trans-5-Chlor-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol

Crystals, mp 141-145 °C; uv max (ethanol): 270 nm (e 1900). Solubility at 21 °C (g/L): water 3, ethanol 30, methanol 250, acetone 125, ethyl acetate 10, dichloromethane 250, hexane <1. pH at 20 °C (0.1% solution in water): 4.56. pH at 23 °C (saturated solution 5.8 g/L): 4.43. pKa1 <3; pKa2 = 7.52, pKa3 = 8.51 /Asenapine maleate/

log Kow = 6.33 at 37 °C

Warning

H302 (33.3%): Harmful if swallowed [Warning Acute toxicity, oral]；H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H335 (100%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including asenapine maleate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Asenapine maleate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Potential pharmacologic interaction (possible disruption of body temperature regulation); use asenapine with caution in patients concurrently receiving drugs with anticholinergic activity.

Potential pharmacologic interaction (additive CNS and respiratory depressant effects). Use with caution with other drugs that can produce CNS depression. Avoid use of alcohol during asenapine therapy.

Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of 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), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, pimozide, paliperidone, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine.

Because of its alpha1-adrenergic blocking activity and potential to cause hypotension, the manufacturer cautions that asenapine may enhance the hypotensive effects of certain antihypertensive agents and other drugs that can cause hypotension. Asenapine also has been associated with bradycardia. The manufacturer recommends that asenapine be used with caution in patients receiving other drugs that can cause hypotension or bradycardia, and that monitoring of orthostatic vital signs be considered in such patients. If hypotension develops, consider reducing the dosage of asenapine.

For more Interactions (Complete) data for Asenapine (13 total), please visit the HSDB record page.

Liver test abnormalities occur in 1% to 2.5% of patients receiving asenapine, but similar rates are reported with placebo therapy (0.6% to 1.3%) and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There has been a single case report of cholestatic serum enzyme elevations arising 3 to 4 weeks after starting asenapine, resolving within a month of stopping. Thus, asenapine may be a rare cause of mild cholestatic liver injury.；Likelihood score: D (possible rare cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that asenapine is expected to be immobile in soil(SRC). The estimated pKa of asenapine is 9.64(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Asenapine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2012).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.1X10+5(SRC), determined from a structure estimation method(2), indicates that asenapine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.64(3) indicates asenapine will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 650(SRC), from an estimated log Kow of 4.77(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Biodegradation data in water were not available(SRC, 2012).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), asenapine, which has an estimated vapor pressure of 1.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase asenapine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.4 hours(SRC), calculated from its rate constant of 9.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase asenapine may be removed from the air by wet or dry deposition(SRC). Asenapine does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of asenapine can be estimated to be 1.1X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that asenapine is expected to be immobile in soil. The estimated pKa of asenapine is 9.64(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/CASE REPORTS/ ... Mr A, a 23-year-old white man, was administered asenapine 10 mg at bedtime in 2010 for a psychotic state characterized by auditory hallucinations and paranoid ideation. The auditory hallucinations were characterized by multiple voices calling him derogatory names. Prior to initiation of this treatment, the patient had received no medication. The patient was administered 3 subsequent doses without clinical improvement over the next 72 hours. On the third day of treatment, he became confused; his confusion was characterized by disorientation to time and situation that was distinct from his psychotic state. His mother reported that he appeared "feverish" due to excess sweating. He went to a general hospital emergency room, where examination revealed his temperature to be 99.8 °F, with elevated blood pressure of 190/87 mm Hg, diaphoresis, elevated creatine kinase (719 IU/L), and leukocytosis characterized by a white blood cell count of 14.6 x 10 (+3)/cu mm. A tentative diagnosis of malignant neuroleptic syndrome was made. Because the patient was psychotic and trying to leave against medical advice, he was sedated with benzodiazepines to such a significant degree that intubation was required and then was admitted to the medical intensive care unit. Hydration, dantrolene, and bromocriptine were administered. His creatine kinase level returned to within normal limits within 36 hours, and he was extubated. After he was transferred to the inpatient psychiatric unit, his psychotic symptoms remained, but he was completely oriented and cooperated with the ward milieu. History revealed that his psychotic symptoms were gradual in onset, and a tentative diagnosis of schizophrenia (per DSM-IV criteria) was made. The above case fits with criteria for neuroleptic malignant syndrome and should remind all clinicians that all antipsychotics, whether first or second generation, have potential for this serious side effect. ...

/OTHER TOXICITY INFORMATION/ In 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; these increases were slightly lower than those observed in patients receiving quetiapine. 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. 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. There were no reports of torsades de pointes or any adverse effects associated with delayed ventricular repolarization during these studies.

/OTHER TOXICITY INFORMATION/ Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including asenapine.

An estimated BCF of 650 was calculated in fish for asenapine(SRC), using an estimated log Kow of 4.77(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

An estimated pKa of 9.64(2) indicates asenapine will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). Asenapine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-6 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a lifetime carcinogenicity study in CD-1 mice asenapine was administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the maximum recommended human dose (MRHD) of 10 mg twice daily. The incidence of malignant lymphomas was increased in female mice, with a no-effect dose resulting in plasma levels estimated to be 1.5 times those in humans receiving the MRHD. The mouse strain used has a high and variable incidence of malignant lymphomas, and the significance of these results to humans is unknown. There were no increases in other tumor types in female mice. In male mice, there were no increases in any tumor type.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Asenapine was not teratogenic in reproduction studies in rats and rabbits at intravenous doses up to 1.5 mg/kg in rats and 0.44 mg/kg in rabbits. These doses are 0.7 and 0.4 times, respectively, the maximum recommended human dose (MRHD) on a mg/sq m basis. Plasma levels of asenapine were measured in the rabbit study, and the area under the curve (AUC) at the highest dose tested was 2 times that in humans receiving the MRHD.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a study in which rats were treated from day 6 of gestation through day 21 postpartum with intravenous doses of asenapine of 0.3, 0.9, and 1.5 mg/kg/day (0.15, 0.4, and 0.7 times the maximum recommended human dose (MRHD) on a mg/sq m basis), increases in post-implantation loss and early pup deaths were seen at all doses, and decreases in subsequent pup survival and weight gain were seen at the two higher doses. A cross-fostering study indicated that the decreases in pup survival were largely due to prenatal drug effects. Increases in post-implantation loss and decreases in pup weight and survival were also seen when pregnant rats were dosed orally with asenapine.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Asenapine did not impair fertility in rats when tested at doses up to 11 mg/kg twice daily given orally. This dose is 10 times the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/sq m basis.

/GENOTOXICITY/ No evidence for genotoxic potential of asenapine was found in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assays in human lymphocytes, the in vitro sister chromatid exchange assay in rabbit lymphocytes, or the in vivo micronucleus assay in rats.

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs appear to be at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo. 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. 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. Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear. The manufacturer states that asenapine is not approved for the treatment of patients with dementia-related psychosis. /Antipsychotics/

Clinical trial experience with asenapine in patients with schizophrenia or bipolar mania who are 65 years of age and older is insufficient to determine whether they respond differently from younger adults. In premarketing clinical studies, 1.1% of approximately 2250 asenapine-treated patients were 65 years of age and older. In geriatric patients (65-85 years of age) with psychosis, plasma asenapine concentrations were on average 30-40% higher compared with younger adults. The highest exposure for asenapine was up to twofold higher than the highest exposure observed in younger individuals. ... Because multiple factors that may increase the pharmacodynamic response to asenapine, resulting in poorer tolerance and orthostasis, could be present in geriatric patients, the manufacturer recommends that such patients be monitored carefully during therapy.

Safety and effectiveness of asenapine have not been established in pediatric patients younger than 18 years of age.

The rate constant for the vapor-phase reaction of asenapine with photochemically-produced hydroxyl radicals has been estimated as 9.2X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Asenapine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Asenapine does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to asenapine may occur through inhalation and dermal contact with this compound at workplaces where asenapine is produced or administered. Exposure to asenapine among the general population may be limited to those administered the drug, used in the treatment of schizophrenia. (SRC)

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including asenapine maleate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Asenapine maleate/

N - Nervous system；N05 - Psycholeptics；N05A - Antipsychotics；N05AH - Diazepines, oxazepines, thiazepines and oxepines；N05AH05 - Asenapine

QN - Nervous system；QN05 - Psycholeptics；QN05A - Antipsychotics；QN05AH - Diazepines, oxazepines, thiazepines and oxepines；QN05AH05 - Asenapine

Asenapine is a serotonin, dopamine, noradrenaline, and histamine antagonist in which asenapine possess more potent activity with serotonin receptors than dopamine. Sedation in patients is associated with asenapine's antagonist activity at histamine receptors. Its lower incidence of extrapyramidal effects are associated with the upregulation of D1 receptors. This upregulation occurs due to asenapine's dose-dependent effects on glutamate transmission in the brain. It does not have any significant activity with muscarinic, cholinergic receptors therefore symptoms associated with anticholinergic drug activity like dry mouth or constipation are not expected to be observed. Asenapine has a higher affinity for all aforementioned receptors compared to first-generation and second-generation antipsychotics except for 5-HT1A and 5-HT1B receptors.

Asenapine is an atypical antipsychotic multireceptor neuroleptic drug which shows strong 5HT2A (serotonin) and D2 (dopamine) receptor antagonism, which has been shown to enhance dopamine (DA) and acetylcholine (Ach) efflux in rat brains. Asenapine may improve cognitive function and negative symptoms in patients with schizophrenia.

The mechanism of action of asenapine, as with other drugs having efficacy in schizophrenia and bipolar disorder, is unknown. It has been suggested that the efficacy of asenapine in schizophrenia is mediated through a combination of antagonist activity at D2 and 5-HT2A receptors. Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors (Ki values of 2.5, 4.0, 0.06, 0.16, 0.03, 1.6, 0.25, and 0.13 nM), dopamine D2, D3, D4, and D1 receptors (Ki values of 1.3, 0.42, 1.1, and 1.4 nM), alpha1 and alpha2-adrenergic receptors (Ki values of 1.2 and 1.2 nM), and histamine H1 receptors (Ki value 1.0 nM), and moderate affinity for H2 receptors (Ki value of 6.2 nM). In in vitro assays asenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors (e.g., Ki value of 8128 nM for M1).

Though 5-HT6 receptors are targets for the treatment of schizophrenia and other psychiatric disorders, the influence of drugs upon signal transduction has not been extensively characterized. Herein, /investigators/ employed a Scintillation Proximity Assay (SPA)/antibody-immunocapture procedure of coupling to G alpha s to evaluate the interaction of a broad range of novel agonists, antagonists and antipsychotics at rat 5-HT(6) receptors stably expressed in HEK293 cells. Serotonin (pEC(50), 7.7) increased [35S]GTP gamma S binding to G alpha s by ca 2-fold without affecting binding to Gi/o or Gq. LSD (9.2), 5-MeODMT (7.9), 5-CT (7.0) and tryptamine (6.1) were likewise full agonists. In contrast, the novel sulfonyl derivatives, WAY181,187 (9.1) and WAY208,466 (7.8), behaved as partial agonists and attenuated the actions of 5-HT. SB271,046 and SB258,585 abolished activation of G alpha s by 5-HT with pKb values of 10.2 and 9.9, respectively, actions mimicked by the novel antagonist, SB399,885 (10.9). SB271,046 likewise blocked partial agonist properties of WAY181,187 and WAY208,466 with pKb values of 9.8 and 9.0, respectively. 5-HT-stimulated (35)S-GTP gamma S binding to G alpha s was antagonised by various antipsychotics including olanzapine (7.8), asenapine (9.1) and SB737,050 (7.8), whereas aripiprazole and bifeprunox were inactive. Further, antagonist properties of clozapine (8.0) were mimicked by its major metabolite, N-desmethylclozapine (7.9). In conclusion, the novel ligands, WAY208,466 and WAY181,187, behaved as partial agonists at 5-HT6 receptors coupled to G alpha s, while SB399,885 was a potent antagonist. Though 5-HT6 receptor blockade is not indispensable for therapeutic efficacy, it may well play a role in the functional actions of certain antipsychotic agents.

Adrenergic (alpha1 and alpha2) and cholinergic muscarinic (M1-M5) receptor binding in rat forebrain was quantified after 4 weeks of twice-daily subcutaneous administration of asenapine or vehicle. Asenapine (0.03, 0.1, and 0.3 mg/kg) produced increases in (3)H-prazosin binding to alpha1-adrenergic receptors in the medial prefrontal cortex (mPFC: 30%, 39%, 57%) and dorsolateral frontal cortex (DFC: 27%, 37%, 53%) and increased (3)H-RX821002 binding to alpha2-adrenergic receptors in mPFC (36%, 43%, 50%) and DFC (41%, 44%, 52%). Despite showing no appreciable affinity for muscarinic receptors, asenapine produced regionally selective increases in binding of (3)H-QNB to M1-M5 receptors in mPFC (26%, 31%, 43%), DFC (27%, 34%, 41%), and hippocampal CA1 (40%, 44%, 42%) and CA3 (25%, 52%, 48%) regions. These regionally selective effects of asenapine on adrenergic and cholinergic muscarinic receptor subtypes may contribute to its beneficial clinical effects in the treatment of schizophrenia and bipolar disorder.

Asenapine is a novel psychopharmacologic agent developed for schizophrenia and bipolar disorder. Like clozapine, asenapine facilitates cortical dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated transmission in rats. The facilitation of NMDA-induced currents in cortical pyramidal cells by clozapine is dependent on dopamine and D(1) receptor activation. Moreover, previous results show that clozapine prevents and reverses the blockade of NMDA-induced currents and firing activity in the pyramidal cells by the noncompetitive NMDA receptor antagonist phencyclidine (PCP). Here, /the authors/ investigate the effects of asenapine in these regards using intracellular electrophysiological recording in vitro. Asenapine (5 nM) significantly facilitated NMDA-induced currents (162 +/- 15% of control) in pyramidal cells of the medial prefrontal cortex (mPFC). The asenapine-induced facilitation was blocked by the D(1) receptor antagonist SCH23390 (1 uM). Furthermore, the PCP-induced blockade of cortical NMDA-induced currents was effectively reversed by 5 nM asenapine. /These/ results demonstrate a clozapine-like facilitation of cortical NMDA-induced currents by asenapine that involves prefrontal dopamine and activation of D(1) receptors. Asenapine and clozapine also share the ability to reverse functional PCP-induced hypoactivity of cortical NMDA receptors. The ability of asenapine to increase both cortical dopaminergic and NMDA receptor-mediated glutamatergic transmission suggests that this drug may have an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

The psychotropic drug asenapine is approved for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Asenapine exhibits higher affinity for several 5-HT receptors and alpha(2) -adrenoceptors than for D(2) receptors. Noteworthy, both blockage of 5-HT(2A) and alpha(2) -adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D(2) receptor antagonists. Previous results show that asenapine, both systemically and locally, increases dopamine, noradrenaline and serotonin release in the medial prefrontal cortex (mPFC), and that the increased dopamine release largely depends on an intracortical action. Using reverse microdialysis in freely moving rats, we here assessed the potency of low concentrations of asenapine to cause a pharmacologically significant blockage in vivo of 5-HT(2A) receptors and alpha (2) -adrenoceptors within the mPFC, and thus its ability to affect cortical monoamine release by these receptors. Intracortical administration of DOI, a 5-HT(2A/2C) receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT(2A) antagonist M100907. Application of clonidine, an alpha(2) -adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective alpha(2) -adrenoceptor antagonist idazoxan blocked, whereas asenapine partially blocked clonidine-induced cortical dopamine and noradrenaline decrease. The effects of asenapine and idazoxan on clonidine-induced serotonin decrease were less pronounced. /These/ results propose that low concentrations of asenapine in the mPFC exhibit a pharmacologically significant 5-HT(2A) and alpha(2) receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder.

24 hours (range of 13.4 - 39.2 hours)

Following an initial more rapid distribution phase, the mean terminal half-life is approximately 24 hrs.

Asenapine is oxidized via CYP1A2 and undergoes direct glucuronidation via UGT1A4. Oxidation via CYP1A2 is asenapine's primary mode of metabolism.

About 50% of the circulating species in plasma have been identified. The predominant species was asenapine N+-glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. Asenapine activity is primarily due to the parent drug.

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of (14)C-asenapine to healthy male volunteers. ... Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

JKZ19V908O

ASENAPINE

Established Pharmacologic Class [EPC] - Atypical Antipsychotic

Asenapine is an Atypical Antipsychotic.

ASENAPINE

Atypical Antipsychotic [EPC]

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus.

Cmax, single 5 mg dose = 4 ng/mL (within 1 hour); Bioavailability, sublingual administration = 35%; Bioavailability, oral administration (swallowed) = <2%; Time to steady state, 5 mg = 3 days; Peak plasma concentration occurs within 0.5 to 1.5 hours. Doubling dose of asenapine results in 1.7-fold increase in maximum concentration and exposure. Drinking water within 2-5 minutes post administration of asenapine results in a decrease in exposure.

Urine (50%) and feces (50%)

20-25 L/kg

Asenapine is administered sublingually because of the low bioavailability (less than 2%) and extensive first-pass metabolism observed following oral administration.

Sublingual tablets of the drug are rapidly absorbed in the sublingual, supralingual, and buccal mucosa following sublingual administration, with peak plasma concentrations occurring within 0.5-1.5 hours.

The absolute bioavailability of sublingual asenapine (5 mg) is 35%. Steady-state plasma concentrations are reached within 3 days with twice-daily sublingual administration.