ASENAPINE- asenapine maleate tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ASENAPINE MALEATE (UNII: CU9463U2E2) (ASENAPINE - UNII:JKZ19V908O)
Available from:
MSN LABORATORIES PRIVATE LIMITED
Administration route:
SUBLINGUAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 - 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 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)]. Pregnancy Exposure Registry There is a pregnancy
Product summary:
Asenapine sublingual tablets are supplied as: Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
69539-059-34

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ASENAPINE - asenapine maleate tablet

MSN LABORATORIES PRIVATE LIMITED

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ASENAPINE SUBLINGUAL TABLETS safely

and effectively. See full prescribing information for ASENAPINE SUBLINGUAL TABLETS.

ASENAPINE sublingual tablets

Initial U.S. Approval: 2009

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED

PSYCHOSIS

See full prescribing information for complete boxed warning.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk

of death. Asenapine sublingual tablets are not approved for the treatment of patients with dementia-

related psychosis. (5.1, 5.2)

INDICATIONS AND USAGE

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

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)

DOSAGE FORMS AND STRENGTHS

Sublingual tablets, black cherry flavor: 10 mg (3)

CONTRAINDICATIONS

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)

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)

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

Antihypertensive Drugs: Asenapine sublingual tablets may cause hypotension. (5.7, 7.1, 12.3)

Paroxetine (CYP2D6 substrate and inhibitor): Reduce paroxetine by half when used in combination with asenapine

sublingual tablets. (7.1, 12.3)

USE IN SPECIFIC POPULATIONS

Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1)

Pediatric Use: Safety and efficacy in the treatment of bipolar I disorder in patients less than 10 years of age, and

patients with schizophrenia ages less than 12 years have not been evaluated. (8.4)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-

RELATED PSYCHOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Administration Instructions

2.2 Schizophrenia

2.3 Bipolar I Disorder

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

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

Psychosis

5.3 Neuroleptic Malignant Syndrome

5.4 Tardive Dyskinesia

5.5 Metabolic Changes

5.6 Hypersensitivity Reactions

5.7 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects

5.8 Falls

5.9 Leukopenia, Neutropenia, and Agranulocytosis

5.10 QT Prolongation

5.11 Hyperprolactinemia

5.12 Seizures

5.13 Potential for Cognitive and Motor Impairment

5.14 Body Temperature Regulation

5.15 Dysphagia

5.16 Risks in Patients with Phenylketonuria

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Drug Interactions with Asenapine Sublingual Tablets

7.2 Drugs Having No Clinically Important Interactions with Asenapine Sublingual Tablets

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Other Specific Populations

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Schizophrenia

14.2 Bipolar I Disorder

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: 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. Asenapine sublingual tablets are not approved for the treatment of

patients with dementia-related psychosis [see Warnings and Precautions (5.1, 5.2)].

1 INDICATIONS AND USAGE

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

Adjunctive treatment to lithium or valproate in adults

Maintenance monotherapy treatment in adults

Sections or subsections omitted from the full prescribing information are not listed.

2 DOSAGE AND ADMINISTRATION

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 tabletsdose 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 [seeClinical Studies (14.2)].

3 DOSAGE FORMS AND STRENGTHS

Asenapine sublingual 10 mg tablets, black cherry flavor, are round, white, uncoated tablets debossed

"B" on one side and "4" on the other side.

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

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 Warningand

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

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 daily

5 mg

twice

daily

10 mg

twice

daily

5 or 10

twice

daily

Mean Change from Baseline in Fasting Glucose at Endpoint

Change from Baseline (mg/dL) (N*)

-0.2

(232)

(158)

(153)

(377)

0 (174)

(84)

(81)

(321)

Proportion of Patients with Shifts from Baseline to Endpoint

Normal to High

<100 to ≥126 mg/dL

(n/N**)

4.1%

(7/170)

4.5%

(5/111)

4.5%

(5/111)

5.0%

(13/262)

2.4%

(3/126)

(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)

(3/44)%

6.3%

(2/32)

10.5%

(10/95)

(0/39)

12.5%

(3/24)

15.8%

(3/19)

12.8%

(10/78)

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

N** = Number of patients at risk at Baseline with assessments at both Baseline and Endpoint.

Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=90)

Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=379).

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*)

-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*)

(0/56)

(0/51)

1.8%

(1/57)

(0/52)

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

Dys lipidemia

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

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 daily

5 mg

twice

daily

10 mg

twice

daily

5 or 10

mg twice

daily

Mean Change from Baseline (mg/dL)

Total cholesterol

(N*)

-2.2

(351)

-2.4

(258)

(199)

(539)

-1.6

(278)

-1.6

(108)

-4.7

(95)

-0.5

(525)

LDL (N*)

(285)

-0.2

(195)

(195)

(465)

(271)

-2.5

(101)

-4.1

(94)

-0.3

(499)

HDL (N*)

(290)

(199)

(199)

(480)

(278)

(108)

(95)

(525)

Fasting triglycerides

(N*)

-7.6

(233)

-1.9

(159)

(154)

(380)

-16.9

(222)

(89)

-8.5

(85)

-3.0

(411)

Proportion of Patients with Shifts from Baseline to Endpoint

Total cholesterol

Normal 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)

(2/174)

(2/66)

(0/63)

(7/333)

Normal 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)

(2/108)

(1/41)

(0/41)

(1/223)

Normal 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)

(16/215)

(4/97)

(4/78)

(29/417)

Fasting triglycerides

Normal 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)

(7/153)

(5/61)

(1/64)

(17/273)

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

Includes patients treated with flexible dose of asenapine 5 or 10 mg twice daily (N=90)

Includes patients treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice

daily (N=379)

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 tablets

2.5 mg twice daily

Asenapine

sublingual tablets

5 mg twice daily

Asenapine sublingual

tablets

10 mg twice daily

Mean Change from Baseline (mg/dL)

Total fasting cholesterol (N*)

-2.3

(57)

(50)

(57)

(52)

Fasting LDL (N*)

-2.5

(57)

-0.2

(50)

(57)

(51)

Fasting HDL (N*)

(57)

(50)

(57)

(52)

Fasting triglycerides (N*)

-6.6

(57)

(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)

(0/52)

Fasting LDL Normal to High

<110 to >=130 (n/N*)

1.8% (1/57)

2.0% (1/50)

1.8%

(1/57)

(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)

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

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

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 daily

5 mg

twice daily

10 mg

twice

daily

5 or 10

mg twice

daily

Change from

Baseline (kg)

(N*)

(348)

(251)

(200)

(532)

(288)

(110)

(98)

(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%

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

Includes patients treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily

(N=90)

† Includes patients treated with flexible dose of asenapine sublingual tablets 5 or 10 mg twice daily

(N=379).

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 <23

Asenapine

sublingual tablets

N=295

BMI 23 - ≤27

Asenapine sublingual

tablets N=290

BMI >27

Asenapine sublingual

tablets N=302

Mean change from Baseline (kg)

% with ≥7% increase in body

weight

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

s ublingual

tablets

2.5 mg

twice daily

Asenapine

sublingual tablets

5 mg

twice daily

Asenapine

sublingual tablets

10 mg

twice daily

Change from Baseline

(kg) (N*)

(89)

(92)

(90)

(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%

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

5.6 Hypersensitivity Reactions

Hypersensitivity reactions have been observed in patients treated with asenapine 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/mm ) 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 10 mg tablet 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 listed. A reaction was considered treatment emergent if it

occurred for the first time or worsened while receiving therapy following baseline evaluation.

6.1 Clinical 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

C l a s s / Preferred

Term

Placebo

N=378

%

Asenapine

Sublingual Tablets

5 mg twice daily

N=274

%

Asenapine

Sublingual Tablets

10mg twice daily

N=208

%

All Asenapine

Sublingual

Tablets§

5mg or 10 mg

twice daily

N=572

%

Gastrointestinal

disorders

Constipation

Dry mouth

Oral hypoesthesia

Salivary

hypersecretion

<1

Stomach

discomfort

<1

Vomiting

General disorders

Fatigue

Irritability

<1

Investigations

Increased weight

<1

Metabolism

disorders

Increased appetite

<1

Nervous

s ys tem

disorders

Akathisia

Dizziness

Extrapyramidal

symptoms

(excluding

akathisia)†

Somnolence‡

Psychiatric

disorders

Insomnia

Vascular

disorders

Hypertension

Akathisia includes: akathisia and hyperkinesia.

Extrapyramidal symptoms included dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle

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