ASENAPINE tablet

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

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Active ingredient:
ASENAPINE (UNII: JKZ19V908O) (ASENAPINE - UNII:JKZ19V908O)
Available from:
Alembic Pharmaceuticals Inc.
Administration route:
SUBLINGUAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
 Asenapine is indicated for: • Bipolar I disorder [see Clinical Studies (14.2)]      •Adjunctive treatment to lithium or valproate in adults Asenapine is contraindicated in patients with: ·             Severe hepatic impairment (Child-Pugh C) [see Specific Populations (8.7), Clinical Pharmacology (12.3)] . ·             A history of hypersensitivity reactions to asenapine. 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 exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-9612388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk  Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at ris
Product summary:
Asenapine sublingual tablets are supplied as: 5-mg Tablets: White to off white, round tablets debossed with “464” on one side and plain on other side. Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-198-60 Cartons of 100 - 10 blister cards of 10 tablets each   NDC 62332-198-31 10-mg Tablets: White to off white, round tablets debossed with “465” on one side and plain on other side. Cartons of 60 - 6 blister cards of 10 tablets each       NDC 62332-199-60 Cartons of 100 - 10 blister cards of 10 tablets each   NDC 62332-199-31   Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
62332-198-10, 62332-198-31, 62332-198-60, 62332-199-10, 62332-199-31, 62332-199-60

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ASENAPINE - asenapine tablet

Alembic Pharmaceuticals Inc.

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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 is not approved for the treatment of patients with dementia-related psychosis. (5.1,

5.2)

RECENT MAJOR CHANGES

Indications and Usage (1) 01/2017

Dosage and Administration (2.3) 01/2017

Contraindications (4) 01/2017

Warnings and Precautions 01/2017

(5.1, 5.2, 5.3, 5.4, 5.5, 5.7, 5.9, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15)

Warnings and Precautions (5.8) 02/2017

INDICATIONS AND USAGE

Asenapine is an atypical antipsychotic indicated for (1): (1)

Bipolar I disorder

o Adjunctive treatment to lithium or valproate in adults (1)

DOSAGE AND ADMINISTRATION

Starting

Dose

Recommended

Dose

Maximum Dose

Bipolar mania - adults: as an

adjunct

lithium

valproate (2.3)

5 mg sublingually twice daily

5 to 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)

DOSAGE FORMS AND STRENGTHS

Sublingual tablets: 5 mg and 10 mg (3) (3)

CONTRAINDICATIONS

Severe hepatic impairment (Child-Pugh C). (8.7, 12.3)

Known hypersensitivity to asenapine, 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 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)

ADVERSE REACTIONS

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

· Bipolar I Disorder Adults (Adjunctive): somnolence, oral hypoesthesia.

To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797

or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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

Paroxetine (CYP2D6 substrate and inhibitor): Reduce paroxetine by half when used in combination with asenapine. (7.1,

12.3) (7)

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 patients less than 10 years of age have not been evaluated. (8.4) (8)

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

2.3 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

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

7.2 Drugs Having No Clinically Important Interactions with Asenapine

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

14.2 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 is not approved for the treatment of patients with

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

1 INDICATIONS AND USAGE

Asenapine is indicated for:

Bipolar I disorder [see Clinical Studies (14.2)]

Adjunctive treatment to lithium or valproate in adults

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)].

2.3 Bipolar I Disorder

Acute Treatment of Manic or Mixed Episodes:

Adjunctive Therapy in Adults: The recommended starting dose of asenapine is 5 mg twice daily when

administered as adjunctive therapy with either lithium or valproate. Depending on the clinical response

and tolerability in the individual patient, the dose can be increased to 10 mg twice daily. The safety of

doses above 10 mg twice daily as adjunctive therapy with lithium or valproate has not been evaluated in

clinical trials.

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

For patients on asenapine, used as adjunctive therapy with lithium or valproate, it is generally

recommended that responding patients continue treatment beyond the acute episode.

3 DOSAGE FORMS AND STRENGTHS

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

side.

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

side.

4 CONTRAINDICATIONS

Asenapine is contraindicated in patients with:

· Severe hepatic impairment (Child-Pugh C) [see Specific Populations (8.7), Clinical Pharmacology

(12.3)].

· A history of hypersensitivity reactions to asenapine. 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 is 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 is not approved for the treatment of patients with dementia-related psychosis [see

Boxed Warning and 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 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. 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 to increase with the

duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief

treatment period, even at low doses. It may also occur after discontinuation of treatment.

There is no known treatment for tardive dyskinesia, although the syndrome may remit, partially or

completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may

suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the

underlying process. The effect that symptomatic suppression has upon the long-term course of tardive

dyskinesia is unknown.

Given these considerations, asenapine should be prescribed in a manner most likely to reduce the risk of

tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who

suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom

alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients

who do require chronic treatment use the lowest dose and the shortest duration of treatment producing a

satisfactory clinical response should be sought. Periodically reassess the need for continued treatment.

If signs and symptoms of TD appear in a patient on asenapine, drug discontinuation should be

considered. However, some patients may require treatment with asenapine despite the presence of the

syndrome.

5.5 Metabolic Changes

Atypical antipsychotic drugs, including asenapine, have caused metabolic changes, including

hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. Although all of the drugs in the

class to date have been shown to produce some metabolic changes, each drug has its own specific risk

profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or

death, has been reported in patients treated with atypical antipsychotics. There have been reports of

hyperglycemia in patients treated with asenapine. Assess fasting plasma glucose before or soon after

initiation of antipsychotic medication, and monitor periodically during long-term treatment.

Adult Patients: Pooled data from the short-term placebo-controlled bipolar mania trials are presented in

Table 1.

TABLE 1: Changes in Fasting Glucose in Adult Patients

Bipolar I Disorder (3-weeks)

Placebo

Asenapine

5 mg twice

daily

10 mg twice

daily

5 mg or 10 mg

twice daily

Mean Change from Baseline in Fasting Glucose at Endpoint

Change from Baseline

(mg/dL) (N )

(174)

(84)

(81)

(321)

Proportion of Patients with Shifts from Baseline to Endpoint

Normal to High

<100 to ≥126 mg/dL

(n/N )

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 )

(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 mg or 10 mg twice daily (N=379).

In a 52-week, double-blind, comparator-controlled trial, the mean increase from baseline of fasting

glucose was 2.4 mg/dL.

Dyslipidemia

Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of

antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during

treatment.

Adult Patients: Pooled data from the short-term, placebo-controlled bipolar mania trials are presented in

Table 3.

TABLE 3: Changes in Lipids in Adult Patients

Bipolar I Disorder (3-weeks)

Placebo

Asenapine

5 mg twice

daily

10 mg twice

daily

5 mg or 10 mg

twice daily

Mean Change from Baseline (mg/dL)

Total cholesterol (N )

-1.6

(278)

-1.6

(108)

-4.7

(95)

-0.5

(525)

LDL (N )

(271)

-2.5

(101)

-4.1

(94)

-0.3

(499)

HDL (N )

(278)

(108)

(95)

(525)

Fasting triglycerides

(N )

-16.9

(222)

(89)

-8.5

(85)

(411)

Proportion of Patients with Shifts from Baseline to Endpoint

Total cholesterol

Normal to High

<200 to ≥240

(mg/dL) (n/N )

(2/174)

(2/66)

(0/63)

(7/333)

Normal to High

<100 to ≥160

(mg/dL) (n/N )

(2/108)

(1/41)

(0/41)

(1/223)

Normal to Low

≥40 to <40

(mg/dL) (n/N )

(16/215)

(4/97)

(4/78)

(29/417)

Fasting triglycerides

Normal to High

<150 to ≥200

(mg/dL) (n/N )

(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 mg or 10 mg twice daily (N=379).

In short-term, placebo-controlled bipolar mania trials, the proportion of patients with total cholesterol

elevations ≥240 mg/dL (at Endpoint) was 7.8% for asenapine-treated patients versus 7.9% for placebo-

treated patients. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint)

was 13.1% for asenapine-treated patients versus 8.6% for placebo-treated patients.

Weight Gain

Weight gain has been observed in patients treated with atypical antipsychotics, including asenapine.

Monitor weight at baseline and frequently thereafter.

Adult Patients: Pooled data on mean changes in body weight and the proportion of subjects meeting a

weight gain criterion of ≥7% of body weight from the short-term, placebo-controlled bipolar mania

trials are presented in Table 5.

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

Bipolar I Disorder (3-weeks)

Placebo

Asenapine

5 mg twice

daily

10 mg twice

daily

5 mg or 10 mg

twice daily

Change from Baseline

(kg) (N )

(288)

(110)

(98)

(544)

Proportion of Patients with a ≥7% Increase in Body Weight

% with ≥7% increase in

body weight

0.4%

6.4%

5.5%

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

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

Adult Patients: In a 52-week, double-blind, comparator-controlled adult trial, the mean weight gain from

baseline was 0.9 kg. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was

14.7%. Table 6 provides the mean weight change from baseline and the proportion of patients with a

weight gain of ≥7% categorized by Body Mass Index (BMI) at baseline.

Table 6: Weight Change Results Categorized by BMI at Baseline: Comparator- Controlled 52-

Week Study in Adult Patients

BMI <23

Asenapine

N=295

BMI 23 -≤27

Asenapine

N=290

BMI >27

Asenapine

N=302

Mean change from Baseline (kg)

% with ≥7% increase in body

weight

5.6 Hypersensitivity Reactions

Hypersensitivity reactions have been observed in patients treated with asenapine. In several cases, these

reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis,

angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.

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 bipolar mania adult trials,

syncope was reported in 0.2% (1/620) of patients treated with therapeutic doses (5 mg or 10 mg twice

daily) of asenapine, compared to 0% (0/329) of patients treated with placebo. During adult pre-

marketing clinical trials with asenapine, including long-term trials without comparison to placebo,

syncope was reported in 0.6% (11/1953) of patients treated with asenapine.

Orthostatic vital signs should be monitored in patients who are vulnerable hypotension (elderly patients,

patients with dehydration, hypovolemia, concomitant treatment with antihypertensive

medications, patients with known cardiovascular disease (history of myocardial infarction or ischemic

heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.

Asenapine should be used cautiously when treating patients who receive treatment with other drugs that

can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug

Interactions (7.1)]. Monitoring of orthostatic vital signs should be considered in all such patients, and a

dose reduction should be considered if hypotension occurs.

5.8 Falls

Asenapine may cause somnolence, postural hypotension, motor and sensory instability, which may lead

to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or

medications that could exacerbate these effects, complete fall risk assessments when initiating

antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

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. Agranulocytosis (including fatal cases) has been

reported with other agents in the class.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count

(WBC) or absolute neutrophil count (ANC) and history of drug induced leukopenia/neutropenia. In

patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia,

perform a complete blood count (CBC) during the first few months of therapy. In such patients, consider

discontinuation of asenapine at the first sign of a clinically significant decline in WBC in the absence of

other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of

infection and treat promptly if such symptoms or signs occur. Discontinue asenapine in patients with

severe neutropenia (absolute neutrophil count <1000/mm ) and follow their WBC until recovery.

5.10 QT Prolongation

The effects of asenapine on the QT/QTc interval were evaluated in a dedicated adult QT study. This

trial involved asenapine doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was

conducted in 151 clinically stable patients, with electrocardiographic assessments throughout the

dosing interval at baseline and steady state. At these doses, asenapine was associated with increases in

QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with asenapine

experienced QTc increases ≥60 msec from baseline measurements, nor did any patient experience a

QTc of ≥500 msec.

Electrocardiogram (ECG) measurements were taken at various time points during the asenapine clinical

trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec

were reported at comparable rates for asenapine and placebo in these short-term trials. There were no

reports of Torsade de Pointes or any other adverse reactions associated with delayed ventricular

repolarization.

The use of asenapine should be avoided in combination with other drugs known to prolong QTc

including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g.,

amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and

antibiotics (e.g., gatifloxacin, moxifloxacin). Asenapine should also be avoided in patients with a

history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of

torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc

interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital

prolongation of the QT interval.

5.11 Hyperprolactinemia

Like other drugs that antagonize dopamine D receptors, asenapine can elevate prolactin levels, and the

elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic

GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive

function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea,

amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating

compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to

decreased bone density in both female and male subjects. In asenapine adult pre-marketing clinical trials,

the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for

placebo.

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, respectively, compared to 0% (0/203) of patients treated with placebo

in pre-marketing short-term bipolar mania trials. During adult pre-marketing clinical trials with

asenapine, including long-term trials without comparison to placebo, seizures were reported in 0.3%

(5/1953) of patients treated with asenapine.

As with other antipsychotic drugs, asenapine should be used with caution in patients with a history of

seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the

seizure threshold may be more prevalent in patients 65 years or older.

5.13 Potential for Cognitive and Motor Impairment

Somnolence was reported in patients treated with asenapine. It was usually transient with the highest

incidence reported during the first week of treatment. In short-term, placebo-controlled bipolar mania

adult trials of therapeutic doses (5 to 10 mg twice daily), somnolence was reported in 23% (145/620) of

patients on asenapine compared to5% (18/329) of placebo patients. In another study, somnolence

occurred at a lower rate in the 5 mg twice daily dose 20% (24/122) versus the 10 mg twice daily dose

26% (31/119) compared to 4% (5/126) in placebo patients. During adult pre-marketing clinical trials

with asenapine, including long-term trials without comparison to placebo, somnolence was reported in

18% (358/1953) of patients treated with asenapine. Somnolence led to discontinuation in 0.6% (12/1953)

of patients in short-term, placebo-controlled trials.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they

are reasonably certain that asenapine 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 acute bipolar I disorder and another indication,

the incidence of adverse reactions suggestive of body temperature increases was low (≤1%) and

comparable to placebo (0%). During pre-marketing clinical trials with asenapine, including long-term

trials without comparison to placebo, the incidence of adverse reactions suggestive of body

temperature increases (pyrexia and feeling hot) was ≤1%.

Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may

contribute to an elevation in core body temperature; use asenapine with caution in patient who may

experience these conditions.

5.15 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has

been reported with asenapine. Asenapine and other antipsychotic drugs should be used cautiously in

patients at risk for aspiration.

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 during the

adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia. The rates

were lower at the 5 mg twice daily dose than the 10 mg twice daily dose for all of these most common

adverse reactions.

The adult information below is derived from a clinical trial database for asenapine consisting of over

5355 patients and/or healthy subjects exposed to one or more sublingual doses of asenapine. A total of

1427 asenapine-treated patients were treated for at least 24 weeks and 785 asenapine-treated patients had

at least 52 weeks of exposure at therapeutic doses.

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.

Adjunctive Therapy in Adult Patients with Bipolar Mania: The following findings are based on a 12

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