were 6.5 ng/mL for asenapine sublingual tablets-treated patients compared to 10.7 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.6% for asenapine sublingual tablets -treated patients versus 0.6% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 6.7ng/mL for asenapine sublingual tablets-treated patients compared to a decrease of 1.0 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.0% for asenapine sublingual tablets-treated patients versus 0.8% for placebo-treated patients.

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 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 sublingual tablets 2.5 mg twice daily, 2.1 ng/mL for patients treated with asenapine sublingual tablets 5 mg twice daily, and 6.4 ng/mL for patients treated with asenapine sublingual tablets 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 sublingual tablets or placebo. Galactorrhea or dysmenorrhea were reported in 0% of patients treated with asenapine sublingual tablets 2.5 mg twice daily, 2% of patients treated with asenapine sublingual tablets 5 mg twice daily, and 1% of patients treated with asenapine sublingual tablets 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 sublingual tablets 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 schizophrenia and bipolar mania. 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 sublingual tablets 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 Sublingual Tablets: Following is a ul of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual asenapine sublingual tablets at multiple doses of ≥5 mg twice daily during any phase of a trial within the database of adult patients. The reactions uled are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions already uled for either adults or pediatric 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 uled in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already uled in the tabulated results from placebo-controlled trials appear in this uling); those occurring in 1/100 to 1/1,000 patients (infrequent); and those occurring in fewer than 1/1,000 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 ul of MedDRA terms not already uled 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 sublingual tablets 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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of asenapine sublingual tablets. 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.

• Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, bulers, peeling/sloughing, and inflammation.
• Choking has been reported by patients, some of whom may have also experienced oropharyngeal muscular dysfunction or hypoesthesia.