5-HT_1A Receptor ( pKi = 14 nM ); 5-HT_1B Receptor ( pKi = 14 nM ); 5-HT_2A Receptor ( pKi = 14 nM );
5-HT_2B Receptor ( pKi = 14 nM ); 5-HT_2C Receptor ( pKi = 14 nM ); 5-HT₅ Receptor ( pKi = 14 nM );
5-HT₅ Receptor ( pKi = 14 nM ); 5-HT₇ Receptor ( pKi = 14 nM ); Alpha-2A adrenergic receptor ( pKi = 14 nM );
α1-adrenergic receptor ( pKi = 14 nM ); Alpha-2B adrenergic receptor ( pKi = 14 nM ); Alpha-2C adrenergic receptor ( pKi = 14 nM );
D₁ Receptor ( pKi = 14 nM ); D₂ Receptor ( pKi = 14 nM ); D₃ Receptor ( pKi = 14 nM );
D₄ Receptor ( pKi = 14 nM ); H₁ Receptor ( pKi = 14 nM ); H₂ Receptor ( pKi = 14 nM )

Asenapine (0.05-0.2 mg/kg; s.c.) does not cause catalepsy; instead, it suppresses the conditioned avoidance response (CAR) in a dose-dependent manner[2].

Absorption, Distribution and Excretion
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.
Following a single 5-mg dose of asenapine, the mean Cmax was approximately 4 ng/mL and was observed at a mean tmax of 1 hour.
For more Absorption, Distribution and Excretion (Complete) data for Asenapine (16 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.

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Biological Half-Life
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.

Hepatotoxicity
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).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of asenapine during breastfeeding. If asenapine is required by the mother, it is not a reason to discontinue breastfeeding. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who were not treated with a second-generation antipsychotic (n = 818). Of the patients who were taking a second-generation antipsychotic drug, 60.4% were on more than one psychotropic. A review of the pediatric medical records, no adverse effects were noted among infants exposed or not exposed to second-generation antipsychotic monotherapy or to polytherapy. The number of women taking asenapine was not reported.
◉ Effects on Lactation and Breastmilk
Galactorrhea has been reported with asenapine according to the manufacturer. Hyperprolactinemia appears to be the cause of the galactorrhea. The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who had primarily diagnoses of major depressive disorder and anxiety disorders, most often treated with SSRI or SNRI antidepressants, but not with a second-generation antipsychotic (n = 818). Among women on a second-generation antipsychotic, 60.4% were on more than one psychotropic compared with 24.4% among women in the control group. Of the women on a second-generation antipsychotic, 59.3% reported “ever breastfeeding” compared to 88.2% of women in the control group. At 3 months postpartum, 23% of women on a second-generation antipsychotic were exclusively breastfeeding compared to 47% of women in the control group. The number of women taking asenapine was not reported.

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Protein Binding
95% protein bound

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Interactions
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.

[1]. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol. 2009 Jan;23(1):65-73.

[2]. Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia. Psychopharmacology (Berl). 2008 Feb;196(3):417-29.

Therapeutic Uses
Antipsychotic Agents
Asenapine is indicated for the treatment of schizophrenia. The efficacy of asenapine was established in two 6-week trials and one maintenance trial in adults. /Included in US product label/
Monotherapy: Asenapine is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Efficacy was established in two 3-week monotherapy trials in adults. /Included in US product label/
Adjunctive Therapy: Asenapine is indicated as adjunctive therapy with either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Efficacy was established in one 3-week adjunctive trial in adults. /Included in US product label/

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Drug Warnings
/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to 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 antipsychotic drugs, treatment with conventional antipsychotic drugs 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 is not clear. Saphris (asenapine) is not approved for the treatment of patients with dementia-related psychosis.
Asenapine maleate is contraindicated in patients with known hypersensitivity to the drug or any components in the formulation.
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients treated with asenapine. From August 2009 to September 2010, the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) received 52 reports of type I hypersensitivity reactions associated with asenapine. Symptoms reported included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash. Some of the cases reported occurrence of more than one hypersensitivity reaction following asenapine administration. Several cases reported hypersensitivity reactions (possible angioedema, respiratory distress, and possible anaphylaxis) occurring after the first dose. In some patients, symptoms resolved after asenapine discontinuance while others required hospitalization or emergency room visits and therapeutic interventions.
An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. /Antipsychotics/
For more Drug Warnings (Complete) data for Asenapine (29 total), please visit the HSDB record page.

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Pharmacodynamics
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.

C17H16CLNO

285.8

285.092

C, 71.45; H, 5.64; Cl, 12.41; N, 4.90; O, 5.60

65576-45-6

Asenapine maleate; 85650-56-2; Asenapine hydrochloride; 1412458-61-7; Asenapine citrate; 1411867-74-7

3036780

White to off-white oily liquid or waxy semi-solid

1.2±0.1 g/cm3

357.9±42.0 °C at 760 mmHg

170.2±27.9 °C

0.0±0.8 mmHg at 25°C

1.610

4.31

0

2

0

20

363

2

ClC1=CC=C2OC3=CC=CC=C3[C@@](C4)([H])[C@](CN4C)([H])C2=C1

VSWBSWWIRNCQIJ-GJZGRUSLSA-N

InChI=1S/C17H16ClNO/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17)15(14)10-19/h2-8,14-15H,9-10H2,1H3/t14-,15-/m0/s1

(2R,6R)-9-chloro-4-methyl-13-oxa-4-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7(12),8,10,14,16-hexaene

Asenapine; (+/-)-Asenapine; Org 5222; Org-5222; Org5222

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~200 mg/mL (~699.9 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (8.75 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)