Asenapine, a dibenzo-oxepino pyrrole derivative, is considered an atypical antipsychotic agent.1, 101
Asenapine is used sublingually and transdermally for the treatment of schizophrenia in adults.1, 101
The efficacy of sublingual asenapine in the management of schizophrenia was evaluated in 3 placebo-controlled and active comparator (haloperidol, olanzapine, or risperidone)-controlled, fixed-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, 82 In 2 of the 3 studies, asenapine was found to be more effective than placebo.1, 2, 82 In the third study, asenapine could not be distinguished from placebo; however, the active control in the trial was found to be superior to placebo.1
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, 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, 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 efficacy of transdermal asenapine for the management of schizophrenia in adults was established, in part, based on efficacy data from clinical trials of sublingual asenapine as well as from the results of a 6-week, fixed-dose, randomized, double-blind, placebo-controlled study using the transdermal formulation of the drug.101, 102 In the study using the transdermal formulation, adults meeting the DSM-IV criteria for schizophrenia were randomized to receive one of two fixed dosages of transdermal asenapine (3.8 mg/24 hours or 7.6 mg/24 hours) or placebo; the primary endpoint was change from baseline in PANSS total score at week 6.101, 102 In this trial, both dosages of transdermal asenapine were superior to placebo in improving the PANSS total score.101, 102 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.101
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic agent.107 The APA states that, with the possible exception of clozapine, 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.107 The choice of an antipsychotic agent should be individualized, considering 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 Patients whose symptoms improve on an antipsychotic agent should continue treatment with an antipsychotic agent long-term; in most patients, it is appropriate to continue the same antipsychotic agent rather than switch to another antipsychotic agent for maintenance therapy.107
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic agents for acute and maintenance treatment of schizophrenia.108 Choice of antipsychotic agent should be based on patient-specific factors and the side effect profiles of the different antipsychotic agents.108 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.108
Asenapine maleate sublingual tablets are used as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age.1 The sublingual tablets are also used as adjunctive therapy with lithium or valproate in adults and for maintenance monotherapy of bipolar I disorder in adults.1
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, 83 The principal rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), 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, 83 A secondary rating instrument used in these trials was the Clinical Global Impression-Bipolar (CGI-BP) scale.1, 3, 83 In both trials, asenapine was initially administered in a sublingual dosage of 10 mg twice daily and then 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, 83 Asenapine was found to be superior to placebo in the reduction of the YMRS total score and the CGI-BP Severity of Illness score (mania) in both studies.1, 3, 83 An active control arm (olanzapine) was used in addition to placebo controls in both of these studies; however, the study design did not allow for direct comparison between asenapine and olanzapine.1, 3, 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 YMRS 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 the 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 1 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
Maintenance of efficacy with sublingual asenapine monotherapy was established in a placebo-controlled, double-blind, multicenter, flexible-dosage, randomized withdrawal study.1, 103 In this trial, all patients received open-label asenapine 5 mg or 10 mg twice daily for 12-16 weeks; patients who met prespecified criteria for continued stability at the end of this treatment period were randomized to continue asenapine treatment or switch to placebo for 26 weeks.1, 103 Asenapine was superior to placebo in terms of time to relapse.1, 103 Relapse was defined as YMRS or Montgomery-Asberg Depression Rating Scale (MADRS) score ≥16; requirement or initiation of any non-study medication to treat mixed, manic, or depressive symptoms (including an antipsychotic agent, antidepressant, or mood-stabilizing agent); requirement or initiation of psychiatric hospitalization; or investigator judgment to discontinue the study due to a mood event.1, 103
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 patients and then titrated up to their target assigned dosage of 5 or 10 mg twice daily at intervals of 3 days.1, 100 All dosages of asenapine evaluated in this study were found to be superior to placebo in improving the YMRS 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 in adults 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 YMRS total score) when given as adjunctive therapy to either lithium or valproate at week 3 in this study.1
Legacy practice guidelines from APA recommend lithium plus an antipsychotic agent or valproate plus an antipsychotic agent for first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.109 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to adverse effect profiles.109 Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic agent.109 Atypical antipsychotics are generally preferred over typical antipsychotics because of their more benign adverse effect profile.109 Following remission of an acute episode, maintenance pharmacologic treatment is recommended; first-line options for maintenance therapy include lithium and valproate.109 The guideline states that, for patients treated with an antipsychotic medication during the acute episode, the need for ongoing antipsychotic therapy should be reassessed upon entering the maintenance phase; antipsychotic agents should generally be discontinued, unless they are required to control persistent psychosis or prevent recurrence.109 The role of asenapine is not specifically addressed.109
Guidelines from the Department of Veterans Affairs and Department of Defense recommend lithium or quetiapine monotherapy for the treatment of acute mania in patients with bipolar disorder.110 If lithium or quetiapine is not selected based on patient preference or characteristics, olanzapine, paliperidone, or risperidone are recommended as alternative treatments.110 If none of these therapies are considered suitable based on patient preference or characteristics, other suggested options include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.110 For patients who experience breakthrough episodes of mania or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic agent (haloperidol, asenapine, quetiapine, olanzapine, or risperidone) is recommended.110 For prevention of mania recurrence, lithium or quetiapine is recommended; alternatives include olanzapine, paliperidone, or risperidone.110
Asenapine maleate is commercially available as rapidly dissolving sublingual tablets containing 2.5 mg, 5 mg, or 10 mg of the drug; the oral bioavailability of the drug after sublingual administration is much higher than following oral administration.1 Asenapine is also 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
Asenapine maleate 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; the tablet will dissolve in saliva within seconds.1 The blister pack should then be slid back into the case until it clicks.1 Patients should be instructed not to eat or drink for 10 minutes following administration of the sublingual tablets. 1 The sublingual tablets should not be split, crushed, chewed, or swallowed.1 Refer to the prescribing information for full instructions for use of asenapine sublingual tablets.1 Store asenapine sublingual tablets at 20-25°C (excursions permitted between 15-30°C).1
The asenapine transdermal system (patch) is applied once daily; each patch should be worn for 24 hours only.101 Instruct patients to wear only one patch at any time.101 The patch should be applied to clean, dry, and intact skin at the selected application site; application sites include the 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 the patch if the individual pouch seal is broken or damaged.101 Do not cut the asenapine 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 and then place in the trash immediately.101 If irritation or a burning sensation occurs while wearing the patch, remove it and apply a new patch to a new application site.101 While showering is permitted, avoid swimming or bathing while wearing the patch.101 Do not apply external heat sources (e.g., heating pad) over the transdermal system; prolonged application of heat over the patch increases plasma concentrations of asenapine.101 Refer to the prescribing information for full instructions for use of the asenapine transdermal system.101 Store asenapine patches at 20-25°C (excursions permitted between 15-30°C).101 Do not store unpouched and keep out of reach of children.101
The sublingual tablets are available as asenapine maleate; the dosage is expressed in terms of asenapine.1 Based on the AUC of asenapine, 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
For the acute management of schizophrenia in adults, the recommended initial and target dosage of asenapine tablets 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 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated in clinical trials.1
For the maintenance management of schizophrenia in adults, the recommended target dosage range of asenapine tablets is 5-10 mg given sublingually twice daily.1 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated in clinical trials.1
For the treatment of schizophrenia in adults, initiate asenapine transdermal system at a dosage of 3.8 mg/24 hours.101 The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week.101 In a short-term, placebo-controlled trial, there was no indication of added benefit at a dosage of 7.6 mg/24 hours, on average, but there was an increase in certain adverse effects.101 The manufacturer states that the safety of asenapine dosages above 7.6 mg/24 hours has not been evaluated in clinical studies.101
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 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated in clinical trials.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 in the individual patient.1 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated in clinical trials.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
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
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 of treatment, 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 The manufacturer states that the safety of asenapine dosages exceeding 10 mg twice daily has not been evaluated in clinical trials.1
Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1, 101 Asenapine is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).1, 101
Dosage adjustment is not required in patients with renal impairment (mild to severe impairment; glomerular filtration rate 15-90 mL/minute).1, 101
Dosage adjustment is not required in geriatric patients based on age alone.1, 101
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, 101 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 compared to patients receiving placebo.1, 101 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, 101 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, 101 The manufacturer states that asenapine is not approved for the treatment of patients with dementia-related psychosis.1, 101
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, 101 The manufacturers state that 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, has been reported with antipsychotic agents.1, 101 Additional signs of NMS may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.1, 101 If NMS is suspected, asenapine should be immediately discontinued and intensive symptomatic treatment and monitoring should be provided.1, 101
Because use of antipsychotic agents, including asenapine, may be associated with tardive dyskinesia (a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements), asenapine should be prescribed in a manner that is most likely to reduce the risk of this syndrome.1, 101 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, 101 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, 101
The risk of tardive dyskinesia appears to be highest among geriatric patients, particularly geriatric women; however, it is not possible to predict which patients are likely to develop the syndrome.1, 101 The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of antipsychotic treatment and the cumulative dosage.1, 101 The syndrome can develop after a relatively short treatment period, even at low dosages; it may also occur after discontinuation of treatment.1, 101
Tardive dyskinesia may remit (partially or completely) if antipsychotic treatment is discontinued.1, 101 Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of tardive dyskinesia, possibly masking the underlying process.1, 101 The effect of symptomatic suppression on the long-term course of the syndrome is unknown.1, 101
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, 101
Atypical antipsychotic agents, including asenapine, have caused metabolic changes including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain.1, 101 While all of these drugs 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, has been reported in patients receiving atypical antipsychotic agents.1, 101 Hyperglycemia has been reported in patients treated with sublingual asenapine.1, 101 In short-term controlled trials in adult patients with schizophrenia or bipolar mania, approximately 0-5 and 0-16% of patients treated with sublingual asenapine experienced shifts from normal to high and from borderline to high fasting glucose concentrations, respectively.1 In a placebo-controlled, 6-week trial in adult patients with schizophrenia, approximately 3 and 1% of patients treated with transdermal asenapine experienced shifts from normal to high and from borderline to high fasting glucose concentrations, respectively.101 Reports of hyperglycemia in patients treated with transdermal asenapine were <1% in the placebo-controlled trial.101 In a longer-term (one-year), comparator-controlled, double-blind study that included mainly patients with schizophrenia, the mean increase in fasting glucose concentrations from baseline was 2.4 mg/dL in patients treated with sublingual asenapine.1
Fasting blood glucose testing should be performed before or soon after initiation of antipsychotic therapy and then monitored periodically during long-term therapy.1, 101
Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotic agents.1, 101 Asenapine generally appears to minimally affect the lipid profile in patients receiving short-term therapy with the drug.1, 101 In short-term, placebo-controlled studies of sublingual asenapine in adults with schizophrenia, the proportion of patients with total cholesterol elevations of 240 mg/dL or more at study end point was 8.3% 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 of sublingual asenapine 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
In the placebo-controlled, 6-week study of transdermal asenapine in adults with schizophrenia, the proportion of patients with total cholesterol elevations of 240 mg/dL or more at study end point was 10.7, 13.6, or 10.2% for patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, or placebo, respectively.101 The proportion of patients with elevations in triglycerides of 200 mg/dL or more at study end point was 17.8, 12.4, or 10.3% for patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, or placebo, respectively.101
The manufacturers recommend baseline (i.e., before or soon after initiation of therapy) and periodic monitoring of fasting lipid evaluations in patients receiving asenapine therapy.1, 101
Weight gain has been observed with atypical antipsychotic therapy, including asenapine.1, 101 In short-term studies of sublingual asenapine in adults with schizophrenia, 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 studies of sublingual asenapine in adults with bipolar mania, 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 In the placebo-controlled, 6-week study of transdermal asenapine in adults with schizophrenia, 18.3, 14.3, and 3.9% of patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, and placebo, respectively, gained 7% or more of their baseline body weight.101
During long-term sublingual asenapine therapy (52 weeks) in adults primarily with schizophrenia, mean weight gain in asenapine-treated patients was 0.9 kg.1, 101 The proportion of patients with a ≥7% increase in body weight at study endpoint was 14.7%.1, 101 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, 101
In a short-term trial of sublingual asenapine in pediatric patients with bipolar mania, 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, 101 In pediatric patients, weight gain should be monitored and assessed against that expected for normal growth.1
Hypersensitivity reactions have been reported in patients treated with sublingual and transdermal asenapine.1, 101 These reactions occurred after the first dose in several cases.1, 101 Clinical manifestations reported included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash.1, 101
Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects
Atypical antipsychotic agents can cause orthostatic hypotension and syncope.1, 101 The risk is usually the greatest during initial dosage titration and when dosage is increased.1, 101
In the placebo-controlled trial of transdermal asenapine, orthostatic hypotension was reported in 1.5, 0, and <1% of patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, and placebo, respectively.101 There were no reports of syncope with either dosage of transdermal asenapine in this trial.101 In premarketing clinical trials of sublingual asenapine in adults, including long-term trials without comparison with placebo, syncope was reported in 0.6% of patients treated with asenapine.1, 101 In short-term bipolar mania trials in pediatric patients, syncope was reported in 1% of patients receiving sublingual 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 known cardiovascular disease (e.g., history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1, 101 Asenapine should be used with caution in patients receiving other drugs that can cause hypotension, bradycardia, respiratory depression, or CNS depression .1, 101 In all such patients, consideration should be given to monitoring orthostatic vital signs, and dosage reduction should be considered if hypotension develops.1, 101
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, 101 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, 101
Leukopenia, Neutropenia, and Agranulocytosis
In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including asenapine.1, 101 Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.1, 101
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, 101 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 frequently during the first few months of therapy.1, 101 In such patients, 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, 101
Patients with clinically important neutropenia should be monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur.1, 101 In patients with severe neutropenia (ANC less than 1000/mm3), asenapine should be discontinued and the leukocyte count monitored until recovery occurs.1, 101
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 (QTc) interval of 2-5 msec compared with placebo in a controlled and dedicated QT study.1, 101 None of the asenapine-treated patients in this study experienced a QTc-interval prolongation of 60 msec or greater compared with baseline, nor did any patient experience a QTc interval of 500 msec or greater.1, 101 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 In the placebo-controlled trial evaluating transdermal asenapine, there were no reports of QT-interval prolongation exceeding 500 msec for asenapine and placebo.101 There were no reports of torsades de pointes or any adverse effects associated with delayed ventricular repolarization during these studies.1, 101
The manufacturers state that asenapine should be avoided in patients concurrently receiving other drugs known to prolong the QTc interval; examples of such drugs include 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 The manufacturers also state 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 QTc interval, including bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval.1, 101
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, 101 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1, 101 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.1, 101
Galactorrhea, amenorrhea, gynecomastia, and impotence were not reported in patients treated with transdermal asenapine or placebo in the placebo-controlled trial.101 In sublingual asenapine 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, 101 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
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, 101
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 with sublingual asenapine, including long-term trials without comparison to placebo, seizures were reported in 0.3% of patients treated with asenapine.1, 101 There were no reports of seizures in sublingual asenapine-treated pediatric patients in a 3-week bipolar mania trial.1 In the placebo-controlled trial evaluating transdermal asenapine, there were no reports of seizures in adult patients treated with asenapine dosages of 3.8 mg/24 hours and 7.6 mg/24 hours.101
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, 101
Cognitive and Motor Impairment
Somnolence, usually transient with the highest incidence reported during the first week of therapy, has been reported in patients receiving sublingual 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 sublingual asenapine-treated adults during premarketing clinical trials, including long-term trials without placebo comparison.1, 101 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 I trial in pediatric patients, somnolence (including sedation and hypersomnia) occurred in 46-53% of patients receiving 2.5-10 mg of asenapine sublingually twice daily.1
Somnolence has also been reported in patients treated with transdermal asenapine.101 In the short-term, placebo-controlled schizophrenia trial evaluating transdermal asenapine in adults, somnolence was reported in 4.4, 3.4, and 1.5% of patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, and placebo, respectively.101 There were no reports of somnolence that led to drug discontinuation.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
Disruption of the body's ability to reduce core body temperature has been attributed to atypical antipsychotic agents.1, 101 In premarketing, short-term, placebo-controlled trials evaluating sublingual asenapine 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 sublingual 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 manufacturers recommend 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, 101
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1, 101 Dysphagia has been reported in patients receiving sublingual asenapine but not with transdermal asenapine to date.1, 101 Asenapine and other antipsychotic agents should be used with caution in patients at risk for aspiration.1, 101
The rate and extent of absorption of asenapine are increased when heat is applied to the transdermal system (patch) after application.101 After application of a heating pad, asenapine exposure was about 3.9 times greater than without heating pad 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
Local skin reactions, such as irritation, have been 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 In the short-term, placebo-controlled schizophrenia trial evaluating the patch in adults, application site reactions were reported in 15.2, 13.7, and 3.9% of patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, and placebo, respectively.101 Erythema, the most common application site reaction, was reported in 9.3, 9.8, and 1.5% of patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, and placebo, respectively.101 Pruritus was reported in 4.9, 3.9, and 1.9% of patients treated with asenapine 3.8 mg/24 hours, asenapine 7.6 mg/24 hours, and placebo, respectively.101 One patient developed hyperpigmentation at multiple application sites that persisted for at least several weeks after discontinuing treatment with the patch.101 Application site reactions occurred more frequently in Black or African American patients compared to Caucasians.101
Inform patients of these 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
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asenapine during pregnancy.1, 101 For more information, clinicians may contact the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or visit [Web].1, 101
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 and at dosages 1.1 and 0.66 times, respectively, the MRHD of 12.8 mg of transdermal asenapine daily.1, 101 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, 101 These dosages are up to 1.1 times the MRHD of 12.8 mg transdermal asenapine daily.101 Advise pregnant women of the potential hazard to a fetus.1, 101
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1, 101 Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1, 101 The symptoms have varied in severity; some neonates recovered within hours to days without specific treatment, while others have required prolonged hospitalization.1, 101 Neonates should be monitored for extrapyramidal and/or withdrawal symptoms and managed appropriately if symptoms occur.1, 101
It is not known whether asenapine is distributed into milk in humans.1, 101 The drug is distributed into milk in rats.1, 101 The effects of asenapine on breast-fed infants and on milk production also are not known.1, 101 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, 101
Safety and efficacy of sublingual asenapine in pediatric patients younger than 10 years of age have not been established.1
Safety and efficacy of sublingual 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 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 (50-week), open-label, uncontrolled safety trial in pediatric patients with bipolar I disorder treated with sublingual asenapine monotherapy.1 To reduce the risk of dystonia in pediatric patients, sublingual asenapine should be titrated according to the manufacturer's recommended dosing schedule.1 Safety and efficacy of sublingual asenapine as adjunctive therapy for the treatment of bipolar disorder have not been established in pediatric patients to date.1
Efficacy of sublingual asenapine for the treatment of schizophrenia was not established in an 8-week, placebo-controlled, double-blind trial in adolescents 12-17 years of age receiving 2.5 or 5 mg of the drug twice daily.1 Clinically relevant adverse reactions in the pediatric schizophrenia trial were generally similar to those observed in the pediatric bipolar I and adult bipolar I and schizophrenia trials.1 No new major safety findings were reported in a 26-week, open-label, uncontrolled safety trial of sublingual asenapine monotherapy in pediatric patients with schizophrenia.1 Safety and efficacy of transdermal asenapine have not been established in pediatric patients.101
Pharmacokinetics of sublingual asenapine in pediatric patients 10-17 years of age generally are similar to those observed in adults.1
Clinical trials with asenapine in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1, 101 In premarketing clinical studies of sublingual asenapine, 1.1% of approximately 2250 asenapine-treated patients were 65 years of age and older.1 In the placebo-controlled trial of transdermal asenapine, 1.6% of approximately 614 patients were 65 years of age and older.101
Asenapine exposure is 30-40% higher in geriatric patients compared with younger adult patients.1, 101 Routine dosage adjustment of asenapine is not necessary based on age alone.1, 101 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, 101
Geriatric patients with dementia-related psychosis treated with asenapine are at an increased risk of death compared with those treated with placebo.1, 101 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, 101 The manufacturers of sublingual and transdermal asenapine state that the drug is not approved for the treatment of patients with dementia-related psychosis .1, 101
In individuals with severe hepatic impairment (Child-Pugh class C), asenapine exposure was an average of 7 times higher than the exposure in individuals with normal hepatic function.1, 101 Asenapine is therefore contraindicated in patients with severe hepatic impairment.1, 101
Following administration 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, 101
The exposure of asenapine 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, 101 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, 101
Adverse effects occurring in 5% or more of adult patients receiving sublingual asenapine therapy for treatment of schizophrenia and at a frequency at least twice that reported with placebo in clinical trials include akathisia (including hyperkinesia), oral hypoesthesia, and somnolence (including sedation and hypersomnia).1
Adverse effects occurring in 5% or more of adult patients receiving sublingual asenapine as monotherapy for bipolar I disorder and at a frequency at least twice that reported with placebo in clinical trials include somnolence, oral hypoesthesia, dizziness, extrapyramidal symptoms other than akathisia, and akathisia.1
Adverse effects occurring in 5% or more of adult patients receiving sublingual asenapine as adjunctive therapy for bipolar I disorder and at a frequency at least twice that reported with placebo in clinical trials include somnolence and oral hypoesthesia.1
Adverse effects occurring in 5% or more of pediatric patients receiving sublingual asenapine as monotherapy for bipolar I disorder and at a frequency at least twice that reported with placebo in clinical trials include somnolence , dizziness, dysgeusia, oral paresthesia, nausea, increased appetite, fatigue, and weight gain.1
Adverse effects occurring in 5% or more of patients receiving transdermal asenapine therapy and at a frequency at least twice that reported with placebo in clinical trials include extrapyramidal disorder, application site reaction, and weight gain.101
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, 101
Asenapine is a weak inhibitor of CYP2D6; the drug does not induce CYP1A2 or CYP3A4.1, 101
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Substrates and Inhibitors of CYP2D6
Clinically important pharmacokinetic interactions are possible when asenapine is used concomitantly with drugs that are both substrates and inhibitors of CYP2D6 (e.g., paroxetine).1, 101
Concomitant administration of paroxetine, which is both a CYP2D6 substrate and inhibitor, and asenapine resulted in increases in peak plasma concentrations and exposure of paroxetine.1, 101 Concomitant administration of paroxetine and sublingual asenapine resulted in a twofold increase in peak plasma concentrations and exposure of paroxetine.1, 101 Asenapine may increase the inhibitory effects of paroxetine on its own metabolism by CYP2D6.1, 101 Paroxetine dosage should be reduced by one-half during concurrent administration of asenapine; asenapine dosage adjustment is not required.1, 101
Clinically important pharmacokinetic interactions are possible when asenapine is used concomitantly with drugs that are potent inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin, enoxacin).1, 101 Concomitant use increases peak plasma concentrations and AUC of asenapine.101
Concomitant administration of fluvoxamine, a potent CYP1A2 inhibitor, at a dosage of 25 mg twice daily and sublingual asenapine slightly increased exposure.1, 101 The full therapeutic dosage of fluvoxamine would be expected to cause a greater increase in the exposure of asenapine.1, 101
Because of possible increased asenapine exposure with potent CYP1A2 inhibitors, asenapine dosage reduction based on clinical response may be necessary.1, 101
No dosage adjustment of sublingual asenapine is required when administered concomitantly with a CYP3A4 inducer (e.g., carbamazepine, phenytoin, rifampin).1
Concomitant administration of carbamazepine, a CYP3A4 inducer, and asenapine slightly decreased both peak plasma concentrations and AUC of asenapine.1, 101
Possible disruption of body temperature regulation may occur with concomitant use of asenapine and anticholinergic agents; sublingual and transdermal asenapine should be used with caution in patients concurrently receiving drugs with anticholinergic activity.1, 101
Drugs that Prolong QT Interval
Additive effect on QT-interval prolongation may occur with concomitant use of asenapine and other drugs known to prolong the corrected QT (QTc) 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 asenapine and other drugs known to prolong the QTc interval.1, 101
Hypotensive Agents and Drugs causing Bradycardia
Because of its α1-adrenergic blocking activity and potential to cause hypotension, asenapine may enhance the 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.1, 101 Asenapine also has been associated with bradycardia.1, 101 Asenapine should be used with caution in patients receiving other drugs that can cause hypotension or bradycardia; consider monitoring orthostatic vital signs in such patients.1, 101 Consider a dosage reduction if hypotension occurs.1, 101
Monitoring of blood pressure is recommended during concurrent use of hypotensive agents and asenapine; the dosage of the hypotensive agent should be adjusted accordingly.1, 101
Additive CNS depressant effects and increased risk of falls may occur with concomitant use of asenapine and drugs that cause CNS or respiratory depression.1, 101 Asenapine should be used with caution in patients receiving other drugs that can produce CNS or respiratory depression; consider monitoring of orthostatic vital signs in such patients.1, 101 Consider a dosage reduction if hypotension occurs.1, 101
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, 101 Sublingual asenapine dosage adjustment is not necessary in patients concurrently receiving cimetidine.1
Concomitant administration of asenapine and desipramine, a substrate of CYP2C19 and CYP2D6, very slightly increased peak plasma concentrations and AUC of desipramine.1, 101
Concomitant administration of imipramine, an inhibitor of CYP1A2, CYP2C19, and CYP3A4, and asenapine slightly increased peak plasma asenapine concentrations and AUCs.1, 101 Sublingual asenapine dosage adjustment is not required in patients concurrently receiving imipramine.1
In a population pharmacokinetic analysis, concurrent administration of lithium did not affect the pharmacokinetics of sublingual asenapine.1 In addition, pre-dose serum concentrations of lithium collected during an adjunctive therapy study were comparable between patients receiving sublingual asenapine and those receiving placebo, indicating that asenapine does not affect serum concentrations of lithium.1 Sublingual asenapine dosage adjustment is not required in patients concurrently receiving lithium.1
Pre-dose serum concentrations of valproate collected during an adjunctive therapy study were comparable between patients receiving sublingual asenapine and those receiving placebo, indicating that asenapine does not affect plasma concentrations of valproate.1 Concomitant administration of valproate and sublingual asenapine slightly increased peak plasma asenapine concentrations and slightly decreased the drug's AUC; sublingual asenapine dosage adjustment is not required in patients receiving valproate concurrently.1
In a population pharmacokinetic analysis, smoking had no effect on asenapine exposure in smokers.1, 101 Dosage adjustment of sublingual asenapine is therefore not necessary based on smoking status.1
Asenapine is a dibenzo-oxepino pyrrole-derivative and has been referred to as an atypical antipsychotic agent.1, 101 Although the exact mechanism of action of asenapine in schizophrenia and bipolar I 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-HT2A]) receptors.1, 101
Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 receptors; dopamine D1, D2A, D2B, D3, and D4 receptors; α1A-, α2A-, α2B-, and α2C-adrenergic receptors; and histamine H1 receptors (moderate affinity for H2 receptors).1 Asenapine acts as an antagonist at these receptors in vitro.1, 101 Asenapine possesses no appreciable affinity for muscarinic cholinergic receptors.1, 101
Asenapine maleate is administered sublingually because of the low bioavailability (less than 2%) observed following oral administration.1 Asenapine is rapidly absorbed following sublingual administration, with peak plasma concentrations occurring within 0.5-1.5 hours.1 The absolute bioavailability of sublingual asenapine (5 mg) is 35%.1 Steady-state plasma concentrations are reached within 3 days with twice-daily sublingual administration.1 Food ingestion immediately before or 4 hours after sublingual administration of a single 5-mg dose in adults decreased asenapine 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 asenapine exposure by 19 and 10%, respectively; effects of water intake 10 or 30 minutes after administration were equivalent.1
Transdermal asenapine has a different pharmacokinetic profile than sublingual asenapine.101 Following transdermal application, peak asenapine concentrations are typically reached between 12-24 hours, with sustained concentrations during wear time (24 hours).101 On average, about 60% of asenapine is released from the transdermal system over 24 hours; steady-state interpatient variability is about 20-30%.101 Steady-state pharmacokinetics of asenapine are dose proportional in the dosage range of 3.8 mg/24 hours to 7.6 mg/24 hours.101 Steady-state plasma concentrations are achieved in about 72 hours after the first application of the patch.101 Based on relative bioavailability and established dose proportionality, the AUC for transdermal asenapine 3.8 mg/24 hours and 7.6 mg/24 hours was considered to be similar to that for sublingual asenapine 5 mg twice daily and 10 mg twice daily, respectively.101 Patch application site (upper arm, upper back, abdomen, hip area) has no effect on asenapine pharmacokinetics.101 Application of a heating pad on asenapine transdermal system for 8 hours led to a faster absorption rate as compared to without a heating pad; mean asenapine exposure was about 3.9 times greater with application of a heating pad compared to that without a heating pad.101
Asenapine appears to undergo extensive extravascular distribution and is 95% bound to plasma proteins (including albumin and α1-acid glycoprotein).1, 101 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, 101 The mean terminal half-life of sublingual asenapine is approximately 24 hours.1 Following removal of transdermal asenapine, the apparent elimination half-life is approximately 30 hours.101 Following administration of a single radiolabeled dose of asenapine, approximately 50 and 40% of the dose was excreted in urine and feces, respectively.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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Sublingual | Tablets | 2.5 mg (of asenapine) | Saphris® Black Cherry Flavor | AbbVie |
5 mg (of asenapine) | Saphris® Black Cherry Flavor | AbbVie | ||
10 mg (of asenapine) | Saphris® Black Cherry Flavor | AbbVie |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Transdermal | System, transdermal | 3.8 mg/24 hours | Secuado® | |
5.7 mg/24 hours | Secuado® | |||
7.6 mg/24 hours | Secuado® |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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99. Landbloom RL, Mackle M, Wu X et al. Asenapine: efficacy and safety of 5 and 10mg bid in a 3-week, randomized, double-blind, placebo-controlled trial in adults with a manic or mixed episode associated with bipolar I disorder. J Affect Dis . 2016; 190:103-10. [PubMed 26496015]
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101. Noven Therapeutics, LLC. Secuado® (asenapine) transdermal system prescribing information. Miami, FL; 2023 Dec. [Web]
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103. Szegedi A, Durgam S, Mackle M et al. Randomized, Double-Blind, Placebo-Controlled Trial of Asenapine Maintenance Therapy in Adults With an Acute Manic or Mixed Episode Associated With Bipolar I Disorder. Am J Psychiatry. 2018 Jan 1;175(1):71-79. doi: 10.1176/appi.ajp.2017.16040419. Epub 2017 Sep 26. PMID: 28946761.
107. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, third edition. 2020. Accessed 2024 Dec 11. [Web]
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