Asenapine (Monograph)

Brand name: Saphris; Secuado
Drug class: Atypical Antipsychotics

Medically reviewed by Drugs.com on Apr 10, 2025. Written by ASHP.

Introduction

Dibenzo-oxepino pyrrole derivative; atypical antipsychotic agent.^{1 101}

Uses for Asenapine

Schizophrenia

Used sublingually and transdermally for treatment of schizophrenia in adults.^{1 2 82 84 93 101 102}

American Psychiatric Association (APA) and Department of Veterans Affairs/Department of Defense recommend antipsychotic agents for acute and long-term maintenance treatment of schizophrenia.^{107 108} Choice of antipsychotic agent should be based on patient preference, past response to therapy, concurrent medical conditions, and drug-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).^{107 108}

Bipolar Disorder

Sublingual tablets used as monotherapy for acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and pediatric patients 10–17 years of age.^{1 3 5 83 99 100}

Sublingual tablets also used as adjunctive therapy with lithium or valproate in adults.¹

Sublingual tablets used for maintenance monotherapy in adults with bipolar I disorder.^{1 5 86 103}

APA recommends lithium or valproate plus an antipsychotic agent for first-line treatment of severe manic or mixed episodes; for patients with less severe symptoms, monotherapy with lithium, valproate, or an antipsychotic agent may be appropriate.¹⁰⁹ Selection of a specific treatment is based on clinical factors (e.g., illness severity, associated features, patient preference, adverse effect profile of the medication).¹⁰⁹ Recommended agents for maintenance treatment include lithium and valproate.¹⁰⁹ Role of asenapine not addressed.¹⁰⁹

Department of Veterans Affairs/Department of Defense recommends lithium or quetiapine monotherapy for first-line treatment of acute mania associated with bipolar disorder; recommended alternative agents include olanzapine, paliperidone, or risperidone.¹¹⁰ If none of these agents are suitable based on patient preference or characteristics, other alternatives include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.¹¹⁰ In patients with breakthrough episodes or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic (haloperidol, asenapine, quetiapine, olanzapine, or risperidone) recommended.¹¹⁰ Recommended agents for maintenance therapy include lithium and quetiapine; alternatives include olanzapine, paliperidone, or risperidone.¹¹⁰

Asenapine Dosage and Administration

General

Pretreatment Screening

• Assess fasting plasma glucose before or soon after initiation of asenapine.^{1 101}

• Obtain a fasting lipid profile at baseline before or soon after initiation of asenapine.^{1 101}

• Monitor weight at baseline.^{1 101}

• Complete fall risk assessment when initiating asenapine in patients with diseases, conditions, or medications that could exacerbate risk for falls.^{1 101}

Patient Monitoring

• Monitor fasting plasma glucose periodically during long-term treatment.^{1 101}

• Assess fasting lipid profile periodically during treatment.^{1 101}

• Monitor weight frequently during therapy.^{1 101} When treating pediatric patients with sublingual asenapine, monitor weight gain and assess against that expected for normal growth.¹

• Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with cardiovascular disease, and patients with cerebrovascular disease.^{1 101} Consider monitoring orthostatic vital signs in patients who receive treatment with other drugs that can induce hypotension, bradycardia, or respiratory or CNS depression.^{1 101}

• Complete fall risk assessments periodically during long-term therapy in patients with diseases, conditions, or medications that could exacerbate risk for falls.^{1 101}

• Perform a CBC during the first few months of therapy in patients with pre-existing low WBC or absolute neutrophil count or a history of drug-induced leukopenia or neutropenia.^{1 101}

• Monitor patients with clinically important neutropenia for fever or other symptoms or signs of infection; treat promptly if such symptoms or signs occur.^{1 101}

Administration

Commercially available as rapidly dissolving sublingual tablets or as a transdermal system (patch).^{1 101}

Sublingual Administration

Asenapine maleate is commercially available as rapidly dissolving sublingual tablets containing 2.5 mg, 5 mg, or 10 mg of the drug.¹

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 (will dissolve in saliva within seconds).¹

Do not eat or drink for 10 minutes following administration.¹ Do not split, crush, chew, or swallow the sublingual tablets.¹ Refer to the prescribing information for full instructions for use.¹

Transdermal Administration

Asenapine is commercially available as a transdermal system (patch) containing 3.8 mg/24 hours, 5.7 mg/24 hours, or 7.6 mg/24 hours.¹⁰¹

Apply the transdermal system (patch) once daily; each patch should only be worn for 24 hours.¹⁰¹ Wear only one patch at any time.¹⁰¹

Apply patch to clean, dry, and intact skin at selected application site (i.e., upper arm, upper back, abdomen, or hip).¹⁰¹ Change (rotate) application sites each time a new patch is applied.¹⁰¹

Do not cut open the pouch until ready to apply the patch; do not use patch if the individual pouch seal is broken or damaged.¹⁰¹

Do not cut the patch.¹⁰¹

If the patch lifts at the edges, reattach it by pressing firmly and smoothing down the edges of the system.¹⁰¹ If the patch comes off completely, apply a new patch.¹⁰¹

To discard, fold the used patch so that the adhesive side sticks to itself, then place in trash immediately.¹⁰¹

If irritation or burning sensation occurs while wearing the patch, remove it and apply a new patch to a new application site.¹⁰¹

Avoid swimming or bathing while wearing the patch; showering is permitted.¹⁰¹

Do not apply external heat sources (e.g., heating pad) over patch. ¹⁰¹

Refer to the prescribing information for full instructions for use.¹⁰¹

Dosage

Sublingual tablets available as asenapine maleate; dosage expressed in terms of asenapine.¹

Based on AUC, the 3.8 mg/24 hours transdermal system corresponds to 5 mg twice daily of sublingual asenapine and the 7.6 mg/24 hours transdermal system corresponds to 10 mg twice daily of sublingual asenapine.¹⁰¹

Pediatric Patients

Bipolar Disorder

Sublingual

Pediatric patients 10–17 years of age: For acute treatment of manic or mixed episodes, recommended dosage is 2.5–10 mg twice daily.¹ Starting dosage is 2.5 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 (according to manufacturer's recommended titration schedule) to reduce risk of dystonia.¹

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

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

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

Transdermal

Initiate at 3.8 mg/24 hours.¹⁰¹ May increase to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week.¹⁰¹ Higher dosage (7.6 mg/24 hours) did not provide additional therapeutic benefit in clinical trial, but was associated with increased adverse effects.¹⁰¹

Safety of dosages >7.6 mg/24 hours not evaluated.¹⁰¹

Bipolar Disorder

Sublingual

Monotherapy for acute treatment of manic and mixed episodes: Initial and target dosage is 5–10 mg twice daily.¹ Safety of dosages >10 mg twice daily not evaluated.¹

Adjunctive therapy with lithium or valproate for acute treatment of manic and mixed episodes: 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

Maintenance treatment of manic and mixed episodes: Continue same dosage used during stabilization (5–10 mg twice daily) as monotherapy.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

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Use is contraindicated.^{1 101}

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.^{1 101}

Renal Impairment

Dosage adjustment not required in patients with renal impairment (mild to severe impairment; GFR 15–90 mL/minute).^{1 101}

Geriatric Patients

Dosage adjustment not required based on age alone.^{1 101}

Cautions for Asenapine

Contraindications

• Severe hepatic impairment (Child-Pugh class C).^{1 101}

• Known hypersensitivity to asenapine or any component of the transdermal system.^{1 101} Anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash reported.^{1 101}

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.^{1 101} (See Boxed Warning.) Most fatalities reported appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (e.g., pneumonia).^{1 101} Asenapine is not approved for the treatment of dementia-related psychosis.^{1 101}

Other Warnings and Precautions

Adverse Cerebrovascular Events, Including Stroke, 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).^{1 101} Asenapine is not approved for the treatment of patients with dementia-related psychosis.^{1 101}

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.^{1 101} Additional signs of NMS may include elevated CPK, myoglobinuria (rhabdomyolysis), and acute renal failure.^{1 101}

If NMS suspected, immediately discontinue asenapine and provide intensive symptomatic treatment and monitoring.^{1 101}

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including asenapine.^{1 101}

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.^{1 101} 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.^{1 101}

Consider discontinuance of asenapine if signs and symptoms of tardive dyskinesia appear.^{1 101} However, some patients may require treatment despite the presence of the syndrome.^{1 101}

Metabolic Changes

Atypical antipsychotic agents, including asenapine, have caused metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain.^{1 101} While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.^{1 101}

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.^{1 101} Hyperglycemia reported in patients treated with sublingual asenapine.^{1 101}

Assess fasting blood glucose before or soon after initiation of antipsychotic therapy, then periodically monitor during long-term therapy.^{1 101}

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with some atypical antipsychotic agents.^{1 101} However, asenapine generally does not substantially affect the lipid profile during short-term therapy.^{1 101}

Baseline (i.e., before or soon after initiation of therapy) and periodic follow-up fasting lipid evaluations recommended during asenapine therapy.^{1 101}

Weight Gain

Weight gain observed with atypical antipsychotic therapy, including asenapine.^{1 101}

Baseline and frequent monitoring of weight during therapy recommended.^{1 101} In pediatric patients, monitor weight gain and assess against that expected for normal growth.¹

Hypersensitivity Reactions

Hypersensitivity reactions reported with sublingual and transdermal asenapine; in several cases, reactions occurred after the first dose.^{1 101} Signs and symptoms included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash.^{1 101}

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.^{1 101}

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 known cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, conduction abnormalities), and patients with cerebrovascular disease).^{1 101} Use with caution in patients receiving other drugs that can cause hypotension, bradycardia, respiratory depression, or CNS depression.^{1 101} In all such patients, consider monitoring of orthostatic vital signs; if hypotension occurs, consider dosage reduction.^{1 101}

Falls

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.^{1 101}

In patients with diseases or conditions or receiving other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.^{1 101}

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia temporally related to antipsychotic agents, including asenapine, reported during clinical trial and/or postmarketing experience.^{1 101} Agranulocytosis (including fatal cases) also reported with other antipsychotic agents.^{1 101}

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count or ANC or a history of drug-induced leukopenia or neutropenia.^{1 101} Monitor CBC frequently during the first few months of therapy in patients with such risk factors.^{1 101} Discontinue asenapine at the first sign of a clinically important decline in WBC count in the absence of other causative factors.^{1 101}

Monitor patients with clinically important neutropenia for fever or other signs and symptoms of infection and treat promptly if they occur.^{1 101} Discontinue asenapine if severe neutropenia (ANC <1000/mm³) occurs; monitor WBC until recovery occurs.^{1 101}

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.^{1 101} Torsades de pointes or adverse effects associated with delayed ventricular repolarization not reported.^{1 101}

Avoid use in patients concurrently receiving other drugs known to prolong the QT_c interval such as class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin).^{1 101} Also avoid use 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).^{1 101}

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.^{1 101}

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.^{1 101}

Seizures

Seizures reported rarely in sublingual asenapine-treated adult patients in clinical trials.^{1 101} No seizures reported to date in pediatric patients treated with sublingual asenapine or in patients treated with transdermal asenapine in clinical trials.^{1 101}

Use with caution in patients with a history of seizures or with conditions that may lower seizure threshold; such conditions may be more prevalent in patients ≥65 years of age.^{1 101}

Cognitive and Motor Impairment

Somnolence, usually transient and with the highest incidence during the first week of therapy, reported in patients receiving sublingual asenapine in clinical trials.¹ Somnolence also reported with transdermal asenapine.¹⁰¹

Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that asenapine therapy does not affect them adversely.^{1 101}

Body Temperature Regulation

Disruption of ability to regulate core body temperature possible with atypical antipsychotic agents.^{1 101}

Use with 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).^{1 101}

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.^{1 101} Dysphagia reported with sublingual asenapine; not reported to date with transdermal asenapine.^{1 101}

Use with caution in patients at risk for aspiration.^{1 101}

External Heat

Rate and extent of asenapine absorption increased when heat is applied to asenapine transdermal system (patch) after application.¹⁰¹

Advise patients to avoid exposing the asenapine patch application site to direct external heat sources (e.g., hair dryers, heating pads, electric blankets, heated water beds).¹⁰¹

Application Site Reactions

Local skin reactions (e.g., irritation) reported with the asenapine transdermal system.¹⁰¹ Erythema, pruritus, papules, discomfort, pain, edema, or irritation may develop at the application site during wear time or immediately after removal of the patch.¹⁰¹ Application site reactions occurred more frequently in Black or African American patients compared to Caucasians.¹⁰¹

Inform patients of potential application site reactions and that increased skin irritation may occur if the patch is applied for a longer period than instructed or if the same application site is used repeatedly.¹⁰¹ Instruct patients to choose a different application site each day to minimize skin reactions.¹⁰¹

Specific Populations

Pregnancy

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].^{1 101}

No studies conducted to date in pregnant women; no available human data informing the drug-associated risk.^{1 101} In animals, asenapine increased post-implantation loss and early pup deaths and decreased subsequent pup survival and weight gain.^{1 101} Advise pregnant women of potential risk to the fetus with asenapine exposure.^{1 101}

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.^{1 101} Symptoms have varied in severity; some infants recovered within hours to days without specific treatment while others required prolonged hospitalization.^{1 101} Monitor neonates for extrapyramidal and/or withdrawal symptoms; if such symptoms occur, manage appropriately.^{1 101}

Lactation

Distributes into milk in rats; not known whether distributes into human milk.^{1 101} Effects on nursing infants and on milk production also not known.^{1 101}

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.^{1 101}

Pediatric Use

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

Safety and efficacy of sublingual asenapine monotherapy for treatment of bipolar I disorder in pediatric patients 10–17 years of age established.¹ Such patients appear to be more sensitive to dystonia if initial dosage titration schedule not followed; titrate dosage according to manufacturer's recommended dosing schedule.¹

Safety and efficacy of sublingual asenapine as adjunctive therapy for the treatment of bipolar disorder not established in pediatric patients to date.¹

Efficacy of sublingual asenapine for the treatment of schizophrenia not established in pediatric patients.¹ Safety and efficacy of transdermal asenapine in pediatric patients not established.¹⁰¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.^{1 101} Risk of poorer tolerance and orthostasis; carefully monitor patients during therapy.^{1 101}

Geriatric patients with dementia-related psychosis treated with asenapine are at an increased risk of death; increased incidence of adverse cerebrovascular events also observed with certain atypical antipsychotic agents.^{1 101}

Asenapine is not approved for the treatment of patients with dementia-related psychosis.^{1 101}

Hepatic Impairment

Substantially higher exposure observed in individuals with severe hepatic impairment (Child-Pugh class C).^{1 101} Use is therefore contraindicated in such patients.^{1 101}

Exposure 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.^{1 101}

Renal Impairment

Exposure was similar in individuals with varying degrees of renal impairment and those with normal renal function; dosage adjustment not required.^{1 101} Effect of renal function on elimination of metabolites and effect of hemodialysis on pharmacokinetics not evaluated.^{1 101}

Common Adverse Effects

Sublingual asenapine in adults with schizophrenia (≥5%): Akathisia (including hyperkinesia), oral hypoesthesia, somnolence (including sedation and hypersomnia).¹

Sublingual asenapine as monotherapy in adults with bipolar I disorder (≥5%): Somnolence, oral hypoesthesia, dizziness, extrapyramidal symptoms other than akathisia, akathisia.¹

Sublingual asenapine as adjunctive therapy in adults with bipolar I disorder (≥5%): Somnolence, oral hypoesthesia.¹

Sublingual asenapine as monotherapy in pediatric patients with bipolar I disorder (≥5%): Somnolence, dizziness, dysgeusia, oral paresthesia, nausea, increased appetite, fatigue, weight gain.¹

Transdermal asenapine (≥5%): Extrapyramidal disorder, application site reaction, weight gain.¹⁰¹

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.^{1 101} Weakly inhibits CYP2D6; does not appear to induce CYP1A2 or CYP3A4.^{1 101}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Substrates and Inhibitors of CYP2D6: Clinically important pharmacokinetic interactions possible if used concomitantly with drugs that are both substrates and inhibitors of CYP2D6 (e.g., paroxetine).^{1 101}

Potent CYP1A2 Inhibitors: Possible increased asenapine exposure with concomitant use with potent inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin, enoxacin).^{1 101} Dosage reduction of asenapine based on clinical response may be necessary.^{1 101}

CYP3A4 Inducers: No dosage adjustment of sublingual asenapine required when administered concomitantly with a CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin).¹

Anticholinergic Agents

Possible disruption of body temperature regulation.^{1 101} Use with caution.^{1 101}

Drugs that Prolong QT Interval

Potential additive effect on QT-interval prolongation if used concomitantly with other drugs known to prolong QT_c interval, including class Ia antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic agents (e.g., chlorpromazine, thioridazine, ziprasidone), and some antibiotics (e.g., gatifloxacin, moxifloxacin).^{1 101}

Avoid concomitant use of other drugs known to prolong QT_c interval.^{1 101}

Hypotensive Agents and Drugs Causing Bradycardia

May enhance hypotensive effects of certain antihypertensive agents (e.g., diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, alpha-blockers) and other drugs that can cause hypotension or bradycardia.^{1 101} Use concomitantly with caution; consider monitoring orthostatic vital signs during concurrent use.^{1 101}

Monitor BP during concurrent use of hypotensive agents.^{1 101} Adjust dosage of hypotensive agents, if necessary, based on BP.^{1 101}

CNS Agents

Possible additive CNS depressant effects, including increased fall risk.^{1 101}

Use concomitantly with caution.^{1 101} Consider monitoring orthostatic vital signs.^{1 101}

Specific Drugs

Asenapine Pharmacokinetics

Absorption

Bioavailability

Asenapine maleate administered sublingually because of the low bioavailability (<2%) following oral administration of tablets.¹

Rapidly absorbed following sublingual administration; peak plasma concentrations occur within 0.5–1.5 hours.¹

Absolute bioavailability of sublingual tablets (5 mg) is 35%.¹

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

Peak concentrations following transdermal application typically reached between 12–24 hours, with sustained concentrations during wear time (24 hours).¹⁰¹

About 60% of asenapine released on average from transdermal system over 24 hours; steady-state interpatient variability is about 20–30%.¹⁰¹

Steady-state plasma concentrations achieved in about 72 hours after first application of the patch.¹⁰¹

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

Special Populations

Smoking does not affect exposure.^{1 101}

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.^{1 101} In individuals with severe hepatic impairment (Child-Pugh class C), exposure was an average of 7 times higher compared with individuals with normal hepatic function.^{1 101}

In individuals with varying degrees of renal impairment, exposure of asenapine was similar to individuals with normal renal function.^{1 101}

In geriatric patients, exposure was 30–40% higher compared with younger adult patients.^{1 101}

Distribution

Extent

Undergoes extensive extravascular distribution.^{1 101}

Distributes into milk in rats; not known whether distributes into milk in humans.^{1 101}

Plasma Protein Binding

95% to plasma proteins (including albumin and α₁-acid glycoprotein).^{1 101}

Elimination

Metabolism

Metabolized mainly through direct glucuronidation by UGT1A4 and oxidative metabolism, primarily by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6.^{1 101}

Elimination Route

Following administration of a single radiolabeled dose; approximately 50% recovered in urine and 40% in feces.^{1 101}

Half-life

Sublingual asenapine: Terminal phase half-life (t½β) averages about 24 hours.¹

Transdermal asenapine: Apparent elimination half-life is approximately 30 hours following removal of the patch.¹⁰¹

Special Populations

Effect of renal function on elimination of metabolites and effect of hemodialysis on pharmacokinetics not evaluated.^{1 101}

Pharmacokinetics of sublingual asenapine 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

Transdermal

Patch

20–25°C (may be exposed to 15–30°C).¹⁰¹ Do not store unpouched.¹⁰¹ Keep out of reach of children.¹⁰¹

Actions

• Dibenzo-oxepino pyrrole-derivative antipsychotic agent; atypical antipsychotic agent.^{1 101}

• 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.^{1 101}

• 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).^{1 101} Asenapine acts as an antagonist at these receptors in vitro.^{1 101}

• Possesses no appreciable affinity for muscarinic cholinergic receptors.^{1 101}

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Instructions for Use) before initiating sublingual or transdermal asenapine therapy and each time the prescription is refilled.^{1 101}

• Counsel patients on proper sublingual administration of asenapine tablets.¹ Provide patients with dosage escalation instructions when initiating treatment with asenapine sublingual tablets.¹

• Counsel patients on proper application of the asenapine transdermal system (patch).¹⁰¹

• Advise patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.^{1 101} Inform patients and caregivers that asenapine is not approved for treating geriatric patients with dementia-related psychosis.^{1 101}

• Advise patients of the risk of serious allergic reactions.^{1 101} Inform 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.^{1 101}

• Advise patients that application site reactions, primarily in the sublingual area, have been reported with sublingual asenapine, including oral ulcers, blisters, peeling/sloughing, and inflammation.¹ Instruct patients to monitor for such reactions during therapy.¹ Inform patients that numbness or tingling of the mouth or throat may occur directly after administration of asenapine sublingual tablets and usually resolves within 1 hour.¹

• Inform patients that application site reactions, including erythema, pruritus, papules, discomfort, pain, edema, or irritation, have been reported with use of transdermal asenapine.¹⁰¹ Inform patients that increased skin irritation may occur if the patch is applied for a longer period than instructed or if the same application site is used repeatedly.¹⁰¹ Instruct patients to select a different application site each day to minimize skin reactions.¹⁰¹ Advise patients to monitor for these reactions while wearing or immediately after removing the patch.¹⁰¹

• Caution patients 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.^{1 101}

• Inform 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.^{1 101} Advise patients to contact their clinician or report to the emergency room if they experience any signs and symptoms of NMS.^{1 101}

• Inform 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.^{1 101}

• Inform patients of the risk of orthostatic hypotension and syncope (fainting), especially when initiating or reinitiating treatment or increasing the dosage of asenapine.^{1 101}

• Inform patients of the risk of leukopenia/neutropenia.^{1 101} Advise patients with a pre-existing low leukocyte count or a history of drug-induced leukopenia/neutropenia that they should have their CBC count monitored during asenapine therapy.^{1 101}

• Advise patients on the signs and symptoms of hyperprolactinemia and advise them to contact their clinician if these abnormalities occur.^{1 101}

• Inform patients about the risk of a movement problem called tardive dyskinesia.^{1 101} Advise patients to contact their clinician if any abnormal muscle movements occur.^{1 101}

• Advise patients to inform their 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).^{1 101}

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 101} Inform patients that third trimester use of asenapine may cause extrapyramidal and/or withdrawal symptoms in a neonate.^{1 101} Inform patients about the pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy.^{1 101}

• Advise patients to avoid overheating or dehydration.^{1 101}

• Advise patients to avoid exposing the asenapine transdermal system to external heat sources (e.g., hair dryers, heating pads, electric blankets, heated water beds) following application.¹⁰¹

• Advise patients of other important precautionary information.^{1 101}

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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