Amanda Mayer is a graduate of the University of Montana, Skaggs School of Pharmacy. She has clinical experience working in inpatient mental health, which is her passion. She has also done fill-in work at retail pharmacies throughout her career. Amanda appreciates the wide variety of professional opportunities available to pharmacists. Amanda loves spending time with her family and spends most of her free time exploring new restaurants, hiking in the summer, and snowboarding and cross-country skiing in the winter.


Topic Overview

Asenapine is a second-generation, atypical, antipsychotic medication that is known to be effective in the treatment of schizophrenia in adults. Asenapine is also used for maintenance treatment in bipolar I disorder as well as treatment for acute manic or mixed episodes associated with bipolar I disorder in adults and pediatric patients 10 years and older. The pharmacological profile and option of a sublingual route of administration with asenapine make it a unique antipsychotic drug of choice in emergency psychiatry cases, the pediatric population, and for maintenance treatment of mixed mood states. Individuals experiencing a manic episode are often treated with benzodiazepines and antipsychotics, although the specific effects of antipsychotics on hostility and aggression in patients with schizophrenia or bipolar disorder have received special attention from emergency clinicians.

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Credits: 1 hour of continuing education credit


Type of Activity: Knowledge


Media: Internet Fee Information: $4.99


Estimated time to complete activity: 1 hour, including Course Test and course evaluation


Release Date: August 30, 2022 Expiration Date: August 30, 2025


Target Audience: This educational activity is for pharmacists.


How to Earn Credit: From August 30, 2022, through August 30, 2025, participants must:


Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Post-test and Evaluation form. The Post-test will be graded automatically. Following successful completion of the Post-test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Learning Objectives: Upon completion of this educational activity, participants should be able to:


Describe the basic pharmacological profile, use, and clinical outcomes of asenapine treatment

Identify the dosing and uses for asenapine

Compare the benefits and risks of asenapine use for patients with chronic mental illness compared to other antipsychotics

Identify the contraindications and potential side effects of asenapine




The following individuals were involved in the development of this activity: Susan DePasquale, MSN, PMHNP-BC, Amanda Mayer, PharmD, and Jeff Goldberg, PharmD. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.


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Asenapine is a second-generation, atypical, antipsychotic medication that is known to be effective in the treatment of acute manic or mixed episodes for adults and children with bipolar I disorder, and adults with schizophrenia. Asenapine is also available in a transdermal formulation that is currently approved and limited to treating adults with schizophrenia. Retrospective reviews of asenapine administration in all age groups suggest that asenapine is a useful psychotropic agent because of its ease of use as a dissolvable sublingual tablet. Pediatric patients diagnosed with severe mixed mood states who require antipsychotic treatment for symptom control may benefit from asenapine as a non-invasive agent; however, more research is needed to determine the efficacy of asenapine as compared to other psychotropic medications in this patient population. Asenapine comes with labeled warnings and contraindications similar to other antipsychotics.


Pharmacological Profile and Mechanism of Action


Asenapine is classified as an atypical antipsychotic agent that is approved by the U.S. Food and Drug Administration to treat schizophrenia.1-3 It is also approved for the treatment of bipolar disorder and mania.3 In 2020, the FDA approved generic forms of asenapine.3


The mechanism of action by which asenapine produces its therapeutic effects is unknown, but it is likely mediated by its ability to act as a dopamine and serotonin (5-HT2A) receptor antagonist.4-6 Asenapine swallowed in tablet form has less than 2% bioavailability, so the oral formulation should always be given sublingually for maximum benefit.1,7


Asenapine has a high binding affinity for many of the serotonin and dopamine receptor subtypes along with alpha1 and alpha2 adrenergic receptors as well as histamine H1 receptors. Asenapine has a moderate binding affinity for H2 receptors, and it has no significant ability to bind to muscarinic receptors.4,8

Dosing Recommendations for Asenapine


Asenapine (Saphris®) is available in 2.5 mg, 5 mg, and 10 mg sublingual tablets. Asenapine tablets should be placed under the tongue and allowed to dissolve, then swallowed with saliva.5 Sublingual tablets are fast-acting; they dissolve within seconds of being placed under the tongue. Patients should be advised to peel back the packaging of the medication and not try to push the tablet through the package, as that will cause the medication to crumble. Patients should also be advised that their hands should be completely dry during this process so as not to start the dissolving of the tablet prior to actual administration. The patient should not eat or drink for 10 minutes after taking the tablet. In a small study (26 patients), eating immediately before taking a dose of asenapine reduced the exposure to asenapine by 20%, and eating four hours after taking a dose reduced exposure by 10%.5 Patients may benefit from pharmacist education and counseling on opening the cassettes that brand name Saphris is dispensed in to avoid administration barriers.


The transdermal formulation of asenapine is seen under the brand name Secuado® and comes in the strengths of 3.8 mg/24 hours, 5.7 mg/24 hours, and 7.6 mg/24 hours. A patch should be applied once daily (once during a 24- hour period). Patients should only wear one patch at a time, and patches should not be cut for size or different doses.4 Application sites include the upper arm, upper back, abdomen, or hip. It is recommended that the application site be rotated with each application to minimize skin reactions. It is appropriate to shower with the patch; however, swimming or taking a bath has not yet been evaluated. External heat sources such as a heating pad may increase asenapine plasma concentrations and are not recommended.4


Bipolar I Disorder


In an acute manic or mixed episode in adults, asenapine may be used as monotherapy, 5 mg or 10 mg sublingually twice a day. The 24-hour maximum dose is 20 mg.5 Dosing recommendations for bipolar disorder are currently only given for the sublingual tablet.

Combination therapy (with lithium or valproate): Begin with 5 mg twice a day; if needed 10 mg twice a day can be used.5

Maintenance therapy: 5 mg – 10 mg twice a day.5 Initially, it is recommended that the patient continue the dose needed for stabilization and then be reevaluated based on response and tolerability.

Dosing for children in acute manic or mixed episodes state recommends an initial start of 2.5 mg twice daily, which can be increased to 5 mg twice daily after three days, then increased to 10 mg twice daily after an additional three days if indicated. Pediatric patients are more susceptible to dystonia if a slower titration process is not followed. Currently, the dosing is approved for children aged 10 and above, with safety and efficacy not yet established in the younger population.




Asenapine 5 mg sublingual tablet twice a day is the recommended starting dose for patients who are diagnosed with schizophrenia. After one week, the dose can be increased to 10 mg twice a day. The 24-hour maximum dose is 20 mg.4,5 Asenapine 3.8 mg/24 hours is the initial dose for the transdermal formulation. The dose may be increased to either 5.7mg/24 hours or 7.6mg/24 hours after one week if needed. The maximum dose of the transdermal formulation is 7.6 mg/24 hours. If switching from oral to transdermal formulation is desired, it is suggested that the 3.8 mg/24 hours dose corresponds to 5 mg sublingually twice daily and the 7.6 mg/24 hours dose corresponds to 10 mg sublingually twice daily. The lowest effective dose should be used and periodically reevaluated with all formulations.


Dosing Adjustments: Geriatrics, Renal, and Hepatic Impairment


There are no specific dosing adjustments for geriatric patients taking asenapine. The standard dosing guidelines should be used.4,5 Asenapine may cause orthostatic hypotension, which is an adverse effect that is more likely to be troublesome for geriatric patients.4 Although exposure levels are higher in elderly patients than in younger adults (approximately 30-40%) no dosage adjustments are recommended based on age alone due to the insufficient

number of elderly patients in clinical trials. It is still unknown if there is a greater response to asenapine in the older population compared to the younger population with regard to higher exposure levels.


Exposure levels of asenapine in patients with mild to severe renal impairment are similar to those with normal renal function, and no dose adjustments are required.5


The use of asenapine is contraindicated if a patient has severe hepatic impairment (Child-Pugh category C). Patients with severe hepatic impairment were found to have asenapine exposure averages 7 times higher than the group with normal hepatic function. If the patient has mild or moderate hepatic impairment, Child-Pugh category A or B, respectively, asenapine can be used with no dosing adjustment needed.4,5 Mild or moderate hepatic impairment groups did show that exposure was approximately 12% higher compared to healthy subjects, but no dosing adjustments are required. Elevated ALT occurred in 2% or less of patients who are taking asenapine,5,9 and transaminase elevations are usually mild and transient.5,10 During clinical trials, the ALT elevations (in some cases) were higher in the patients taking a placebo.5 The ALT elevations associated with asenapine resolve in several weeks and discontinuing the use of the drug or changing the dose is not needed. No cases of acute liver failure, chronic hepatitis, or vanishing bile duct syndrome have been associated with asenapine.9


Drug-Drug Interactions


The Lexicomp Drug Interactions database lists 106 drug-drug interactions involving asenapine.4 Concurrent use of asenapine and the drugs listed below may be contraindicated, or concurrent use should be done very cautiously with recommended dosing adjustments and close monitoring.4


Acetylcholinesterase inhibitors: Concurrent use may increase the risk of EPS.

Antidiabetic drugs: Asenapine can cause hyperglycemia.

Antihypertensives: May cause hypotension.

Anti-Parkinson drugs/dopamine agonists: Atypical antipsychotics may decrease the effectiveness of dopamine agonists that are used to treat Parkinson’s disease.

CNS depressants: Concurrent use may enhance CNS depressant effect.

CYP1A2 inducers: Asenapine is a substrate of the CYP1A2 enzyme, and drugs that are CYP1A2 inducers (such as leflunomide) could decrease the serum level of asenapine.

CYP1A2 inhibitors: Asenapine is a substrate of the CYP1A2 enzyme, and drugs that are strong inhibitors of CYP1A2 (such as fluvoxamine) could increase the serum level of asenapine.

CYP2D6 inhibitors: Asenapine is a weak CYP2D6 inhibitor, and it may increase the serum level of drugs that are a substrate of CYP2D6 (such as paroxetine). The Saphris prescriber information sheet suggests reducing paroxetine dose by half when used in combination with Saphris.5

Drugs that lower seizure threshold, for example, bupropion.

QTc prolonging drugs: Risks associated with higher serum concentrations of a QT-prolonging drug have been well described, and some have been withdrawn from the U.S., market due to prolonged QTc intervals. The specific risks associated with concurrent use of multiple QT-prolonging drugs (apart from a pharmacokinetic interaction) have not been well- described. The following medications are listed by Clinical pharmacology as contraindicated with asenapine due to QT prolongation or risk of torsade de pointes: cisapride, dronedarone, fluconazole, halofantrine, mesoridazine, pimozide, posaconazole, and thioridazine.


Asenapine Treatment for Psychiatric Conditions


In adults, asenapine has been approved and used to treat bipolar I disorder and schizophrenia.5,11,12 For pediatric patients, aged 10–17 years of age, asenapine also received approval as a monotherapy for the treatment of bipolar I disorder with manic or mixed mood episodes.4,5,13

Bipolar I Disorder


Bipolar disorder is a psychiatric disorder characterized by episodes of mania, hypomania, and major depression.11,12 There are two types of bipolar disorder, type I and type II. Manic episodes are a feature of type I but not type II, and patients who have type I almost always have major depressive and hypomanic episodes. Bipolar disorder can also present with mixed features, which are also called mixed episodes.12 The onset of bipolar I disorder may occur during childhood or adolescence.13 Early onset of bipolar I disorder is more common than other serious psychiatric conditions (e.g., schizophrenia).13 Studies indicate that the onset of bipolar disorder occurs before the age of 13 in 14–28% of patients and between 13 and 18 years of age in 36–38% of patients.13


Asenapine is used to treat patients diagnosed with acute manic or mixed episodes in adults with bipolar I disorder. It can also be used as maintenance treatment, and as an adjunct, in combination with lithium or valproic acid.4,5


Asenapine offers a treatment option for patients diagnosed with bipolar I disorder with manic or mixed episodes during childhood or adolescence. As mentioned above, asenapine is approved in the U.S., as a monotherapy to treat children and adolescents aged 10–17 years with this condition.10 Asenapine is not approved for pediatric use in patients with other forms of bipolar I disorder.13 The recommended dose is 2.5–10 mg administered sublingually, twice a day.13 Stepanova, et al. (2018) provided a summary of the effects and safety of using asenapine in the pediatric population.13 They reported that trial participants who were administered asenapine versus placebo for treatment of acute bipolar I disorder showed improvement in symptoms of mania. The asenapine doses used were 2.5, 5, 10 mg, sublingually, twice a day.13 These patients should be closely monitored for treatment efficacy and adverse effects, as is the case generally with the use of all antipsychotics.13

A recent randomized, double-blind, placebo-controlled study and a review of the literature both confirmed that asenapine alone is an effective maintenance therapy for patients who have bipolar disorder.14,15 Use of asenapine as a maintenance therapy is less clear when compared to other drugs. According to Post (2019), asenapine may be considered a third-line treatment for this purpose.16


Studies comparing monotherapy with asenapine to haloperidol and olanzapine as a treatment for acute mania or mixed episodes found that asenapine reduced mania rating scores, sustained remission, and was equivalent or at times superior to these drugs for treating bipolar disorder.17,18


Asenapine can be used as an adjunct agent or in combination with lithium or valproic acid for the treatment of manic or mixed episodes in adult patients who have bipolar I disorder. The use of a mood stabilizer and an atypical antipsychotic is the preferred treatment for severe manic episodes.19 Combination therapy as a treatment for acute mania has been proven to be superior to a mood stabilizer plus a placebo and superior to monotherapy with lithium or valproic acid.19,20 The data on asenapine combination therapy is not extensive, but this is a labeled use for the drug. There are a small number of case reports, one 12-week randomized controlled trial, and several case series that found that asenapine and lithium or valproic acid could significantly reduce the severity of manic symptoms, decrease the frequency of manic episodes, and have an acceptable safety profile.15,21-23 There are no studies that have compared the therapeutic effectiveness of asenapine and lithium or valproic acid in combination with other atypical antipsychotics.




Antipsychotics are the drug of choice for treating schizophrenia. Asenapine is an effective treatment for acute exacerbations of schizophrenia and prevents relapses when used as a long-term maintenance therapy.24-26 Comparison of asenapine to other atypical antipsychotics has been limited to olanzapine and, depending on the measured outcome, asenapine has been found to be either equivalent or inferior to olanzapine.25

The onset of schizophrenia may occur during childhood or adolescence but this is rare. The potential onset of schizophrenia does increase as a child gets older, with peak onset reportedly appearing from age 15 and thereafter.13 Asenapine is not currently approved for pediatric patients with schizophrenia.13 The results of the trial on the efficacy of asenapine in treating schizophrenia were not conclusive but did provide valuable information on the drug’s safety profile in pediatric patients.13


Adverse Effects, Contraindications and Warnings


Contraindications include hypersensitivity to asenapine or any of the components of the product. Other contraindications include severe hepatic impairment (Child-Pugh category C). Adverse effects listed with an incidence of ≥ 5% or twice the incidence of placebo: akathisia, dizziness, dysgeusia, fatigue, increased appetite, increased weight, nausea, oral hypoesthesia, oral paresthesia, and somnolence.5


Adverse effects of asenapine such as CNS depression, motor, and sensory instability, and orthostatic hypotension can increase the risk for falls and subsequent fractures.4,5 The U.S. Food and Drug Administration (FDA) issued a warning in 2017 that the use of antipsychotics may cause falls and fractures.27 A pre-treatment fall assessment and periodic assessment of fall risk during the use of antipsychotics is recommended.


Elderly and Dementia


Asenapine is not approved for the treatment of dementia-related psychosis.4,5 McKeirnan (2019) reported that the Centers for Medicare and Medicaid stated that an estimated 16% of elderly people in nursing homes as of 2017 had been prescribed antipsychotics.28 Except for in an emergency, the American Psychiatric Association (APA) has recommended that antipsychotics should “only be used for the treatment of agitation or psychosis in patients with dementia when symptoms are severe, are dangerous, and/or cause significant distress to the patient.”28 The prescribing information for many of the atypical antipsychotics has a U.S. Black Boxed Warning that advises

clinicians about the use of these drugs in elderly patients who have dementia and the corresponding increased risk of death.28


Atypical antipsychotics can be used to treat serious behavioral and emotional problems in patients with dementia. However, the use of antipsychotics where dementia has been diagnosed should be restricted to situations where other treatments have been unsuccessful, and the patient’s health or the safety of others is at risk.29 McKeirnan (2019) has suggested that all members of the health team, including pharmacists, “should guide pharmacologic and nonpharmacologic therapy choices based on unique individual patient profiles, keeping in mind the great risks associated with antipsychotic use in elderly with dementia.”28


Temperature Regulation


The antipsychotics have been associated with altered thermoregulation and can have anticholinergic effects, both of which can put the patient at risk for an elevated temperature.4,5 During pre-market clinical trials of asenapine, the incidence of adverse effects that suggested an elevated body temperature was ≤ 1% for the asenapine-treated group and 0.0% for the placebo group.4 Dehydration, high ambient temperature, the concurrent use of anticholinergic drugs, and strenuous exercise may increase this risk.4,5 Aside from cases of neuroleptic malignant syndrome (NMS), there is no published information on asenapine and elevated body temperature.


Orthostatic Hypotension and Cardiovascular Conditions


Asenapine has a high level of peripheral alpha-adrenergic receptor antagonism and can cause orthostatic hypotension.4,5 Elderly patients are more likely to have orthostatic hypotension, probably due to decreased baroreceptor sensitivity. Asenapine should be used cautiously if the patient has cardiovascular or cerebrovascular disease, takes medication that can cause hypotension, is dehydrated or hypovolemic, or cannot tolerate a sudden drop in blood pressure.4,5 Cardiac concerns with asenapine use include QTc prolongation, which is a risk factor for potentially dangerous arrhythmias.4,5

The use of asenapine should be avoided if the patient has congenital long QT syndrome or if taking a medication that can prolong the QT interval.4,5 The risk of QTc prolongation is magnified by hypokalemia and hypomagnesemia.4,5 Drug-induced acquired QT prolongation is defined as a QTc interval that is > 500 msec or a QTc interval increase ≥ 60 msec of the patient’s baseline QTc interval. The risk of QT prolongation caused by asenapine is low, and only two cases of prolonged QT caused by asenapine have been published in the medical literature.31-35 Clinical studies and literature reviews have found that asenapine increased the QT interval 2-5 msec, asenapine did not cause a QT interval increase ≥ 60 msec of the baseline or a QT interval > 500 msec, and there are no reports of asenapine causing torsade de pointes.5,31 However, the prescribing information does state that asenapine can cause a prolonged QT interval, and when administering or prescribing asenapine, clinicians should carefully evaluate a patient’s risk factor profile for QT prolongation and torsades de pointes.31




During clinical trials and post-marketing experience with asenapine, cases of leukopenia and neutropenia related to the use of the drug were reported. These blood dyscrasias, as well as agranulocytosis, have been associated with the use of other antipsychotics.4,5 Patients who have a low white blood cell count (WBC), a low absolute neutrophil count (ANC), or have had drug-induced leukopenia or neutropenia may be susceptible to these hematologic adverse effects. The complete blood count (CBC) should be closely monitored for the first few months of use, and if a blood dyscrasia develops or if the ANC is < 1,000/mm3 the patient should stop taking asenapine.4,5


Central Nervous System


Sedation and somnolence are common CNS adverse effects of asenapine. The atypical antipsychotics may also lower the seizure threshold. During pre-marketing trials of asenapine, seizures were reported in 5/1953 (0.3%) of adult patients.5 In short-term pre-marketing trials, seizures were

reported in 0% and 0.3% of patients treated with 5 mg or 10 mg of asenapine, respectively, compared to 0% of patients treated with placebo.5 Asenapine should be used cautiously in patients who have a seizure disorder or may be at risk for seizures.4,5


Atypical antipsychotics can cause movement disorders such as extrapyramidal symptoms (EPS), akathisia, dystonias, Parkinsonism, and tardive dyskinesia.4,5 These adverse effects can occur with the use of typical and atypical antipsychotics, but the risk for EPS is much lower than with typical antipsychotics.4 Drug-induced movement disorders are thought to be primarily caused by dopamine receptor antagonism and an imbalance between dopaminergic and cholinergic activity in the nigrostriatal tract, an area of the brain that controls motor movements. Extrapyramidal symptoms are a well- known adverse effect of typical antipsychotics. The atypical antipsychotics do not have the level of D2 receptor antagonism as the typical antipsychotics, but they can cause EPS as well, although the risk is less.36-38


Asenapine has a high binding affinity association rate for dopamine2 receptors, so it is expected that it would be associated with a significantly higher prevalence of movement disorders compared with placebo; however, this has not been shown to date.39 The risk for movement disorders increases substantially when dopamine2 receptors occupancy exceeds 80%.40 Three case reports of asenapine-induced dystonic reaction were found in the medical literature.41-43


Akathisia is one of the more commonly reported adverse events from asenapine use, with a majority of these events being either mild or moderate in severity.44 Akathisia caused by asenapine has been reported to occur in 1.9% - 8.3% of patients.14,44,45 Parkinsonism caused by asenapine has been reported, but this appears to be a rare adverse effect of the drug.44 The true risk for and incidence of antipsychotic-induced tardive dyskinesia is unknown; estimates from > 20% - 32.4% have been reported, with a yearly increase of five percent.45,46 A recent (2018) meta-analysis of the published literature concluded that atypical antipsychotics are much less likely to cause tardive dyskinesia.47 Factors that increase the risk for developing tardive dyskinesia

may include African American ethnicity, alcohol or substance use, cognitive disturbance, diabetes, development of other EPS, high dose and long duration of use, female gender, and older age.48,49 Given the consequences of this type of EPS and that antipsychotic-induced tardive dyskinesia can be permanent, even a much smaller degree of risk would have serious implications.


Weight Gain, Hyperglycemia, and Dyslipidemia


Weight gain is a relatively common adverse effect of atypical antipsychotics, including asenapine. During a 52-week controlled trial of asenapine, the mean weight gain from baseline was 0.9 kg, and at the end of the trial, 14.7% of the patients had a minimum of 7% body weight gain.5


There is limited published information about asenapine and hyperglycemia. Asenapine is considered to have a low potential for causing hyperglycemia, and the prescribing information states that in short-term trials (3 weeks and 6 weeks), the mean change in fasting glucose was -0.2 – 0.0 mg/dl in the placebo-treated patients and in the asenapine-treated patients it was 1.1 mg/dL – 4.1 mg/dL, depending on the dose.5 Patients who have diabetes or who are prediabetic are more likely to develop hyperglycemia from an atypical antipsychotic, and it has been estimated people who take an atypical antipsychotic have a two- to threefold increased prevalence of hyperglycemia and diabetes compared to the general population.32


The incidence of dyslipidemias (including elevated total serum cholesterol, increased LDL cholesterol and decreased HDL cholesterol, and elevated fasting serum triglycerides) varies between the atypical antipsychotics, and asenapine is considered to have a low risk.32 The prescribing information notes that during short-term clinical trials of asenapine as a treatment for bipolar disorder, the number of patients who developed a serum cholesterol > 240 mg/dL was 7.8% of the asenapine-treated patients and 7.9% of the placebo-treated patients. In these same trials, 13.1% of the asenapine patients developed a serum triglyceride level > 200 mg/dL versus 8.6% of the placebo-treated patients.5 In the short-term clinical trials with schizophrenic patients, 8.3% of the asenapine patients developed serum

cholesterol > 240 mg/dL versus 7% of the placebo-treated patients, and 13.2% of the asenapine-treated patients developed a serum triglyceride level

> 200 mg/dL versus 10.5% of the placebo-treated patients.5 There is limited information that compares asenapine and other atypical antipsychotics, but Maina, et al. (2014) found that 6.8% of patients receiving olanzapine and 2.8% of patients receiving asenapine developed dyslipidemia.50




Atypical antipsychotics, including asenapine, may increase serum prolactin levels and have been associated with sexual and reproductive dysfunction. The risk is thought to be highest for paliperidone and risperidone, and asenapine has been shown to have either no effect on serum prolactin, clinically insignificant elevations or the number of patients who develop clinically significant prolactin levels is very low.33,51 If the patient has an elevated prolactin level and is symptomatic, treatment with the drug can be discontinued, and the serum prolactin level should return to normal within several days. In cases of hyperprolactinemia, the dose can be reduced, a low- potency antipsychotic can be used as a replacement, a prolactin-sparing antipsychotic can be prescribed, women can be prescribed estrogen, or the patient can continue to take the offending drug and a full or partial dopamine agonist can be prescribed.52,53 Galactorrhea or dysmenorrhea were rare side effects reported in 2% or less of asenapine-treated patients compared to 1% in placebo-treated patients.54,55




Antipsychotics, including asenapine, have been associated with esophageal dysmotility and aspiration.19 Asenapine should be used cautiously in patients who are at risk for aspiration; for example, in an elderly, patient who has Alzheimer’s disease or dementia, or a patient > 75 years of age.4,5

Constipation, xerostomia, oral hypoesthesia, hypersalivation, stomach discomfort, and vomiting are side effects associated with asenapine. Although these side effects have a low incidence of less than 10%, they should be monitored in all patients taking asenapine.56


Neuroleptic Malignant Syndrome (NMS)


Three cases of NMS caused by asenapine have been reported. All three had what is considered the typical presentation of NMS, described as delayed onset, altered mental status, hyperthermia, and rigidity.57-59 The pathophysiology of NMS is not fully understood but is believed to be partially due to dopamine receptor blockade.60,61 Factors that increase the risk for NMS may include male gender, a rapid dose titration, dehydration, and a prior episode of NMS. A high dose of an antipsychotic may increase the risk of developing NMS, but most cases are caused by doses that are within the prescribed therapeutic range.60 The onset of signs and symptoms usually begins within two weeks of starting therapy with an antipsychotic, and almost all cases of NMS occur within 30 days of the first dose. Neuroleptic Malignant Syndrome can occur after the first dose or after years of taking the same drug at the same dose, and it can happen when the use of the drug is discontinued. Asenapine should be discontinued if NMS is developed.


Restarting treatment with an antipsychotic after NMS has resolved is complicated and risky. Recurrence of NMS after restarting therapy with an antipsychotic is associated with a 10%-90% incidence.61,62 Reoccurrence of NMS is unpredictable; however, Wijdicks (2019) reported that a decrease in the risk of recurrent NMS is possible with the following interventions - waiting

>14 days for resumption of antipsychotic treatment, using low potency antipsychotics, avoiding rapid titration or high initial doses, and avoiding the use of lithium.61


Suicidal Behavior


The prescribing information for asenapine does not have a warning of increased suicidal thought and behavior but it does state: “The possibility of a

suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.”5 Atypical antipsychotics may be prescribed for patients who have unipolar major depression; however, major depression is a strong risk factor for suicide.63-65


Pregnancy and Breastfeeding


The use of antipsychotics during the third trimester has been associated with EPS and withdrawal signs and symptoms in neonates.4 There is little to no information about asenapine and the risk for pregnancy and birth complications like congenital malformations, low gestational weight, premature birth, and stillbirth.66 There are no controlled studies of its use in pregnant women. Asenapine was classified as a pregnancy risk category C drug which meant that animal studies have shown that the drug can cause fetal harm, and the benefits of a category C drug during pregnancy may outweigh the risks.67 The A-X system is still widely used, albeit informally, and the FDA has required that manufacturers no longer use the A-X system in prescribing information and to change package inserts to comply with the FDA’s Pregnancy and Lactation Labeling Rule (PLLR).67


Asenapine Case Studies


The following case studies were obtained from a PubMed search. The first case study discusses the use of asenapine in a 71-year-old female diagnosed with bipolar disorder and mania.34 The second case study discusses the use of asenapine in a 44-year-old female diagnosed with bipolar disorder.43


Case Study 1: Bipolar I Disorder with Mania


The authors reported a case of a 71-year-old female with a long history of bipolar disorder who was admitted with mania. Prior medications for the treatment of bipolar disorder included sodium valproate and olanzapine;

however, the patient was reportedly non-adherent with medications for 5 months prior to admission.34


The patient was administered olanzapine 10 mg twice daily when admitted. A course of electroconvulsive therapy (ECT) was planned a week later due to poor remission of symptoms, and the patient had a history of a successful response to ECT therapy in the past.34 She had no significant comorbid medical conditions, and all laboratory testing was normal, including electrolytes. An electrocardiogram (ECG) was normal with QTc of 383 ms. Two cycles of ECT were completed, and she was switched from olanzapine to asenapine 5 mg twice daily because the patient complained of weight gain on olanzapine. Prior to a 3rd ECT session, the patient reportedly developed ventricular trigeminy with a QTc of 459 ms.34 Due to this change in her ECG, the ECT session was not pursued but the patient underwent repeated blood testing, e.g., electrolytes and cardiac enzymes, which were normal. A repeat ECG 12 hours later also showed ventricular trigeminy, and prolonged QTc.34


Asenapine was stopped as it was suspected to be the cause of the onset of arrhythmia and QTc prolongation. The day following discontinuation, the ventricular trigeminy stopped, and the patient’s QTc shortened to 428 ms. The patient was able to continue with ECT and was discharged after 19 days from the time of admission with a prescription of sodium valproate 600 mg twice daily.34




A prolonged QT interval placed the patient at risk of developing ventricular arrhythmias that included torsade de pointes, which could be fatal. The patient also developed ventricular trigeminy, which the authors described as a type of extrasystole that recent research suggests could lead to the possible development of nonischemic dilated cardiomyopathy, even in the absence of known cardiac disease.34 Cardiac rhythm monitoring was recommended by the authors whenever starting, switching, or increasing the dose of antipsychotics, especially in elderly or other high-risk individuals. Significant cardiac changes can occur when starting or switching

antipsychotics, even in an antipsychotic medication considered as having a lower risk profile for causing QTc changes that place a patient at risk of a dangerous cardiac arrhythmia.34


Case Study 2: Bipolar I Disorder


In this case study, the authors report on a potential drug-drug interaction between asenapine and ciprofloxacin.43 The patient was a 44-year- old, non-smoker, single white female. The patient had a history of bipolar I disorder. The patient was admitted to the hospital because of a worsening depressed mood.43


The patient had been taking asenapine 5mg for the 1.5 months prior to her admission in this case. The patient had a prior, severe dystonic reaction to haloperidol. The patient’s prescribed medications were continued and they “included baclofen 20mg/d, dexlansoprazole 60mg/d, fluoxetine 20mg/d, lorazepam 1mg/d and divalproex 2250mg/d.”43


The patient had a urinary tract infection (UTI) at admission, and she was administered ciprofloxacin 500mg, twice daily. Within 33 hours of taking ciprofloxacin, the patient was unable to close her jaw, which was indicative of acute dystonia. The patient was administered 50mg of diphenhydramine intramuscularly to treat her acute dystonia, and the condition resolved.43 Ciprofloxacin was discontinued and the patient was prescribed nitrofurantoin 100mg, twice daily, in its place. Asenapine was continued with no complications thereafter.43




In this case, the authors stated that the potential drug-drug interaction between asenapine and ciprofloxacin had not been previously reported.43 Asenapine is a newer second-generation antipsychotic that is primarily metabolized by Uridine 5′-diphospho-glucuronosyltransferase 1A4 (UGT1A4) and cytochrome p450 (CYP)1A2.43 Ciprofloxacin is a potent inhibitor of CYP1A2 but not of UGT1A4.43 Ciprofloxacin has a half-life of 4 hours, and it reaches a

steady state after 3 days.43 Interactions between ciprofloxacin and second- generation antipsychotics that are metabolized through the CYP1A2 pathway have been published, such as a case involving elevated olanzapine serum levels when co-administered with ciprofloxacin.43,68


In this case, the authors determined that ciprofloxacin precipitated the patient’s dystonia.43 The patient’s UTI could have been an additional contributing factor, but the authors noted that the dystonia did not appear until after the initiation of ciprofloxacin, and given ciprofloxacin’s pharmacokinetics, it was considered the primary cause of the patient’s dystonia.43




Asenapine can be administered as monotherapy and as adjunctive therapy and has been reported to be effective in the treatment of mixed mood states and mania associated with bipolar I disorder and in schizophrenia in adult and pediatric patients. Some studies have identified that the use of asenapine acts as a mood stabilizer and helps to lower clinical depression in cases of bipolar I disorder. Common adverse effects have been reviewed, and the adverse effects of asenapine are suggested to be less than those associated with other antipsychotics, such as olanzapine.


As a second-generation antipsychotic drug, asenapine has been approved by the U.S. Food and Drug Administration and shows high affinity to serotonin receptors, dopamine receptors, alpha 1 and 2 receptors, histamine (H1) receptors, and moderate affinity to histamine (H2) receptors. Asenapine is unique from other antipsychotic agents because it has no affinity towards muscarinic receptors as well as in its mode of administration as a sublingual rapidly dissolving agent. While numerous studies exist on the metabolic and cardiovascular risk of antipsychotics in patients who are elderly or are diagnosed with comorbid liver and renal disease, more research is needed on the benefit and risk of asenapine in comparison to other antipsychotics.

Course Test


For the treatment of bipolar I disorder, asenapine


can be used as a monotherapy.

is only approved as an adjunct treatment.

is only recommended for people who are age 18 and older.

should never be used with lithium.


Asenapine has a high level of peripheral alpha-adrenergic receptor antagonism, which is most likely to be concern for





orthostatic hypotension.


Asenapine is approved for pediatric patients, aged 10–17 years, with



bipolar I disorder with manic or mixed episodes.

any psychosis due to a medical condition.

postural hypotension.


Asenapine should be stopped in a patient who develops an ANC level of


< 1,500/mm3

> 1,500/mm3

< 1,000/mm3



Asenapine is            CYP2D6 inhibitor.


a strong

a weak

not identified as a

a moderate

The recommended starting dose for asenapine for the treatment of schizophrenia is a     sublingual tablet twice a day.


10 mg

30 mg

5 mg

20 mg


True or False: There are no specific dosing adjustments for geriatric patients taking asenapine.





With atypical antipsychotics such as asenapine, extrapyramidal symptoms (EPS)


may occur but the risk is lower than with typical antipsychotics.

do not occur.

occur because of their high level of D2 receptor antagonism.

occur when these drugs are discontinued.


Which of the following is NOT considered a likely risk factor for developing tardive dyskinesia in patients prescribed antipsychotics?


African-American ethnicity


High dose and long duration of use of antipsychotic

Male gender


True or False: Asenapine is contraindicated if a patient has mild, moderate, or severe hepatic impairment.






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