Asenapine (Monograph)

Brand name: Saphris
Drug class: Atypical Antipsychotics
VA class: CN709
Chemical name: (3aRS,12bRS)-5-Chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1)
Molecular formula: C₁₇H₁₆ClNO•C₄H₄O₄
CAS number: 85650-56-2

Medically reviewed by Drugs.com on Nov 3, 2023. Written by ASHP.

Introduction

Dibenzo-oxepino pyrrole derivative; atypical or second-generation antipsychotic agent.^{1 4 6 8 28 74 85}

Uses for Asenapine

Schizophrenia

Acute and maintenance treatment of schizophrenia in adults.^{1 2 4 82 84 88 89 93}

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).²⁸

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}

Bipolar Disorder

Acute treatment as monotherapy or adjunctive therapy with lithium or valproate of manic or mixed episodes associated with bipolar I disorder (with or without psychotic features).^{1 3 5 74 94 99 100}

Maintenance treatment as monotherapy of bipolar I disorder.^{1 5 86}

Asenapine Dosage and Administration

Administration

Sublingual Administration

Administer tablets sublingually twice daily.¹

Do not remove sublingual tablet from blister pack until just prior to administration.¹ With dry hands, pull blister pack out of case and peel back colored tab to expose the tablet; do not push tablet through blister pack.¹ Gently remove tablet and place under the tongue, then allow to dissolve completely (usually takes about 10 seconds).^{1 6}

Do not eat or drink for 10 minutes following administration.^{1 74} Do not split, crush, chew, or swallow the sublingual tablets.¹ (See Food and Water under Pharmacokinetics.)

Dosage

Available as asenapine maleate; dosage expressed in terms of asenapine.^{1 4 81}

Pediatric Patients

Bipolar Disorder

Manic and Mixed Episodes: Monotherapy

Sublingual

Children and adolescents 10–17 years of age: Initially, 2.5 mg twice daily.¹ Recommended target dosage is 2.5–10 mg twice daily.¹ Based on individual patient response and tolerability, may increase to 5 mg twice daily after 3 days and then to 10 mg twice daily after 3 additional days.¹ Carefully titrate dosage to reduce risk of dystonia.¹ (See Pediatric Use under Cautions.) Safety of dosages >10 mg twice daily not evaluated.¹

Adults

Schizophrenia

Sublingual

For acute treatment, recommended initial and target dosage is 5 mg twice daily.¹ May increase to 10 mg twice daily after 1 week based on tolerability.¹ The higher dosage (10 mg twice daily) did not provide additional therapeutic benefit in clinical trials, but was clearly associated with increased adverse effects.^{1 82} Safety of dosages >10 mg twice daily not evaluated.¹

For maintenance treatment, recommended target dosage range is 5–10 mg twice daily.¹

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.²⁸ Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.²⁸ Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.²⁸

Bipolar Disorder

Manic and Mixed Episodes: Monotherapy or Combination Therapy

Sublingual

Monotherapy for acute treatment: Initial and target dosage is 5–10 mg twice daily.^{1 3 83} Safety of dosages >10 mg twice daily not evaluated.¹

Adjunctive therapy with lithium or valproate for acute treatment: Initially, 5 mg twice daily.¹ May increase dosage to 10 mg twice daily based on clinical response and tolerability.¹ Safety of dosages >10 mg twice daily not evaluated.¹

In responsive patients, continue drug therapy beyond the acute response.¹

Monotherapy for maintenance treatment: Continue same dosage used during stabilization (5–10 mg twice daily).¹ Based on clinical response and tolerability, may decrease 10-mg twice-daily dosage to 5 mg twice daily.¹ Safety of dosages >10 mg twice daily not evaluated.¹

Prescribing Limits

Pediatric Patients

Bipolar Disorder

Manic and Mixed Episodes

Sublingual

Safety of dosages >10 mg twice daily not evaluated.¹

Adults

Schizophrenia

Sublingual

Safety of dosages >10 mg twice daily not evaluated.¹

Bipolar Disorder

Manic and Mixed Episodes

Sublingual

Safety of dosages >10 mg twice daily not evaluated.¹

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Use is contraindicated.^{1 7 95}

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.^{1 7 95} (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Routine dosage adjustment not required.^{1 7 95} (See Absorption: Special Populations, under Pharmacokinetics and also see Elimination: Special Populations, under Pharmacokinetics.)

Geriatric Patients

Routine dosage adjustment not required.¹ (See Geriatric Use under Cautions and also see Absorption: Special Populations, under Pharmacokinetics.)

Gender, Race, or Smoking Status

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

Cautions for Asenapine

Contraindications

• Severe hepatic impairment (Child-Pugh class C).¹

• Known hypersensitivity to asenapine maleate or any components in the formulation.^{1 96} (See Hypersensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of antipsychotic agents in geriatric patients with dementia-related psychosis.^{1 28 39 73 75}

Analyses of 17 dementia-related psychosis placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.^{1 73}

Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{1 73}

Antipsychotic agents, including asenapine, are not approved for the treatment of dementia-related psychosis.^{1 39 73} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning; Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions; and also see Dysphagia under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions reported with asenapine.^{1 96} Symptoms included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash.^{1 96} Some cases reported occurrence of more than one hypersensitivity reaction, and several reported hypersensitivity reactions occurring after the first dose.^{1 96} In some patients, symptoms resolved after asenapine discontinuance; others required hospitalization or emergency room visits and therapeutic interventions.⁹⁶ (See Contraindications under Cautions and also see Advice to Patients.)

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.^{1 28} Asenapine is not approved for the treatment of patients with dementia-related psychosis.¹ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex characterized by hyperpyrexia, muscle rigidity, delirium, and autonomic instability, reported with antipsychotic agents,¹ including asenapine.⁹⁴

If NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring.¹

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including asenapine.^{1 84}

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate.¹ In patients requiring chronic treatment, use lowest dosage and shortest duration of treatment needed to achieve a satisfactory clinical response; periodically reassess need for continued therapy.¹

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.²⁸ Consider discontinuance of asenapine if signs and symptoms of tardive dyskinesia appear.¹ However, some patients may require treatment despite the presence of the syndrome.¹

Metabolic Changes

Atypical antipsychotic agents, including asenapine, have caused metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain.¹ While all atypical antipsychotics 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 Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, 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 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.¹

Assess blood glucose before or soon after initiation of antipsychotic therapy, then periodically monitor during long-term therapy.¹ (See Advice to Patients.)

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with some atypical antipsychotics.¹ However, asenapine does not substantially affect the lipid profile during short-term therapy.¹

Baseline (i.e., before or soon after initiation of therapy) and periodic follow-up fasting lipid evaluations recommended during asenapine therapy.¹

Weight Gain

Weight gain observed with atypical antipsychotic therapy, including asenapine.^{1 84 93}

Manufacturer recommends baseline and frequent monitoring of weight during therapy.¹ In pediatric patients, monitor weight gain and assess against that expected for normal growth.¹

Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects

Risk of orthostatic hypotension and syncope reported with atypical antipsychotics, particularly during initial dosage titration and when dosage is increased.¹

In clinical trials in adults, including long-term trials without comparison with placebo, syncope was reported in 0.6% of asenapine-treated patients.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.¹

Monitor orthostatic vital signs in patients 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 MI, ischemic heart disease, heart failure, conduction abnormalities), and patients with cerebrovascular disease.¹ Use with caution in patients receiving other drugs that can cause hypotension, bradycardia, respiratory depression, or CNS depression (see Interactions).¹ In all such patients, consider monitoring of orthostatic vital signs; if hypotension occurs, consider dosage reduction.¹

Falls

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.¹

In patients with diseases, conditions, or other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.¹

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia temporally related to antipsychotic agents, including asenapine, reported during clinical trial and/or postmarketing experience.^{1 78} Agranulocytosis (including fatal cases) also reported with other antipsychotic agents.¹

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count or ANC or a history of drug-induced leukopenia or neutropenia.^{1 78} Monitor CBC during the first few months of therapy in patients with such risk factors.¹ Discontinue asenapine at the first sign of a clinically important decline in WBC count in the absence of other causative factors.¹

Carefully monitor patients with clinically important neutropenia for fever or other signs and symptoms of infection (e.g., fever) and treat promptly if they occur.¹ Discontinue asenapine if severe neutropenia (ANC <1000/mm³) occurs; monitor WBC until recovery occurs.¹

Prolongation of QT Interval

Relatively small increases (2–5 msec with asenapine compared with placebo) in corrected QT (QT_c) interval observed in adults with schizophrenia in a controlled and dedicated QT study; these increases were slightly lower than those observed in patients receiving quetiapine.^{1 6 10} During clinical trials, post-baseline QT-interval prolongations >500 msec reported at similar rates for asenapine and placebo; torsades de pointes or adverse effects associated with delayed ventricular repolarization not reported.¹

Avoid use in patients concurrently receiving other drugs known to prolong the QT_c interval, in patients with a history of cardiac arrhythmias, and in other circumstances that may increase risk of torsades de pointes and/or sudden death (e.g., bradycardia, hypokalemia or hypomagnesemia, presence of congenital QT-interval prolongation).¹ (See Drugs that Prolong QT Interval under Interactions.)

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence); chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both females and males.¹

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

Seizures

Seizures reported in 0.3% of asenapine-treated adult patients in schizophrenia and bipolar mania clinical trials.¹ No seizures reported in pediatric patients in a short-term bipolar mania trial.¹

Use with caution in patients with a history of seizures or conditions that may lower seizure threshold; such conditions may be more prevalent in patients ≥65 years of age.¹

Cognitive and Motor Impairment

Somnolence, usually transient and with the highest incidence during the first week of therapy, reported in 13–26% of adult patients and 46–53% of pediatric patients receiving asenapine in clinical trials.¹ (See Specific Drugs under Interactions and also see Advice to Patients.)

Body Temperature Regulation

Disruption of ability to regulate core body temperature possible with atypical antipsychotic agents, including asenapine; ≤1% of asenapine-treated patients in premarketing clinical trials experienced adverse effects suggestive of body temperature increases (e.g., pyrexia, feeling hot).¹

Use caution 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 associated with the use of antipsychotic agents.¹ Dysphagia reported with asenapine.¹ Use with caution in patients at risk for aspiration.¹

Specific Populations

Pregnancy

No studies conducted to date in pregnant women.¹ No available human data informing the drug-associated risk.¹ In animal reproduction studies, asenapine was not teratogenic at dosages 0.7 and 0.4 times, respectively, the maximum recommended human dosage (MRHD).¹ In animals, the drug increased post-implantation loss and early pup deaths and decreased subsequent pup survival and weight gain.¹ Advise pregnant women of potential risk to the fetus with asenapine exposure.¹

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester.^{1 90 91 92} Symptoms have varied in severity; some infants recovered within hours to days without specific treatment while others required prolonged hospitalization.^{1 90 91 92} Monitor neonates for extrapyramidal and/or withdrawal symptoms; if such symptoms occur, manage appropriately.¹

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].¹

Lactation

Asenapine distributes into milk in rats; not known whether distributes into human milk.¹ Effects of the drug on nursing infants and on milk production also not known.¹

Weigh benefit of asenapine therapy to the woman and benefits of breast-feeding against potential risk to infant from exposure to the drug or from the underlying maternal condition.¹

Pediatric Use

Safety and efficacy not evaluated in pediatric patients <10 years of age.¹

Safety and efficacy of asenapine monotherapy for treatment of bipolar I disorder in pediatric patients 10–17 years of age established.^{1 100} Such patients appear to be more sensitive to dystonia if initial dosage titration schedule not followed; titrate dosage according to manufacturer's recommended schedule (see Dosage under Dosage and Administration).¹ Safety and efficacy as adjunctive therapy for the treatment of bipolar disorder not established in pediatric patients to date.¹ (See Elimination: Special Populations, under Pharmacokinetics.)

Efficacy for the treatment of schizophrenia not established in pediatric patients <18 years of age.^{1 97} In a short-term (i.e., 8 weeks' duration), placebo-controlled trial in adolescents 12–17 years of age with schizophrenia, asenapine (2.5 or 5 mg twice daily) 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 the pediatric bipolar and adult bipolar and schizophrenia trials.^{1 97} In addition, no important safety findings reported in a 26-week, open-label, uncontrolled safety trial in pediatric patients with schizophrenia.^{1 97}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹ Risk of poorer tolerance and orthostasis; carefully monitor.¹ (See Geriatric Patients under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death;^{1 28 39 73 75} increased incidence of adverse cerebrovascular events also observed with certain atypical antipsychotic agents.^{1 74} Asenapine is not approved for the treatment of patients with dementia-related psychosis.¹ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Substantially higher exposures observed in individuals with severe hepatic impairment (Child-Pugh class C).^{1 95} Use is therefore contraindicated in such patients.^{1 95} (See Absorption: Special Populations, under Pharmacokinetics.)

Exposure is not substantially altered in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment; dosage adjustment is therefore not necessary in such patients.^{1 95}

Renal Impairment

Exposure was similar in individuals with varying degrees of renal impairment and those with normal renal function; dosage adjustment not required.^{1 95} (See Absorption: Special Populations, under Pharmacokinetics and also see Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Adults with schizophrenia (acute treatment): Akathisia (including hyperkinesia),^{1 6 82 93} oral hypoesthesia,^{1 6 82} somnolence (including sedation and hypersomnia).^{1 2 6 82 93} Akathisia appears to be dose related.¹ Tolerability profile in the maintenance treatment of schizophrenia was similar to that seen with acute treatment.^{1 93}

Adults with bipolar disorder (acute treatment; monotherapy or adjunctive therapy): 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} akathisia.¹ All common adverse effects appear to be dose related.¹ Tolerability profile in the maintenance treatment of manic or mixed episodes associated with bipolar 1 disorder was similar to that seen with acute treatment.¹

Pediatric patients with bipolar disorder (acute treatment; monotherapy): Somnolence (including sedation and hypersomnia),¹ dizziness,¹ dysgeusia,¹ oral hypoesthesia,¹ nausea,¹ increased appetite,¹ fatigue,¹ weight gain.¹ Frequency of fatigue appears to be dose related.¹

Drug Interactions

Metabolized mainly by direct glucuronidation by UGT1A4 and oxidative metabolism by CYP isoenzymes, principally by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6.^{1 3 6 7} Weakly inhibits CYP2D6; does not appear to induce CYP1A2 or CYP3A4.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drugs that are both substrates and inhibitors of CYP2D6: Clinically important pharmacokinetic interactions possible.^{1 7} (See Specific Drugs under Interactions.)

Potent CYP1A2 inhibitors: Possible increased asenapine exposure; dosage reduction of asenapine based on clinical response may be necessary.^{1 98}

Drugs that Prolong QT Interval

Potential additive effect on QT-interval prolongation; avoid concomitant use of other drugs known to prolong QT_c interval.^{1 10 76 77 79} (See Prolongation of QT Interval under Cautions.)

Hypotensive Agents and Drugs causing Bradycardia

May enhance hypotensive effects of certain antihypertensive agents and other drugs that can cause hypotension or bradycardia.¹ Use concomitantly with caution; consider monitoring orthostatic vital signs during concurrent use.¹ (See Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects under Cautions and also see Specific Drugs under Interactions.)

Monitor BP during concurrent use of hypotensive agents.¹ If hypotension develops, consider reducing dosage of asenapine.¹ Adjust dosage of hypotensive agents, if necessary, based on BP.¹ (See Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects under Cautions and also see Advice to Patients.)

Specific Drugs

Asenapine Pharmacokinetics

Absorption

Bioavailability

Administered sublingually because of the low bioavailability (<2%) and extensive first-pass metabolism observed following oral administration of tablets.^{1 4 6 74}

Rapidly absorbed in the sublingual, supralingual, and buccal mucosa following sublingual administration; peak plasma concentrations occur within 0.5–1.5 hours.^{1 3 6 10 74}

Absolute bioavailability of sublingual tablets (5 mg) is 35%.^{1 3 74}

Steady-state plasma concentrations reached within 3 days with twice-daily administration.¹

Food and Water

Food ingestion immediately before or 4 hours after sublingual administration of a single 5-mg dose in adults decreased exposure by 20 or 10%, respectively, probably due to increased hepatic blood flow.¹

Water intake 2 and 5 minutes following sublingual administration of asenapine 10 mg in adults decreased exposure by 19 and 10%, respectively; effects of water intake 10 or 30 minutes after administration were equivalent.¹ (See Administration under Dosage and Administration.)

Special Populations

Smoking does not affect exposure.¹

In individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure was similar to those with normal hepatic function.¹ In individuals with severe hepatic impairment (Child-Pugh class C), exposures were an average of 7 times higher compared with individuals with normal hepatic function.^{1 95}

In individuals with varying degrees of renal impairment, exposure of asenapine was similar to individuals with normal renal function.^{1 95}

In geriatric patients, exposure was 30–40% higher compared with younger adult patients.¹

Distribution

Extent

Rapidly distributed; large volume of distribution indicates extensive extravascular distribution.^{1 74}

Distributes into milk in rats; not known whether asenapine and/or its metabolites distribute into milk in humans.¹

Plasma Protein Binding

95% to plasma proteins (including albumin and α₁-acid glycoprotein).^{1 74}

Elimination

Metabolism

Metabolized mainly through direct glucuronidation by UGT1A4 and oxidative metabolism, primarily by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6.^{1 3 6 7}

Metabolites (primarily asenapine N-glucuronide, also N-desmethylasenapine and N-desmethylasenapine N-carbamoyl glucuronide) are largely inactive.^{1 3 7}

Elimination Route

Following administration of a single radiolabeled dose, about 90% of the dose was recovered; approximately 50% recovered in urine and 40% in feces.¹

Half-life

Terminal phase half-life (t_½β) averages about 24 hours.^{1 74}

Special Populations

Effect of renal function on elimination of metabolites and effect of hemodialysis on pharmacokinetics not evaluated.¹

Pharmacokinetics in pediatric patients 10–17 years of age generally similar to those in adults.¹

Stability

Storage

Sublingual

Tablets

20–25°C (may be exposed to 15–30°C).¹

Actions

• Exact mechanism of asenapine in schizophrenia and bipolar disorder unknown; efficacy 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}

• 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}

• Possesses no appreciable affinity for muscarinic cholinergic receptors^{1 2 3 6 7 8 9 74 85} or β-adrenergic receptors.⁷

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 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.^{1 96}

• Importance of informing patients that application site reactions (e.g., oral ulcers, blisters, peeling/sloughing, inflammation), primarily in the sublingual area, have been reported.¹ Instruct patients to monitor for such reactions during therapy.¹

• Risk of somnolence (i.e., sleepiness, drowsiness).¹ Importance of advising patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they gain experience with the drug’s effects.¹

• Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, and confusion.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 (e.g., sitting on the edge of the bed for several minutes before standing in the morning, slowly rising from a seated position).¹

• Risk of leukopenia/neutropenia.¹ Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during asenapine therapy.¹

• Importance of informing patients in whom chronic asenapine use is contemplated of risk of tardive dyskinesia.^{1 67} Importance of advising 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 and that these effects are not serious and are typically transient (i.e., resolving within 1 hour) following sublingual administration.^{1 74 81 88}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription 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 neonates) and about the pregnancy exposure registry (see Pregnancy under 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 correctly taking sublingual tablets.¹ Do not remove sublingual tablet from the blister pack until just before administration.¹ With dry hands, pull blister pack out of case, peel back the colored tab on the pack, and gently remove the tablet.¹ Place the sublingual tablet under the tongue and allow to dissolve completely.¹ Importance of sliding the blister pack back into the case until it clicks after use.¹ Importance of not eating or drinking for 10 minutes following administration.^{1 74} (See Food and Water under Pharmacokinetics.)

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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