AHFS Class:

• Atypical Antipsychotics 28:16.08.04

Generic Name(s):

• Asenapine Maleate

• Asenapine

Chemical Name:

• (3a RS ,12b RS )-5-Chloro-2,3,3a,12b-tetrahydro-2-methyl-1 H -dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1)

Molecular Formula:

• C₁₇H₁₆ClNO • C₄H₄O₄

Asenapine maleate is considered an atypical or second-generation antipsychotic agent.1,4,6,8,28,74,85

Psychotic Disorders

Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse.28 Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia.28 Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.28,70,71,72

Schizophrenia

Asenapine maleate is an antipsychotic agent that is administered sublingually in the acute and maintenance treatment of schizophrenia.1,2,4,82,88,89,93 Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors.28,68 Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment.28,68 The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms.28 Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition).28 Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.28

The short-term efficacy of sublingual asenapine in the acute management of schizophrenia was evaluated in 4 placebo-controlled and active comparator (haloperidol, olanzapine, or risperidone)-controlled, fixed- or flexible-dose clinical trials of 6 weeks' duration in adults who met DSM-IV criteria for schizophrenia and were experiencing an acute exacerbation of their schizophrenic illness.1,2,4,82,88,89 In 2 of the 4 studies, asenapine was found to be more effective than placebo.1,2,4,82,89 In the third study, asenapine could not be distinguished from placebo; however, the active control (olanzapine) in the trial was found to be superior to placebo.1 In the fourth study, which was flexible dosage in design, neither asenapine nor the active comparator olanzapine demonstrated superior efficacy when compared with placebo.88,89

In the 2 positive studies for asenapine, the main efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS), which assesses schizophrenia symptoms and general psychopathology, and the primary endpoint was change from baseline to the end of treatment on the PANSS total score.1,2,4,82 In the first trial, which compared asenapine (5 mg sublingually twice daily) with placebo, asenapine was found to be superior to placebo in improving the PANSS total score.1,2 In the second trial, which compared fixed dosages of asenapine (5 mg or 10 mg sublingually twice daily) with placebo, asenapine was also found to be superior to placebo in improving the PANSS total score; however, the 10-mg twice-daily dosage did not demonstrate an additional therapeutic benefit compared with the 5-mg twice-daily dosage and did not differ substantially from placebo.1,4,82 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.1

In a longer-term (52-week), double-blind study in adult patients with schizophrenia or schizoaffective disorder who were randomized to receive either sublingual asenapine (5 or 10 mg twice daily) or olanzapine (10-20 mg once daily), asenapine was found to be effective and well tolerated and caused less frequent weight gain but more frequent extrapyramidal symptoms (primarily akathisia) than olanzapine.84 The long-term efficacy of asenapine (5 or 10 mg twice daily based on tolerability) in prevention of relapse in schizophrenia patients was demonstrated in a 26-week, randomized, placebo-controlled trial that followed 26 weeks of open-label treatment; asenapine was found to be more effective than placebo in prevention of relapse or impending relapse in these patients and was well tolerated over the course of this 52-week trial.1,93

The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial.28 The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.28 Conventional antipsychotic agents also may be an appropriate first-line option for some patients, including those who have been treated successfully in the past with or who prefer conventional agents.13,28 The choice of an antipsychotic agent should be individualized, considering past response to therapy, current symptomatology, concurrent medical conditions, other medications and treatments, adverse effect profile, and the patient's preference for a specific drug, including route of administration.13,28,70

For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Bipolar Disorder

Asenapine maleate sublingual tablets are used as monotherapy or adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder (with or without psychotic features).1,3,5,74,94,99,100 The drug also is used for the maintenance monotherapy of bipolar I disorder.1,5,86 According to DSM-IV criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractability, increased goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation, and engaging in high-risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).68

Efficacy of sublingual asenapine monotherapy in the treatment of acute mania has been demonstrated in 2 similarly designed, short-term (i.e., 3 weeks' duration), placebo-controlled and active comparator-controlled trials in adults who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features.1,3,4,74,83 The principal rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score).1,3,4,31,83 A secondary rating instrument used in these trials was the Clinical Global Impression-Bipolar (CGI-BP) scale.1,3,4,83 In both trials, asenapine was initially administered in a sublingual dosage of 10 mg twice daily and the dosage could then be adjusted to 5 or 10 mg twice daily from day 2 onward based on efficacy and tolerability; 90% of patients remained on the 10-mg twice-daily dosage.1,3,4,83 Asenapine was found to be superior to placebo in the reduction of the Y-MRS total score and the CGI-BP Severity of Illness score (mania) in both studies; improvements in the Y-MRS total score were observed as early as day 2 in these studies.1,3,4,83 An active control arm (olanzapine) was used in addition to placebo controls in both of these studies; however, study design did not allow for direct comparison between asenapine and olanzapine.1,3,4,83 In another short-term (3 weeks' duration), placebo-controlled study that compared 2 fixed dosages of asenapine monotherapy (5 or 10 mg twice daily) with placebo in adults with manic or mixed episodes associated with bipolar I disorder, both dosages of asenapine were found to be substantially superior to placebo in improving the Y-MRS total score and the CGI-BP Severity of Illness overall score.1,99 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.1

Following completion of either of the similarly designed, short-term monotherapy efficacy studies, patients with bipolar I disorder experiencing acute manic or mixed episodes were eligible for a 9-week, double-blind extension study evaluating the efficacy and safety of asenapine versus olanzapine.5 In this study, no significant difference in efficacy between asenapine and olanzapine was found and asenapine was well tolerated during the extended treatment.5 Patients completing either of the two 3-week acute efficacy trials and the subsequent 9-week, double-blind extension trial could then enter a longer-term (40-week) extension that was designed to evaluate asenapine therapy over one year of treatment; long-term asenapine therapy (5 or 10 mg twice daily sublingually) was found to be generally well tolerated in this study.86

Efficacy and safety of sublingual asenapine monotherapy in the treatment of acute mania in pediatric patients were established in a short-term (i.e., 3 weeks' duration), placebo-controlled, fixed-dosage trial in 403 pediatric patients 10-17 years of age with bipolar I disorder who were currently experiencing manic or mixed episodes.1,100 Asenapine (2.5, 5, or 10 mg twice daily) was initiated at a dosage of 2.5 mg twice daily in all the patients and titrated up to a target fixed dosage of 5 and then 10 mg twice daily at intervals of 3 days in the patients receiving these higher dosages.1,100 All dosages of asenapine evaluated in this study were found to be superior to placebo in improving the Y-MRS total score and the CGI-BP Severity of Illness overall score from baseline to week 3.1,100

Efficacy of sublingual asenapine as adjunctive therapy in acute mania has been established in a 12-week, placebo-controlled trial with a 3-week primary efficacy endpoint in adults with bipolar I disorder with a manic or mixed episode with or without psychotic features who were partially responsive to lithium or valproate monotherapy after at least 2 weeks of treatment.1 Asenapine was found to be more effective than placebo in the reduction of manic symptoms (as measured by the Y-MRS total score) when given as an adjunctive therapy to either lithium or valproate at week 3 in this study.1

The manufacturer states that if asenapine is used for extended periods in bipolar disorder, the long-term risks and benefits of the drug should be reassessed periodically on an individualized basis.1 (See Dosage and Administration: Dosage.)

For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic agent such as olanzapine may be adequate.69 For more severe manic or mixed episodes, combination therapy with an antipsychotic agent and lithium or valproate is recommended as first-line therapy.69 For further information on the management of bipolar disorder, see Uses: Bipolar Disorder, in Lithium Salts 28:28.

Administration

Asenapine maleate is commercially available as rapidly dissolving sublingual tablets, since the oral bioavailability of the drug after sublingual administration is much higher than following oral administration (see Description).1,4,6 The tablets are administered sublingually twice daily.1

Patients should be instructed not to remove a sublingual tablet from the blister pack until just prior to administration.1 With dry hands, the blister pack should be pulled out of the case and the colored tab should be peeled back to expose the sublingual tablet; the tablet should not be pushed through the blister pack.1 The tablet should then be gently removed and placed under the tongue and allowed to dissolve completely (this usually takes about 10 seconds).1,6 The blister pack should then be slid back into the case until it clicks.1 Because ingestion of food or water following asenapine administration decreases the drug's exposure, patients should be instructed not to eat or drink for 10 minutes following administration of the sublingual tablets. 1,74 The sublingual tablets should not be split, crushed, chewed, or swallowed.1

Dosage

Available as asenapine maleate; dosage expressed in terms of asenapine.1,4,81

Schizophrenia

For the acute management of schizophrenia in adults, the recommended initial and target dosage of asenapine is 5 mg given sublingually twice daily.1 If tolerated, the dosage may be increased to 10 mg twice daily after 1 week.1 In short-term controlled studies, there was no indication of additional clinical benefit with a higher dosage (10 mg sublingually twice daily) of the drug, but the higher dosage clearly was associated with an increase in certain adverse effects.1,82 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated.1

For the maintenance management of schizophrenia in adults, the recommended target dosage range of asenapine is 5-10 mg given sublingually twice daily.1 Asenapine 5 or 10 mg given twice daily has been shown to be effective and well tolerated for up to 52 weeks in patients with schizophrenia or schizoaffective disorder.1,84,93

The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence.28 Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent.28 In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.28

Bipolar Disorder

As monotherapy for the acute management of manic or mixed episodes associated with bipolar I disorder in adults, the recommended initial and target asenapine dosage is 5-10 mg given sublingually twice daily.1,3,83 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated in clinical trials.1

As monotherapy for the maintenance treatment of manic or mixed episodes associated with bipolar I disorder in adults, the same dosage used during stabilization (5-10 mg twice daily) should be continued.1 Based on clinical response and tolerability in the individual patient, a dosage of 10 mg twice daily can be decreased to 5 mg twice daily.1 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not evaluated in clinical trials.1

In short-term monotherapy clinical trials in adults, the initial dosage of asenapine was 10 mg given sublingually twice daily.3,83 On the second and subsequent days of the studies, the dosage could be lowered to 5 mg twice daily based on tolerability; however, less than 10% of patients had their dosage reduced during these trials.3,83 In a 1-year extension study, the mean total daily dosage in the asenapine-treated patients was approximately 16 mg and the total daily modal dosage was 20 mg.86

For the acute management of manic or mixed episodes associated with bipolar I disorder in pediatric patients 10-17 years of age, the initial dosage of asenapine is 2.5 mg given sublingually twice daily and the recommended target dosage is 2.5-10 mg given sublingually twice daily.1 Dosage may be adjusted based on individual response and tolerability.1 After 3 days, the dosage may be increased to 5 mg twice daily; after 3 additional days, the dosage may be increased to 10 mg twice daily.1 Because pediatric patients appear to be more sensitive to dystonia with initial dosing, asenapine should be titrated according to the manufacturer's recommended titration schedule.1 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated in pediatric patients.1

When administered as adjunctive therapy with lithium or valproate for the acute management of manic or mixed episodes associated with bipolar I disorder in adults, the recommended initial asenapine dosage is 5 mg given sublingually twice daily.1 The dosage may then be increased to 10 mg sublingually twice daily based on clinical response and tolerability.1 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated.1

For patients receiving asenapine as either monotherapy or as adjunctive therapy with lithium or valproate, it is generally recommended that patients responding to therapy continue to receive the drug beyond the acute response.1 Asenapine 5 or 10 mg given sublingually twice daily has been shown to be well tolerated for up to 52 weeks in adults with bipolar disorder.86

Special Populations

Dosage adjustment is not routinely required in patients with renal impairment or in geriatric patients.1,7,95 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment.1,7,95 Asenapine is contraindicated in patients with severe hepatic impairment.1,95 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not routinely required based on gender, race, or smoking status.1

Contraindications

Asenapine maleate is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).1

Asenapine also is contraindicated in patients with known hypersensitivity to the drug or any components in the formulation.1,96 Anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash have been reported in patients receiving asenapine.1,96 (See Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.1,39,73 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed a 1.6- to 1.7-fold increase in mortality among geriatric patients who were mainly receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.1,73 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1,73 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.1,73 The manufacturer states that asenapine is not approved for the treatment of patients with dementia-related psychosis.1 (See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and see Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients treated with asenapine.1,96 From August 2009 to September 2010, the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) received 52 reports of type I hypersensitivity reactions associated with asenapine.96 Clinical manifestations reported included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash.1,96 Some of the cases reported occurrence of more than one hypersensitivity reaction following asenapine administration.96 Several cases reported hypersensitivity reactions (possible angioedema, respiratory distress, and possible anaphylaxis) occurring after the first dose.1,96 In some patients, symptoms resolved after asenapine discontinuance while others required hospitalization or emergency room visits and therapeutic interventions.96 (See Cautions: Contraindications and also see Advice to Patients.)

Other Warnings and Precautions

Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis

An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1,28 The manufacturer states that asenapine is not approved for the treatment of patients with dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex characterized by hyperpyrexia, muscle rigidity, delirium, and autonomic instability, has been reported with antipsychotic agents,1 including asenapine.94 If NMS is suspected, antipsychotic therapy should be immediately discontinued and intensive symptomatic treatment and monitoring should be provided.1 (See Advice to Patients.) For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Tardive Dyskinesia

Because use of antipsychotic agents, including asenapine, may be associated with tardive dyskinesia (a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements),1,84 asenapine should be prescribed in a manner that is most likely to reduce the risk of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment needed to achieve a satisfactory clinical response should be used, and the need for continued treatment should be reassessed periodically.1

The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months.28 If signs and symptoms of tardive dyskinesia appear in an asenapine-treated patient, asenapine discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.1 For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Metabolic Changes

Atypical antipsychotic agents, including asenapine, have caused metabolic changes including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain.1 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.1 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents.1,11,12,14,15,16,17,18,20,21,22,23,25,40,41,42,46,65 Hyperglycemia has been reported in patients treated with asenapine.1 In short-term controlled trials in patients with schizophrenia or bipolar mania, approximately 0-5 and 6-16% of asenapine-treated patients experienced shifts from normal to high and from borderline to high fasting glucose concentrations, respectively.1 In a longer-term (one-year), comparator-controlled, double-blind study, the mean increase in fasting glucose concentrations from baseline was 2.4 mg/dL in the asenapine-treated patients.1

Fasting blood glucose testing should be performed before or soon after initiation of antipsychotic therapy and then periodically during long-term therapy.1 (See Advice to Patients.)

For further information on managing the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Cautions: Precautions and Contraindications, in Clozapine 28:16.08.04.

Dyslipidemia

Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotic agents.1 Asenapine appears to minimally affect the lipid profile in patients receiving short-term therapy with the drug.1 In short-term, placebo-controlled studies of asenapine in adults with schizophrenia, the proportion of patients with total cholesterol elevations of 240 mg/dL or more at study end point was approximately 8% for asenapine-treated patients compared with 7% for placebo recipients and the proportion of patients with elevations in triglycerides of 200 mg/dL or more at study end point was 13.2% for asenapine-treated patients compared with 10.5% for placebo recipients.1 In short-term, placebo-controlled bipolar mania trials in adults, the proportion of patients with total cholesterol elevations of 240 mg/dL or more at study end point was 7.8% for asenapine-treated patients compared with 7.9% for placebo recipients and the proportion of patients with elevations in triglycerides of 200 mg/dL or more at end point was 13.1% for asenapine-treated patients compared with 8.6% for placebo recipients.1

The manufacturer recommends baseline (i.e., before or soon after initiation of therapy) and periodic follow-up fasting lipid evaluations in patients receiving asenapine therapy.1

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy, including asenapine.1,84,93 In short-term schizophrenia studies in adults, mean weight gain of 1.1 kg was reported in patients receiving asenapine compared with no change in weight in those receiving placebo; 4.9% of asenapine-treated patients gained 7% or more of their baseline body weight compared with 1.6% of those receiving placebo.1 In short-term bipolar mania studies in adults, mean weight gain of 1.3 kg was reported in patients receiving asenapine compared with a gain of 0.2 kg in those receiving placebo; 5.5% of patients receiving asenapine gained 7% or more of their baseline body weight compared with 0.4% of those receiving placebo.1

During long-term asenapine therapy (52 weeks) in adults primarily with schizophrenia, mean weight gain in asenapine-treated patients was 0.9 kg.1,84 22% of patients receiving asenapine with a baseline body mass index (BMI) less than 23 gained 7% or more of their baseline body weight compared with 13% of patients with a baseline BMI of 23-27 and 9% of patients with a BMI exceeding 27 at baseline.1,84

In a short-term bipolar mania trial in pediatric patients, mean weight gain of 1.4-1.7 kg was reported in patients receiving asenapine compared with a gain of 0.5 kg in those receiving placebo; 8-12% of asenapine-treated patients gained 7% or more of their baseline body weight compared with 1.1% of those receiving placebo.1

The manufacturer recommends baseline and frequent monitoring of weight in all patients receiving asenapine.1 In pediatric patients, weight gain should be monitored and assessed against that expected for normal growth.1

Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects

Atypical antipsychotic agents can cause orthostatic hypotension and syncope.1 The risk is usually the greatest during initial dosage titration and when dosage is increased.1 In premarketing clinical trials in adults, including long-term trials without comparison with placebo, syncope was reported in 0.6% of patients treated with asenapine.1 In short-term bipolar mania trials in pediatric patients, syncope was reported in 1% of patients receiving asenapine 2.5 or 5 mg twice daily and in no patients receiving asenapine 10 mg twice daily or placebo.1

Orthostatic vital signs should be monitored in patients receiving asenapine who are susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients concomitantly receiving antihypertensive therapy), patients with cardiovascular disease (e.g., history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1 Asenapine should be used with caution in patients receiving other drugs that can cause hypotension, bradycardia, respiratory depression, or CNS depression (see Drug Interactions).1 In all such patients, consideration should be given to monitoring orthostatic vital signs, and dosage reduction should be considered if hypotension develops.1

Falls

Asenapine therapy may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.1 For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.1

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including asenapine.1,78 Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.1

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count or absolute neutrophil count (ANC) or a history of drug-induced leukopenia and neutropenia.1,78 Patients with a preexisting low leukocyte count or ANC or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored during the first few months of therapy.1 Discontinuance of asenapine should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.1

Patients with clinically important neutropenia should be monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.1 In patients with severe neutropenia (ANC less than 1000/mm³), asenapine should be discontinued and the leukocyte count monitored until recovery occurs.1 Lithium reportedly has been used successfully in the treatment of several cases of leukopenia associated with aripiprazole, clozapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.78

Prolongation of QT Interval

In adult patients with schizophrenia, asenapine (in sublingual dosages of 5, 10, 15, or 20 mg twice daily) was associated with relatively small increases in the corrected QT (QT_c) interval of 2-5 msec compared with placebo in a controlled and dedicated QT study; these increases were slightly lower than those observed in patients receiving quetiapine.1,6,10 None of the asenapine-treated patients in this study experienced a QT_c-interval prolongation of 60 msec or greater compared with baseline, nor did any patient experience a QT_c interval of 500 msec or greater.1,10 During short-term clinical trials in patients receiving 5 or 10 mg of asenapine sublingually twice daily, post-baseline QT-interval prolongation exceeding 500 msec was reported at similar rates for asenapine and placebo.1 There were no reports of torsades de pointes or any adverse effects associated with delayed ventricular repolarization during these studies.1

The manufacturer states that asenapine should be avoided in patients concurrently receiving other drugs known to prolong the QT_c interval (see Drug Interactions: Drugs that Prolong QT Interval).1 The manufacturer also states that asenapine should be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QT_c interval, including bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval.1

Hyperprolactinemia

Similar to other antipsychotic agents and drugs with dopamine D₂ antagonistic activity, asenapine can cause elevated serum prolactin concentrations, which may persist during chronic use of the drug.1 In premarketing clinical trials in adults, adverse effects related to abnormal prolactin concentrations occurred in 0.4% of asenapine-treated patients compared with none of those receiving placebo.1 In a 3-week clinical trial in pediatric patients with bipolar mania, such adverse effects were reported in 0, 2, or 1% of patients receiving asenapine 2.5, 5, or 10 mg sublingually twice daily compared with 1% of patients receiving placebo.1 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.1

If asenapine therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.1

Seizures

Seizures occurred in 0 and 0.3% of adult patients with schizophrenia and bipolar mania receiving asenapine sublingual dosages of 5 and 10 mg twice daily, respectively, in premarketing short-term clinical trials.1 In adult premarketing clinical trials, including long-term trials without comparison to placebo, seizures were reported in 0.3% of patients treated with asenapine.1 There were no reports of seizures in asenapine-treated pediatric patients in a 3-week bipolar mania trial.1

As with other antipsychotic agents, asenapine should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold; such conditions may be more prevalent in patients 65 years of age or older.1

Cognitive and Motor Impairment

Somnolence, usually transient with the highest incidence reported during the first week of therapy, has been reported in patients receiving asenapine.1 In short-term, placebo-controlled schizophrenia trials in adults, somnolence was reported in 15 and 13% of patients receiving asenapine sublingual dosages of 5 mg and 10 mg twice daily, respectively, compared with 7% of placebo recipients.1 In short-term, placebo-controlled bipolar mania trials in adults, somnolence was reported in 23% of asenapine-treated patients (5-10 mg sublingually twice daily) compared with 5% of placebo recipients.1 In the 3-week, fixed-dose study, somnolence occurred in fewer patients receiving 5 mg of asenapine sublingually twice daily (20%) compared with those receiving 10 mg of the drug sublingually twice daily (26%).1 Somnolence was reported in 18% of asenapine-treated adults during premarketing clinical trials, including long-term trials without placebo comparison.1 Somnolence led to discontinuance of the drug in 0.6% of patients in short-term, placebo-controlled trials.1 In a 3-week, placebo-controlled bipolar trial in pediatric patients, somnolence (including sedation and hypersomnia) occurred in 46-53% of patients receiving 2.5-10 mg sublingually twice daily.1 (See Drug Interactions: Other CNS Agents and see also Advice to Patients.)

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to atypical antipsychotic agents.1 In premarketing, short-term, placebo-controlled trials for schizophrenia and acute bipolar I disorder, the incidence of adverse reactions suggestive of body temperature increases was low (1% or less) and comparable to placebo.1 During premarketing clinical trials with asenapine, including long-term trials without comparison to placebo, up to 1% of asenapine-treated patients experienced adverse effects suggestive of body temperature increases (e.g., pyrexia, feeling hot).1

The manufacturer recommends caution when asenapine is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Dysphagia has been reported in patients receiving asenapine.1 Asenapine and other antipsychotic agents should be used with caution in patients at risk for aspiration.1

Specific Populations

Pregnancy

Pregnancy registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy.1 For more information, clinicians may contact the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or visit [Web].1

Risk summary: Studies have not been conducted with asenapine in pregnant women.1 There are no available human data informing the drug-associated risk.1 Asenapine was not teratogenic in animal reproduction studies with IV administration to rats and rabbits during organogenesis at dosages 0.7 and 0.4 times, respectively, the maximum recommended human dosage (MRHD) of 10 mg sublingually twice daily.1 In a pre- and postnatal study in rats, IV administration of asenapine at dosages up to 0.7 times the MRHD produced increases in post-implantation loss and early pup deaths and decreases in subsequent pup survival and weight gain.1 The background risk of major birth defects and miscarriage for the indicated populations is unknown.1 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 and 15-20%, respectively.1 Pregnant women should be advised of the potential risk to the fetus with asenapine exposure.1

Fetal/neonatal adverse reactions: Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1,90,91,92 Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1,90,91,92 The symptoms have varied in severity; some neonates recovered within hours to days without specific treatment, while others have required prolonged hospitalization.1,90,91,92 Neonates should be monitored for extrapyramidal and/or withdrawal symptoms and managed appropriately if symptoms occur.1

Lactation

It is not known whether asenapine is distributed into milk in humans.1 The drug is distributed into milk in rats.1 The effects of asenapine on breast-fed infants and on milk production also are not known.1 The benefit of asenapine therapy to the woman as well as the benefits of breast-feeding to the infant should be weighed against the potential risk to the infant from exposure to the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of asenapine in pediatric patients younger than 10 years of age have not been established.1

Safety and efficacy of asenapine monotherapy for the management of bipolar I disorder in pediatric patients 10-17 years of age have been established in a double-blind, placebo-controlled trial of 3 weeks' duration.1,100 (See Bipolar Disorder under Uses.) In a phase I study, pediatric patients 10-17 years of age appeared to be more sensitive to dystonia when the initial dosage titration schedule was not followed.1 Similar safety findings were reported in a long-term, open-label, uncontrolled safety trial in pediatric patients with bipolar I disorder treated with asenapine monotherapy.1 To reduce the risk of dystonia in pediatric patients, asenapine should be titrated according to the manufacturer's recommended schedule.1 (See Bipolar Disorder under Dosage and Administration: Dosage.) Safety and efficacy of asenapine as adjunctive therapy for the treatment of bipolar disorder have not been established in pediatric patients to date.1

Efficacy of asenapine for the treatment of schizophrenia has not been established in pediatric patients younger than 18 years of age.1,97 In a short-term (i.e., 8 weeks' duration), double-blind, placebo-controlled trial in adolescents 12-17 years of age with schizophrenia, asenapine did not substantially improve the PANSS total score compared with placebo.1,97 Tolerability of asenapine in this trial generally was similar to that observed in pediatric bipolar and adult bipolar and schizophrenia trials.1,97 In addition, no important safety findings were reported in a 26-week, open-label, uncontrolled safety trial in pediatric patients with schizophrenia treated with asenapine monotherapy.1,97

Pharmacokinetics of asenapine in pediatric patients 10-17 years of age are similar to those observed in adults.1

Geriatric Use

Clinical trial experience with asenapine in patients with schizophrenia or bipolar mania who are 65 years of age and older is insufficient to determine whether they respond differently from younger adults.1 In premarketing clinical studies, 1.1% of approximately 2250 asenapine-treated patients were 65 years of age and older.1

Asenapine exposure is 30-40% higher in geriatric patients compared with younger adult patients.1 Routine dosage adjustment of asenapine is not necessary based on age alone.1 However, multiple factors that may increase the pharmacodynamic response to asenapine, resulting in poorer tolerance and orthostasis, could be present in geriatric patients, and such patients should be monitored carefully during therapy.1

Geriatric patients with dementia-related psychosis treated with asenapine are at an increased risk of death compared with those treated with placebo.1,39,73 In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1,28 The manufacturer of asenapine states that the drug is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions and see also Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions).1 For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Hepatic Impairment

In individuals with severe hepatic impairment (Child-Pugh class C), asenapine exposures were an average of 7 times higher than the exposures in individuals with normal hepatic function.1,95 Asenapine is therefore contraindicated in patients with severe hepatic impairment.1

Following a single 5-mg sublingual dose of asenapine in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, asenapine exposure was not substantially altered compared with that in individuals with normal hepatic function; therefore, dosage adjustment is not required in patients with mild or moderate hepatic impairment.1,95

Renal Impairment

The exposure of asenapine following a single 5-mg dose was similar in individuals with varying degrees of renal impairment and individuals with normal renal function; therefore, dosage adjustment is not required in renally impaired patients.1,95 The effect of renal impairment on the elimination of the drug's metabolites and the effect of dialysis on the pharmacokinetics of asenapine have not been evaluated.1

Common Adverse Effects

Adverse effects occurring in 5% or more of adult patients receiving sublingual asenapine therapy for acute treatment of schizophrenia and at a frequency at least twice that reported with placebo in short-term clinical trials include akathisia (including hyperkinesia),1,6,82,93 oral hypoesthesia,1,6,82 and somnolence (including sedation and hypersomnia).1,2,6,82,93 Akathisia was found to be dose related in these studies.1 The tolerability profile of asenapine in the maintenance treatment of schizophrenia in adults was similar to that seen with acute treatment.1,93

Adverse effects occurring in 5% or more of adult patients receiving sublingual asenapine therapy for acute monotherapy of manic or mixed episodes associated with bipolar I disorder and at a frequency at least twice that reported with placebo in short-term clinical trials include somnolence (including sedation and hypersomnia),1,3,5,6,74,83,94 oral hypoesthesia,1 dizziness,1,3,5,6,74,83 extrapyramidal symptoms other than akathisia (e.g., dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, tremor),1,3,6,83,94 and akathisia.1 The most common adverse effects reported during the adjunctive therapy trial in adults with bipolar 1 disorder were somnolence and oral hypoesthesia.1 The incidence of the most common adverse effects was lower at the 5-mg twice-daily dosage than at the 10-mg twice-daily dosage.1 The tolerability profile of asenapine in the maintenance treatment of manic or mixed episodes associated with bipolar 1 disorder in adults was similar to that seen with acute treatment.1

Adverse effects occurring in 5% or more of pediatric patients receiving sublingual asenapine therapy for acute monotherapy of manic or mixed episodes associated with bipolar I disorder and at a frequency at least twice that reported with placebo in short-term clinical trials include somnolence (including sedation and hypersomnia),1 dizziness,1 dysgeusia,1 oral hypoesthesia,1 nausea,1 increased appetite,1 fatigue,1 and weight gain.1 Frequency of fatigue was found to be dose related in the pediatric study.1

Asenapine is cleared mainly through direct glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) enzyme 1A4 and oxidative metabolism by cytochrome P-450 (CYP) isoenzymes, principally by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6.1,3,6,7

Asenapine is a weak inhibitor of CYP2D6; the drug does not induce CYP1A2 or CYP3A4.1,7

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions are possible when asenapine is used concomitantly with drugs that are both substrates and inhibitors of CYP2D6 (e.g., paroxetine) or that are inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine).1,7,98 Because of possible increased asenapine exposure with potent CYP1A2 inhibitors, asenapine dosage reduction based on clinical response may be necessary.1 (See Drug Interactions: Ciprofloxacin, Drug Interactions: Fluvoxamine, and Drug Interactions: Paroxetine.)

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); asenapine should be used with caution in patients concurrently receiving drugs with anticholinergic activity.1 (See Body Temperature Regulation under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation); concomitant use of asenapine and other drugs known to prolong the corrected QT (QT_c) interval, including class Ia antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine should be avoided.1,10,76,77,79 (See Prolongation of QT Interval under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hypotensive Agents and Drugs causing Bradycardia

Because of its α₁-adrenergic blocking activity and potential to cause hypotension, the manufacturer cautions that asenapine may enhance the hypotensive effects of certain antihypertensive agents and other drugs that can cause hypotension.1 Asenapine also has been associated with bradycardia.1 The manufacturer recommends that asenapine be used with caution in patients receiving other drugs that can cause hypotension or bradycardia, and that monitoring of orthostatic vital signs be considered in such patients.1

Monitoring of blood pressure is recommended during concurrent use of hypotensive agents and asenapine.1 If hypotension develops, dosage adjustment of hypotensive agents may be necessary.1 (See Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Advice to Patients.)

Other CNS Agents

Potential pharmacologic interaction (additive CNS depressant effects; increased fall risk).1 Asenapine should be used with caution in patients receiving other drugs that can produce CNS or respiratory depression.1

Carbamazepine

Concomitant administration of carbamazepine, a CYP3A4 inducer, and asenapine slightly decreased both peak plasma concentrations and the area under the plasma concentration-time curve (AUC) of asenapine in healthy individuals.1,7 Asenapine dosage adjustment is not required in patients receiving these drugs concurrently.1,7

Cimetidine

Concomitant administration of cimetidine, an inhibitor of CYP3A4, CYP2D6, and CYP1A2, and asenapine slightly decreased peak plasma asenapine concentrations and very slightly increased the drug's AUC.1,7 Asenapine dosage adjustment is not necessary in patients concurrently receiving cimetidine.1,7

Ciprofloxacin

An acute dystonic reaction was reported in an asenapine-treated patient after ciprofloxacin, a CYP1A2 inhibitor, was initiated.98 Because of the risk of increased asenapine exposure,1,98 a reduced dosage of asenapine based on clinical response may be necessary during concurrent use.1

Fluvoxamine

Concomitant administration of fluvoxamine, a potent CYP1A2 inhibitor, at a dosage of 25 mg twice daily and asenapine slightly increased peak plasma asenapine concentrations and AUCs.1,7 The manufacturer states that the full therapeutic dosage of fluvoxamine would be expected to cause a greater increase in plasma concentrations of asenapine, and that a dosage reduction of asenapine may be necessary based on clinical response during concurrent use.1

Imipramine

Concomitant administration of imipramine, an inhibitor of CYP1A2, CYP2C19, and CYP3A4, and asenapine slightly increased peak plasma asenapine concentrations and AUCs.1 Asenapine did not affect plasma concentrations of imipramine's metabolite, desipramine, which is a CYP2D6 substrate.1,7 Asenapine dosage adjustment is not required in patients concurrently receiving imipramine.1

Lithium

In a population pharmacokinetic analysis, concurrent administration of lithium did not affect the pharmacokinetics of asenapine.1 In addition, pre-dose serum concentrations of lithium collected during an adjunctive therapy study were comparable between patients receiving asenapine and those receiving placebo, indicating that asenapine does not affect serum concentrations of lithium.1 Asenapine dosage adjustment is not required in patients concurrently receiving lithium.1

Paroxetine

Concomitant administration of paroxetine, which is both a CYP2D6 substrate and inhibitor, and asenapine resulted in a twofold increase in peak plasma concentrations and exposure of paroxetine.1,7 Concomitant administration of paroxetine and asenapine slightly decreased peak plasma asenapine concentrations and AUCs.1,7 The manufacturer states that asenapine may increase the inhibitory effects of paroxetine on its own metabolism by CYP2D6.1 Paroxetine dosage should be reduced by one-half during concurrent administration of asenapine; asenapine dosage adjustment is not required.1

Valproate

Pre-dose serum concentrations of valproate collected during an adjunctive therapy study were comparable between patients receiving asenapine and those receiving placebo, indicating that asenapine does not affect plasma concentrations of valproate.1 Concomitant administration of valproate and asenapine slightly increased peak plasma asenapine concentrations and slightly decreased the drug's AUC; asenapine dosage adjustment is not required in patients receiving valproate concurrently.1

Smoking

In a population pharmacokinetic analysis, smoking had no effect on asenapine exposure in smokers.1 Dosage adjustment of asenapine is therefore not necessary based on smoking status.1

Description

Asenapine is a dibenzo-oxepino pyrrole-derivative antipsychotic agent and has been referred to as an atypical or second-generation antipsychotic agent.1,6,8,28,74 Although the exact mechanism of action of asenapine in schizophrenia and bipolar disorder is unknown, it has been suggested that the efficacy of asenapine in schizophrenia may be mediated through a combination of antagonist activity at central dopamine type 2 (D₂) and serotonin type 2 (5-hydroxytryptamine [5-HT_2A]) receptors.1,2,6,7,8,89

Asenapine exhibits high affinity for serotonin 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT_5A, 5-HT₆, and 5-HT₇ receptors; dopamine D₁, D_2A, D_2B, D₃, and D₄ receptors; α_1A-, α_2A-, α_2B-, and α_2C-adrenergic receptors; and histamine H₁ receptors (moderate affinity for H₂ receptors).1,2,3,6,7,8,9,74,85 Asenapine acts as an antagonist at these receptors in vitro.1,85 Asenapine possesses no appreciable affinity for muscarinic cholinergic receptors;1,2,3,6,7,8,9,74,85 the drug also does not exhibit affinity for β-adrenergic receptors.7

Asenapine is administered sublingually because of the low bioavailability (less than 2%) and extensive first-pass metabolism observed following oral administration.1,4,6,74 Sublingual tablets of the drug are rapidly absorbed in the sublingual, supralingual, and buccal mucosa following sublingual administration,1,3,6,10,74 with peak plasma concentrations occurring within 0.5-1.5 hours.1 The absolute bioavailability of sublingual asenapine (5 mg) is 35%.1,74 Steady-state plasma concentrations are reached within 3 days with twice-daily sublingual administration.1 Asenapine appears to undergo extensive extravascular distribution and is 95% bound to plasma proteins (including albumin and α₁-acid glycoprotein).1 The drug is cleared mainly through direct glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) enzyme 1A4 and oxidative metabolism by cytochrome P-450 (CYP) isoenzymes, principally by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6 in vitro.1,3,6,7 The mean terminal half-life of the drug is approximately 24 hours.1,74 Following administration of a single radiolabeled dose of asenapine, approximately 50 and 40% of the dose was excreted in urine and feces, respectively.1

Advice to Patients

Importance of advising patients and caregivers that elderly patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1,28,39,73 Patients and caregivers also should be informed that asenapine is not approved for treating elderly patients with dementia-related psychosis.1,73

Risk of serious allergic reactions.1,96 Importance of informing patients of the signs and symptoms of such reactions (e.g., difficulty breathing; swelling of the face, tongue, or throat; lightheadedness; itching) and to immediately seek emergency medical attention if they develop any of these signs and symptoms.1,96

Importance of informing patients that application site reactions, primarily in the sublingual area, have been reported with asenapine, including oral ulcers, blisters, peeling/sloughing, and inflammation.1 Patients should be instructed to monitor for such reactions during therapy.1

Because somnolence (i.e., sleepiness, drowsiness) may be associated with asenapine, patients should be cautioned about performing activities requiring mental alertness, such as driving or operating hazardous machinery, while taking asenapine until they gain experience with the drug's effects.1

Importance of informing patients and caregivers about the risk of a rare but life-threatening nervous system problem called neuroleptic malignant syndrome (NMS), which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in blood pressure, confusion, and kidney damage.1

Importance of informing patients about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain), how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring for such changes, including blood glucose, lipids, and weight, during therapy.1

Risk of orthostatic hypotension and syncope (fainting), especially when initiating or reinitiating treatment or increasing the dosage.1 Importance of informing patients about interventions that may help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning, slowly rising from a seated position).1

Risk of leukopenia/neutropenia.1 Importance of advising patients with a pre-existing low leukocyte count or a history of drug-induced leukopenia/neutropenia that they should have their complete blood cell (CBC) count monitored during asenapine therapy.1

Importance of clinicians informing patients in whom chronic asenapine use is contemplated about the risk of a movement problem called tardive dyskinesia.1,67 Importance of informing patients to report any muscle movements that cannot be stopped to a healthcare professional.67

Importance of informing patients that oral hypoesthesia, oral paresthesia, and/or dysgeusia (abnormal or altered taste) may occur with asenapine therapy and that these effects are not serious and are typically transient (i.e., resolving within 1 hour) following sublingual administration of the drug.1,74,81,88

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (see Drug Interactions) and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,92 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy, including that third trimester use of asenapine may cause extrapyramidal and/or withdrawal symptoms in a neonate, and about the pregnancy exposure registry (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1,92 Importance of advising patients not to stop taking asenapine if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications.92

Importance of avoiding overheating or dehydration.1

Importance of not removing a sublingual tablet from the blister pack until just before administering a dose; importance of pulling blister pack out of the case with dry hands and then peeling back the colored tab on the pack and gently removing the sublingual tablet.1 The sublingual tablet should then be placed under the tongue and allowed to dissolve completely.1 Importance of not eating or drinking for 10 minutes following administration.1,74 Importance of sliding the blister pack back into the case until it clicks after use.1 (See Dosage and Administration: Administration.)

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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