Asenapine
Brand names: Saphris
Drug class:
Antineoplastic Agents
Usage of Asenapine
Schizophrenia
Acute and maintenance treatment of schizophrenia in adults.
American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).
Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.
Bipolar Disorder
Acute treatment as monotherapy or adjunctive therapy with lithium or valproate of manic or mixed episodes associated with bipolar I disorder (with or without psychotic features).
Maintenance treatment as monotherapy of bipolar I disorder.
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How to use Asenapine
Administration
Sublingual Administration
Administer tablets sublingually twice daily.
Do not remove sublingual tablet from blister pack until just prior to administration. With dry hands, pull blister pack out of case and peel back colored tab to expose the tablet; do not push tablet through blister pack. Gently remove tablet and place under the tongue, then allow to dissolve completely (usually takes about 10 seconds).
Do not eat or drink for 10 minutes following administration. Do not split, crush, chew, or swallow the sublingual tablets. (See Food and Water under Pharmacokinetics.)
Dosage
Available as asenapine maleate; dosage expressed in terms of asenapine.
Pediatric Patients
Bipolar Disorder Manic and Mixed Episodes: Monotherapy SublingualChildren and adolescents 10–17 years of age: Initially, 2.5 mg twice daily. Recommended target dosage is 2.5–10 mg twice daily. Based on individual patient response and tolerability, may increase to 5 mg twice daily after 3 days and then to 10 mg twice daily after 3 additional days. Carefully titrate dosage to reduce risk of dystonia. (See Pediatric Use under Cautions.) Safety of dosages >10 mg twice daily not evaluated.
Adults
Schizophrenia SublingualFor acute treatment, recommended initial and target dosage is 5 mg twice daily. May increase to 10 mg twice daily after 1 week based on tolerability. The higher dosage (10 mg twice daily) did not provide additional therapeutic benefit in clinical trials, but was clearly associated with increased adverse effects. Safety of dosages >10 mg twice daily not evaluated.
For maintenance treatment, recommended target dosage range is 5–10 mg twice daily.
In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug. Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.
Bipolar Disorder Manic and Mixed Episodes: Monotherapy or Combination Therapy SublingualMonotherapy for acute treatment: Initial and target dosage is 5–10 mg twice daily. Safety of dosages >10 mg twice daily not evaluated.
Adjunctive therapy with lithium or valproate for acute treatment: Initially, 5 mg twice daily. May increase dosage to 10 mg twice daily based on clinical response and tolerability. Safety of dosages >10 mg twice daily not evaluated.
In responsive patients, continue drug therapy beyond the acute response.
Monotherapy for maintenance treatment: Continue same dosage used during stabilization (5–10 mg twice daily). Based on clinical response and tolerability, may decrease 10-mg twice-daily dosage to 5 mg twice daily. Safety of dosages >10 mg twice daily not evaluated.
Prescribing Limits
Pediatric Patients
Bipolar Disorder Manic and Mixed Episodes SublingualSafety of dosages >10 mg twice daily not evaluated.
Adults
Schizophrenia SublingualSafety of dosages >10 mg twice daily not evaluated.
Bipolar Disorder Manic and Mixed Episodes SublingualSafety of dosages >10 mg twice daily not evaluated.
Special Populations
Hepatic Impairment
Severe hepatic impairment (Child-Pugh class C): Use is contraindicated.
Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary. (See Absorption: Special Populations, under Pharmacokinetics.)
Renal Impairment
Routine dosage adjustment not required. (See Absorption: Special Populations, under Pharmacokinetics and also see Elimination: Special Populations, under Pharmacokinetics.)
Geriatric Patients
Routine dosage adjustment not required. (See Geriatric Use under Cautions and also see Absorption: Special Populations, under Pharmacokinetics.)
Gender, Race, or Smoking Status
Dosage adjustment not routinely required based on gender, race, or smoking status.
Warnings
Contraindications
Warnings/Precautions
Warnings
Increased Mortality in Geriatric Patients with Dementia-related PsychosisIncreased risk of death with use of antipsychotic agents in geriatric patients with dementia-related psychosis.
Analyses of 17 dementia-related psychosis placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.
Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).
Antipsychotic agents, including asenapine, are not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning; Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions; and also see Dysphagia under Cautions.)
Sensitivity Reactions
Hypersensitivity ReactionsHypersensitivity reactions reported with asenapine. Symptoms included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash. Some cases reported occurrence of more than one hypersensitivity reaction, and several reported hypersensitivity reactions occurring after the first dose. In some patients, symptoms resolved after asenapine discontinuance; others required hospitalization or emergency room visits and therapeutic interventions. (See Contraindications under Cautions and also see Advice to Patients.)
Other Warnings and Precautions
Cerebrovascular Events in Geriatric Patients with Dementia-related PsychosisIncreased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. Asenapine is not approved for the treatment of patients with dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)
Neuroleptic Malignant SyndromeNeuroleptic malignant syndrome (NMS), a potentially fatal symptom complex characterized by hyperpyrexia, muscle rigidity, delirium, and autonomic instability, reported with antipsychotic agents, including asenapine.
If NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring.
Tardive DyskinesiaTardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including asenapine.
Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients requiring chronic treatment, use lowest dosage and shortest duration of treatment needed to achieve a satisfactory clinical response; periodically reassess need for continued therapy.
APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months. Consider discontinuance of asenapine if signs and symptoms of tardive dyskinesia appear. However, some patients may require treatment despite the presence of the syndrome.
Metabolic ChangesAtypical antipsychotic agents, including asenapine, have caused metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain. While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile. (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)
Hyperglycemia and Diabetes MellitusHyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents. Hyperglycemia reported in patients treated with asenapine. In short-term controlled trials in patients with schizophrenia or bipolar mania, approximately 0–5 and 6–16% of asenapine-treated patients experienced shifts from normal to high and from borderline to high fasting glucose concentrations, respectively. In a longer-term (one-year), comparator-controlled, double-blind study, the mean increase in fasting glucose concentrations from baseline was 2.4 mg/dL.
Assess blood glucose before or soon after initiation of antipsychotic therapy, then periodically monitor during long-term therapy. (See Advice to Patients.)
DyslipidemiaUndesirable changes in lipid parameters observed in patients treated with some atypical antipsychotics. However, asenapine does not substantially affect the lipid profile during short-term therapy.
Baseline (i.e., before or soon after initiation of therapy) and periodic follow-up fasting lipid evaluations recommended during asenapine therapy.
Weight GainWeight gain observed with atypical antipsychotic therapy, including asenapine.
Manufacturer recommends baseline and frequent monitoring of weight during therapy. In pediatric patients, monitor weight gain and assess against that expected for normal growth.
Orthostatic Hypotension, Syncope, and Other Hemodynamic EffectsRisk of orthostatic hypotension and syncope reported with atypical antipsychotics, particularly during initial dosage titration and when dosage is increased.
In clinical trials in adults, including long-term trials without comparison with placebo, syncope was reported in 0.6% of asenapine-treated patients. In short-term bipolar mania trials in pediatric patients, syncope was reported in 1% of patients receiving asenapine 2.5 or 5 mg twice daily and in no patients receiving asenapine 10 mg twice daily.
Monitor orthostatic vital signs in patients who are susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients concomitantly receiving antihypertensive therapy), patients with cardiovascular disease (e.g., history of MI, ischemic heart disease, heart failure, conduction abnormalities), and patients with cerebrovascular disease. Use with caution in patients receiving other drugs that can cause hypotension, bradycardia, respiratory depression, or CNS depression (see Interactions). In all such patients, consider monitoring of orthostatic vital signs; if hypotension occurs, consider dosage reduction.
FallsMay cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.
In patients with diseases, conditions, or other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.
Leukopenia, Neutropenia, and AgranulocytosisLeukopenia and neutropenia temporally related to antipsychotic agents, including asenapine, reported during clinical trial and/or postmarketing experience. Agranulocytosis (including fatal cases) also reported with other antipsychotic agents.
Possible risk factors for leukopenia and neutropenia include preexisting low WBC count or ANC or a history of drug-induced leukopenia or neutropenia. Monitor CBC during the first few months of therapy in patients with such risk factors. Discontinue asenapine at the first sign of a clinically important decline in WBC count in the absence of other causative factors.
Carefully monitor patients with clinically important neutropenia for fever or other signs and symptoms of infection (e.g., fever) and treat promptly if they occur. Discontinue asenapine if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.
Prolongation of QT IntervalRelatively small increases (2–5 msec with asenapine compared with placebo) in corrected QT (QTc) interval observed in adults with schizophrenia in a controlled and dedicated QT study; these increases were slightly lower than those observed in patients receiving quetiapine. During clinical trials, post-baseline QT-interval prolongations >500 msec reported at similar rates for asenapine and placebo; torsades de pointes or adverse effects associated with delayed ventricular repolarization not reported.
Avoid use in patients concurrently receiving other drugs known to prolong the QTc interval, in patients with a history of cardiac arrhythmias, and in other circumstances that may increase risk of torsades de pointes and/or sudden death (e.g., bradycardia, hypokalemia or hypomagnesemia, presence of congenital QT-interval prolongation). (See Drugs that Prolong QT Interval under Interactions.)
HyperprolactinemiaMay cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence); chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both females and males.
If contemplating asenapine therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.
SeizuresSeizures reported in 0.3% of asenapine-treated adult patients in schizophrenia and bipolar mania clinical trials. No seizures reported in pediatric patients in a short-term bipolar mania trial.
Use with caution in patients with a history of seizures or conditions that may lower seizure threshold; such conditions may be more prevalent in patients ≥65 years of age.
Cognitive and Motor ImpairmentSomnolence, usually transient and with the highest incidence during the first week of therapy, reported in 13–26% of adult patients and 46–53% of pediatric patients receiving asenapine in clinical trials. (See Specific Drugs under Interactions and also see Advice to Patients.)
Body Temperature RegulationDisruption of ability to regulate core body temperature possible with atypical antipsychotic agents, including asenapine; ≤1% of asenapine-treated patients in premarketing clinical trials experienced adverse effects suggestive of body temperature increases (e.g., pyrexia, feeling hot).
Use caution in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).
DysphagiaEsophageal dysmotility and aspiration associated with the use of antipsychotic agents. Dysphagia reported with asenapine. Use with caution in patients at risk for aspiration.
Specific Populations
PregnancyNo studies conducted to date in pregnant women. No available human data informing the drug-associated risk. In animal reproduction studies, asenapine was not teratogenic at dosages 0.7 and 0.4 times, respectively, the maximum recommended human dosage (MRHD). In animals, the drug increased post-implantation loss and early pup deaths and decreased subsequent pup survival and weight gain. Advise pregnant women of potential risk to the fetus with asenapine exposure.
Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester. Symptoms have varied in severity; some infants recovered within hours to days without specific treatment while others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms; if such symptoms occur, manage appropriately.
National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].
LactationAsenapine distributes into milk in rats; not known whether distributes into human milk. Effects of the drug on nursing infants and on milk production also not known.
Weigh benefit of asenapine therapy to the woman and benefits of breast-feeding against potential risk to infant from exposure to the drug or from the underlying maternal condition.
Pediatric UseSafety and efficacy not evaluated in pediatric patients <10 years of age.
Safety and efficacy of asenapine monotherapy for treatment of bipolar I disorder in pediatric patients 10–17 years of age established. Such patients appear to be more sensitive to dystonia if initial dosage titration schedule not followed; titrate dosage according to manufacturer's recommended schedule (see Dosage under Dosage and Administration). Safety and efficacy as adjunctive therapy for the treatment of bipolar disorder not established in pediatric patients to date. (See Elimination: Special Populations, under Pharmacokinetics.)
Efficacy for the treatment of schizophrenia not established in pediatric patients <18 years of age. In a short-term (i.e., 8 weeks' duration), placebo-controlled trial in adolescents 12–17 years of age with schizophrenia, asenapine (2.5 or 5 mg twice daily) did not substantially improve the PANSS total score compared with placebo. Tolerability of asenapine in this trial generally was similar to that observed in the pediatric bipolar and adult bipolar and schizophrenia trials. In addition, no important safety findings reported in a 26-week, open-label, uncontrolled safety trial in pediatric patients with schizophrenia.
Geriatric UseInsufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults. Risk of poorer tolerance and orthostasis; carefully monitor. (See Geriatric Patients under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)
Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death; increased incidence of adverse cerebrovascular events also observed with certain atypical antipsychotic agents. Asenapine is not approved for the treatment of patients with dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)
Hepatic ImpairmentSubstantially higher exposures observed in individuals with severe hepatic impairment (Child-Pugh class C). Use is therefore contraindicated in such patients. (See Absorption: Special Populations, under Pharmacokinetics.)
Exposure is not substantially altered in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment; dosage adjustment is therefore not necessary in such patients.
Renal ImpairmentExposure was similar in individuals with varying degrees of renal impairment and those with normal renal function; dosage adjustment not required. (See Absorption: Special Populations, under Pharmacokinetics and also see Elimination: Special Populations, under Pharmacokinetics.)
Common Adverse Effects
Adults with schizophrenia (acute treatment): Akathisia (including hyperkinesia), oral hypoesthesia, somnolence (including sedation and hypersomnia). Akathisia appears to be dose related. Tolerability profile in the maintenance treatment of schizophrenia was similar to that seen with acute treatment.
Adults with bipolar disorder (acute treatment; monotherapy or adjunctive therapy): Somnolence (including sedation and hypersomnia), oral hypoesthesia, dizziness, extrapyramidal symptoms other than akathisia (e.g., dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, tremor), akathisia. All common adverse effects appear to be dose related. Tolerability profile in the maintenance treatment of manic or mixed episodes associated with bipolar 1 disorder was similar to that seen with acute treatment.
Pediatric patients with bipolar disorder (acute treatment; monotherapy): Somnolence (including sedation and hypersomnia), dizziness, dysgeusia, oral hypoesthesia, nausea, increased appetite, fatigue, weight gain. Frequency of fatigue appears to be dose related.
What other drugs will affect Asenapine
Metabolized mainly by direct glucuronidation by UGT1A4 and oxidative metabolism by CYP isoenzymes, principally by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6. Weakly inhibits CYP2D6; does not appear to induce CYP1A2 or CYP3A4.
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Drugs that are both substrates and inhibitors of CYP2D6: Clinically important pharmacokinetic interactions possible. (See Specific Drugs under Interactions.)
Potent CYP1A2 inhibitors: Possible increased asenapine exposure; dosage reduction of asenapine based on clinical response may be necessary.
Drugs that Prolong QT Interval
Potential additive effect on QT-interval prolongation; avoid concomitant use of other drugs known to prolong QTc interval. (See Prolongation of QT Interval under Cautions.)
Hypotensive Agents and Drugs causing Bradycardia
May enhance hypotensive effects of certain antihypertensive agents and other drugs that can cause hypotension or bradycardia. Use concomitantly with caution; consider monitoring orthostatic vital signs during concurrent use. (See Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects under Cautions and also see Specific Drugs under Interactions.)
Monitor BP during concurrent use of hypotensive agents. If hypotension develops, consider reducing dosage of asenapine. Adjust dosage of hypotensive agents, if necessary, based on BP. (See Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects under Cautions and also see Advice to Patients.)
Specific Drugs
Drug
Interaction
Comments
Antiarrhythmics (class Ia and III; e.g., amiodarone, procainamide, quinidine, sotalol)
Increased risk of QT-interval prolongation
Avoid concomitant use
Anticholinergic agents
Possible disruption of body temperature regulation
Use with caution
Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone)
Increased risk of QT-interval prolongation
Avoid concomitant use
Carbamazepine
Carbamazepine slightly decreased peak asenapine concentrations and AUC
Asenapine dosage adjustment not required
Cimetidine
Cimetidine (inhibitor of CYP3A4, CYP2D6, and CYP1A2) slightly decreased peak concentrations of asenapine and very slightly increased asenapine AUC
Asenapine dosage adjustment not required
Ciprofloxacin
Possible increased asenapine exposure; dystonia reported in asenapine-treated patient after ciprofloxacin (CYP1A2 inhibitor) was initiated
Asenapine dosage reduction based on clinical response may be necessary
CNS agents
Possible additive CNS depressant effects, including increased fall risk
Use concomitantly with caution
Perform fall risk assessments (see Falls under Cautions)
Fluvoxamine
Fluvoxamine (potent CYP1A2 inhibitor) slightly increased peak asenapine concentrations and AUC at a suboptimal dosage; therapeutic fluvoxamine dosage may cause a greater increase in asenapine concentrations
Asenapine dosage reduction based on clinical response may be necessary
Gatifloxacin
Increased risk of QT-interval prolongation
Avoid concomitant use
Hypotensive agents
Additive hypotensive effects
Use concomitantly with caution; monitor BP and consider monitoring orthostatic vital signs
Adjust dosage of hypotensive agent if hypotension develops
Imipramine
Imipramine (CYP1A2, CYP2C19, and CYP3A4 inhibitor) slightly increased peak asenapine concentrations and AUC
Asenapine did not affect concentrations of imipramine’s metabolite, desipramine (CYP2D6 substrate)
Asenapine dosage adjustment not required
Lithium
Pharmacokinetics of asenapine not affected; asenapine does not appear to affect lithium concentrations
Asenapine dosage adjustment not required
Moxifloxacin
Increased risk of QT-interval prolongation
Avoid concomitant use
Paroxetine
Twofold increase in peak concentrations and exposure of paroxetine (CYP2D6 substrate and inhibitor)
Slight decrease in peak asenapine concentrations and AUCs
Reduce paroxetine dosage by half if used concomitantly; asenapine dosage adjustment not required
Smoking
Pharmacokinetic interaction unlikely
Dosage adjustment based on smoking status not necessary
Tetrabenazine
Increased risk of QT-interval prolongation
Avoid concomitant use
Valproic acid
Valproate slightly increased peak asenapine concentrations and slightly decreased asenapine AUCs; asenapine does not appear to affect valproate concentrations
Asenapine dosage adjustment not required
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