drowsing [1%:<1000/mm 3 ), discontinue asenapine and monitor WBC until recovery occurs. 1 Prolongation of QT Interval Relatively small increases (2 5 msec with asenapine compared with placebo) in corrected QT (QT c ) interval observed in patients with schizophrenia in a controlled and dedicated QT study; these increases were slightly lower than those observed in patients receiving quetiapine. 1 6 10 During clinical trials, post-baseline QT-interval prolongations> 500 msec reported at similar rates for asenapine and placebo; torsades de pointes or adverse effects associated with delayed ventricular repolarization not reported. 1 Avoid use in patients concurrently receiving other drugs known to prolong the QT c interval, in patients with a history of cardiac arrhythmias, and in other circumstances that may increase risk of torsades de pointes and/or sudden death (e.g., bradycardia, hypokalemia or hypomagnesemia, presence of congenital QT-interval prolongation). 1 (See Drugs that Prolong QT Interval under Interactions.) Hyperprolactinemia May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence); chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density. 1 If contemplating asenapine therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin-dependent in vitro. 1 Seizures Seizures reported in 0.3% of asenapine-treated patients in schizophrenia and bipolar mania clinical trials. 1 Use with caution in patients with a history of seizures or conditions that may lower seizure threshold (e.g., dementia of the Alzheimer s type); conditions that lower seizure threshold may be more prevalent in patients 65 years of age. 1 Cognitive and Motor Impairment Somnolence, usually transient and with the highest incidence during the first week of therapy, reported in 13 24% of asenapine-treated patients in clinical trials. 1 (See Specific Drugs under Interactions and see also Advice to Patients.) Body Temperature Regulation Disruption of ability to regulate core body temperature possible with antipsychotic agents, including asenapine; 1% of asenapine-treated patients in clinical trials experienced adverse effects suggestive of body temperature increases (e.g., pyrexia, feeling hot). 1 Use appropriate caution in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration). 1 Suicide Attendant risk with psychotic illnesses and bipolar disorder; closely supervise high-risk patients. 1 83 Prescribe in the smallest quantity consistent with good patient management to reduce risk of overdosage. 1 Dysphagia Esophageal dysmotility and aspiration associated with the use of antipsychotic agents. 1 Dysphagia reported in 0.1% of asenapine-treated patients in clinical trials. 1 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer s dementia. 1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.) Concomitant Illnesses Not adequately evaluated in patients with a recent history of MI or unstable cardiovascular disease. 1 Risk of orthostatic hypotension; use with caution in patients with cardiovascular disease. 1 (See Hemodynamic Effects under Cautions.) Specific Populations Pregnancy Category C. 1 Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms. 1 90 91 92 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization. 1 90 91 92 Lactation Distributes into milk in rats; not known whether distributes into human milk. 1 Caution if used in nursing women. 1 Manufacturer recommends avoiding breast-feeding. 1 Pediatric Use Safety and effectiveness not established in pediatric patients <18 years of age. 1 81 Geriatric Use Insufficient experience in patients 65 years of age to determine whether they respond differently than younger adults. 1 Risk of poorer tolerance and orthostasis; carefully monitor. 1 Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death; 1 28 39 73 75 increased incidence of adverse cerebrovascular events also observed with certain atypical antipsychotic agents. 1 74 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.) Hepatic Impairment Increased exposures observed in individuals with severe hepatic impairment. 1 95 Use not recommended in patients with severe hepatic impairment (Child-Pugh class C). 1 95 (See Hepatic Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.) Renal Impairment Exposure was similar in individuals with varying degrees of renal impairment and those with normal renal function; dosage adjustment not required. 1 95 (See Absorption: Special Populations, under Pharmacokinetics and also see Elimination: Special Populations, under Pharmacokinetics.) Common Adverse Effects Patients with schizophrenia: somnolence (including sedation and hypersomnia), 1 2 6 82 93 akathisia (including hyperkinesia), 1 6 82 93 oral hypoesthesia. 1 6 82 Patients with bipolar disorder: somnolence (including sedation and hypersomnia), 1 3 5 6 74 83 94 dizziness, 1 3 5 6 74 83 extrapyramidal symptoms other than akathisia (e.g., dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, tremor), 1 3 6 83 94 weight gain. 1 3 6 83 94 Interactions for Asenapine Maleate Metabolized mainly by direct glucuronidation by UGT1A4 and oxidative metabolism by CYP isoenzymes, principally by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6. 1 3 6 7 Weakly inhibits CYP2D6; does not appear to induce CYP1A2 or CYP3A4. 1 Risks of using asenapine in combination with other drugs not extensively evaluated. 1 Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes Use caution if concurrently administered with drugs that are both substrates and inhibitors of CYP2D6 or that are inhibitors of CYP1A2. 1 7 (See Specific Drugs under Interactions.) Drugs that Prolong QT Interval Potential additive effect on QT-interval prolongation; avoid concomitant use of other drugs known to prolong QT c interval. 1 10 76 77 79 (See Prolongation of QT Interval under Cautions.) Hypotensive Agents and Drugs causing Bradycardia May enhance hypotensive effects of certain antihypertensive agents and other drugs that can cause hypotension or bradycardia. 1 Use concomitantly with caution; consider monitoring orthostatic vital signs in such patients. 1 If hypotension develops, consider reducing dosage of asenapine. 1 (See Hemodynamic Effects under Cautions and also see Advice to Patients.) Specific Drugs Drug Interaction Comments Alcohol Possible additive CNS effects 1 Avoid concomitant use 1 Antiarrhythmics (class Ia and III; e.g., amiodarone, procainamide, quinidine, sotalol) Increased risk of QT-interval prolongation 1 Avoid concomitant use 1 Anticholinergic agents Possible disruption of body temperature regulation 1 Use with caution 1 Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone) Increased risk of QT-interval prolongation 1 76 77 Avoid concomitant use 1 Carbamazepine Carbamazepine decreased peak plasma asenapine concentrations and AUCs by 16% 1 7 Asenapine dosage adjustment not required 1 Cimetidine Cimetidine decreased peak plasma concentrations of asenapine by 13% and slightly increased (by 1%) asenapine AUCs 1 7 Asenapine dosage adjustment not required 1 CNS agents Possible additive CNS and respiratory depressant effects 1 Use concomitantly with caution 1 Fluvoxamine Fluvoxamine increased peak plasma asenapine concentrations and AUCs by 13 and 29%, respectively; therapeutic fluvoxamine dosage may cause a greater increase in plasma asenapine concentrations 1 7 Use concomitantly with caution 1 Gatifloxacin Increased risk of QT-interval prolongation 1 Avoid concomitant use 1 Hypotensive agents Additive hypotensive effects 1 Use concomitantly with caution; 1 consider monitoring orthostatic vital signs and reducing asenapine dosage if hypotension develops 1 Imipramine Imipramine increased peak plasma asenapine concentrations and AUCs by 17 and 10%, respectively 1 Asenapine did not affect plasma concentrations of imipramine s metabolite, desipramine 1 7 Asenapine dosage adjustment not required 1 Lithium Pharmacokinetics of asenapine not affected; asenapine does not appear to affect serum lithium concentrations 1 Moxifloxacin Increased risk of QT-interval prolongation 1 Avoid concomitant use 1 Paroxetine Concurrent administration of a single dose of paroxetine and multiple asenapine doses results in an almost twofold increase in paroxetine exposure 1 7 Concomitant administration of paroxetine (20 mg once daily for 9 days) and a single 5-mg dose of asenapine decreased peak plasma asenapine concentrations and AUCs by 13 and 9%, respectively 1 7 Use concomitantly with caution; asenapine dosage adjustment not required 1 Smoking Pharmacokinetic interaction unlikely 1 Tetrabenazine Increased risk of QT-interval prolongation 79 Avoid concomitant use 1 79 Valproic acid Valproate increased peak serum asenapine concentrations by 2% and decreased asenapine AUCs by 1%; asenapine does not appear to affect plasma valproate concentrations 1 Asenapine dosage adjustment not required 1 Asenapine Maleate Pharmacokinetics Absorption Bioavailability Administered sublingually because of the low bioavailability (> <2%) and extensive first-pass metabolism observed following oral administration of tablets. 1 4 6 74 Rapidly absorbed in the sublingual, supralingual, and buccal mucosa following sublingual administration; peak plasma concentrations occur within 0.5 1.5 hours. 1 3 6 10 74 Absolute bioavailability of sublingual tablets (5 mg) is 35%. 1 3 74 Steady-state plasma concentrations reached within 3 days with twice-daily administration. 1 Food and Water Food ingestion immediately before or 4 hours after sublingual administration of a single 5-mg dose decreased exposure by 20 or 10%, respectively, probably due to increased hepatic blood flow. 1 Water intake 2 and 5 minutes following sublingual administration of asenapine 10 mg decreased exposure by 19 and 10%, respectively; effects of water intake 10 or 30 minutes after administration were equivalent. 1 (See Administration under Dosage and Administration.) Special Populations In individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure was 12% higher compared with those with normal hepatic function. 1 In individuals with severe hepatic impairment (Child-Pugh class C), exposures were an average of 7 times higher compared with individuals with normal hepatic function. 1 95 In individuals with varying degrees of renal impairment, exposure was similar to individuals with normal renal function. 1 95 In geriatric patients with psychosis, exposure was an average of 40% higher compared with younger adult patients. 1 Distribution Extent Rapidly distributed; large volume of distribution indicates extensive extravascular distribution. 1 74 Distributes into milk in rats; not known whether asenapine and/or its metabolites distribute into milk in humans. 1 Plasma Protein Binding 95% to plasma proteins (including albumin and α 1 -acid glycoprotein). 1 74 Elimination Metabolism Metabolized mainly through direct glucuronidation by UGT1A4 and oxidative metabolism, primarily by CYP1A2 and, to a lesser extent, by CYP3A4 and CYP2D6. 1 3 6 7 Metabolites (primarily asenapine N -glucuronide, also N -desmethylasenapine and N -desmethylasenapine N -carbamoyl glucuronide) are largely inactive. 1 3 7 Elimination Route Following administration of a single radiolabeled dose, about 90% of the dose was recovered; approximately 50% recovered in urine and 40% in feces. 1 Half-life Terminal phase half-life (t β ) averages about 24 hours. 1 74 Special Populations Smoking does not affect clearance. 1 Effect of renal function on elimination of metabolites and effect of hemodialysis on pharmacokinetics not evaluated. 1 Decreased clearance observed with increasing age, suggesting a 30% higher exposure in geriatric patients compared with younger adult patients. 1 Stability Storage Sublingual Tablets 15 30 C. 1 Actions Exact mechanism of asenapine and other antipsychotic agents in schizophrenia and bipolar disorder unknown; efficacy in schizophrenia may be mediated through a combination of antagonist activity at central dopamine type 2 (D 2 ) and serotonin type 2 (5-hydroxytryptamine [5-HT 2A ]) receptors. 1 2 6 7 8 89 Exhibits high affinity for serotonin 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5 , 5-HT 6 , and 5-HT 7 receptors; dopamine D 1 , D 2 , D 3 , and D 4 receptors; α 1 - and α 2 -adrenergic receptors; and histamine H 1 receptors (moderate affinity for H 2 receptors). 1 2 3 6 7 8 9 74 85 Asenapine acts as an antagonist at these receptors in vitro. 1 85 Possesses no appreciable affinity for muscarinic cholinergic receptors 1 2 3 6 7 8 9 74 85 or β-adrenergic receptors. 7 Advice to Patients Importance of advising patients and caregivers that elderly patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. 1 28 39 73 Patients and caregivers also should be informed that asenapine is not approved for treating elderly patients with dementia-related psychosis. 1 73 Risk of serious allergic reactions. 1 96 Importance of informing patients of signs and symptoms of such reactions (e.g., difficulty breathing; swelling of the face, tongue, or throat; lightheadedness; itching) and to immediately seek emergency medical attention if they develop. 1 96 Importance of informing patients that application site reactions (e.g., oral ulcers, blisters, peeling/sloughing, inflammation), primarily in the sublingual area, have been reported. 1 Instruct patients to monitor for such reactions during therapy. 1 Risk of somnolence (i.e., sleepiness, drowsiness). 1 Importance of advising patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they gain experience with the drug s effects. 1 Importance of avoiding alcohol during asenapine therapy. 1 Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, and confusion. 1 Importance of patients being aware of the symptoms of hyperglycemia and diabetes mellitus (e.g., increased thirst, increased urination, increased appetite, weakness). 1 Importance of informing patients with diabetes, those with risk factors for diabetes, and those who develop hyperglycemia symptoms during treatment that they should have their blood glucose monitored at the beginning of and periodically during asenapine treatment. 1 Risk of weight gain. 1 Importance of patients being aware of need to monitor their weight during therapy. 1 Risk of orthostatic hypotension and syncope (fainting), especially when initiating or reinitiating treatment or increasing the dosage. 1 Importance of informing patients about interventions that may help (e.g., sitting on the edge of the bed for several minutes before standing in the morning, slowly rising from a seated position). 1 Risk of leukopenia/neutropenia. 1 Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during asenapine therapy. 1 Importance of informing patients in whom chronic asenapine use is contemplated of risk of tardive dyskinesia. 1 67 Importance of advising patients to report any muscle movements that cannot be stopped to a healthcare professional. 67 Importance of informing patients that oral hypoesthesia, oral paresthesia, and/or dysgeusia (abnormal or altered taste) may occur and that these effects are not serious and are typically transient (i.e., resolving within 1 hour) following sublingual administration. 1 74 81 88 Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures). 1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. 1 92 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions). 1 92 Importance of advising patients not to stop taking asenapine if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications. 92 Importance of advising patients not to breast-feed during asenapine therapy. 1 Importance of avoiding overheating or dehydration. 1 Importance of correctly taking sublingual tablets. 1 Do not remove sublingual tablet from the blister pack until just before administration. 1 With dry hands, pull blister pack out of case, peel back the colored tab on the pack, and gently remove the tablet. 1 Place the sublingual tablet under the tongue and allow to dissolve completely. 1 Importance of sliding the blister pack back into the case until it clicks after use. 1 Importance of not eating or drinking for 10 minutes following administration. 1 74 (See Food and Water under Pharmacokinetics.) Importance of informing patients of other important precautionary information. 1 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Asenapine Maleate Routes Dosage Forms Strengths Brand Names Manufacturer Sublingual Tablets 5 mg (of asenapine) Saphris Merck 5 mg (of asenapine) Saphris Black Cherry Flavor Merck 10 mg (of asenapine) Saphris Merck 10 mg (of asenapine) Saphris Black Cherry Flavor Merck AHFS DI Essentials. Copyright 2017, Selected Revisions July 3, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. Merck & Co., Inc. Saphris (asenapine maleate) sublingual tablets prescribing information. Whitehouse Station, NJ; 2013 Mar. 2. 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lack of information Asenapine Maleate irritating
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