Asenapine

Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder.[2]

Asenapine
Clinical data
Trade namesSaphris, Sycrest, Secuado
Other namesORG-5222
AHFS/Drugs.comMonograph
MedlinePlusa610015
License data
Pregnancy
category
  • AU: C
Routes of
administration		Sublingual, transdermal
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only) [1]
  • US: ℞-only
  • EU: Rx-only [2]
Pharmacokinetic data
Bioavailability35% (sublingual), <2% (Oral)[3][4][1][5]
Protein binding95%[3][4][1][5]
Metabolismhepatic (glucurinodation by UGT1A4 and oxidative metabolism by CYP1A2)[3][4][1][5]
Elimination half-life24 hours[3][4][1][5]
ExcretionKidney (50%), Faecal (40%; ~5–16% as unchanged drug in faeces)[3][4][1][5]
Identifiers
IUPAC name
  • (3aRS,12bRS)-rel-5-Chloro-2,3,3a,12b-tetrahydro-
    2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.059.828
Chemical and physical data
FormulaC17H16ClNO
Molar mass285.77 g·mol−1
3D model (JSmol)
SMILES
  • Clc4cc2c(Oc1c(cccc1)[C@@H]3CN(C[C@@H]23)C)cc4
InChI
  • 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 Y
  • Key:VSWBSWWIRNCQIJ-GJZGRUSLSA-N Y

  • as salt: InChI=1S/C17H16ClNO.C4H4O4/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17)15(14)10-19;5-3(6)1-2-4(7)8/h2-8,14-15H,9-10H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1-/t14-,15-;/m1./s1
  • Key:GMDCDXMAFMEDAG-CHHFXETESA-N
 NY (what is this?)  (verify)

It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.[6]

It was initially approved in the United States in 2009[7] and approved as a generic medication in 2020.[8]

Medical uses

Asenapine has been approved by the FDA for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.[7] In Australia asenapine's approved (and also listed on the PBS) indications include the following:[9]

  • Schizophrenia
  • Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder
  • Maintenance treatment, as monotherapy, of bipolar I disorder

In the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.[1][5][2]

Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed.[10] A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado.[11]

Schizophrenia

A Cochrane systematic review found that while Asenapine has some preliminary evidence that it improves positive, negative, and depressive symptoms, it does not have enough research to merit a certain recommendation of Asenapine for the treatment of schizophrenia.[12]

Acute mania

As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs (with the exception of ziprasidone) such as risperidone and olanzapine. Drop-out rates (in clinical trials) were also unusually high with asenapine.[13] According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.[14]

Adverse effects

Adverse effect incidence[3][4][1][5]

Very common (>10% incidence) adverse effects include:

Common (1-10% incidence) adverse effects include:

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01-0.1% incidence) adverse effects include:

Unknown incidence adverse effects

  • Allergic reaction
  • Restless legs syndrome
  • Nausea
  • Oral mucosal lesions (ulcerations, blistering and inflammation)
  • Salivary hypersecretion
  • Hyperprolactinaemia

Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and a 2013 meta-analysis found significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22).[17] Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis.[17] This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic.[17] The same meta-analysis suggested that asenapine had a relatively high risk of extrapyramidal symptoms compared to other atypical antipsychotics but a lower risk than first-generation or typical antipsychotics.[17]

Discontinuation

For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing to avoid acute withdrawal syndrome or rapid relapse.[18] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[19] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[19] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[19] Symptoms generally resolve after a short period of time.[19]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[20] It may also result in recurrence of the condition that is being treated.[21] Rarely tardive dyskinesia can occur when the medication is stopped.[19]

Pharmacology

Pharmacodynamics
See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Asenapine[22][7]
SitepKiKi (nM)Action
5-HT1A8.62.5Partial agonist
5-HT1B8.44.0Antagonist
5-HT2A10.20.06Antagonist
5-HT2B9.80.16Antagonist
5-HT2C10.50.03Antagonist
5-HT5A8.81.6Antagonist
5-HT69.50.25Antagonist
5-HT79.90.13Antagonist
α18.91.2Antagonist
α2A8.91.2Antagonist
α2B9.50.32Antagonist
α2C8.91.2Antagonist
D18.91.4Antagonist
D28.91.3Antagonist
D39.40.42Antagonist
D49.01.1Antagonist
H19.01.0Antagonist
H28.26.2Antagonist
mACh<58128Antagonist

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors.[23] At all other targets asenapine is an antagonist.[22] As of November 2010 asenapine is also in clinical trials at UC Irvine to treat stuttering.

Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors.[22]

References
  1. "Sycrest 5mg sublingual tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 9 September 2020.
  2. "Sycrest EPAR". European Medicines Agency (EMA). Retrieved 9 September 2020.
  3. "Product Information Saphris (asenapine maleate)" (PDF). TGA eBusiness Services. Merck Sharp & Dohme (Australia) Pty Limited. 14 January 2013. Retrieved 23 October 2013.
  4. "Saphris (asenapine maleate) tablet". DailyMed. Organon Pharmaceuticals. March 2013. Retrieved 23 October 2013.
  5. "Product information Sycrest – EMEA/H/C/001177 –II/0012" (PDF). European Medicines Agency. N.V. Organon. 21 February 2013. Retrieved 23 October 2013.
  6. Minassian, A; Young, JW (August 2010). "Evaluation of the clinical efficacy of asenapine in schizophrenia". Expert Opinion on Pharmacotherapy. 11 (12): 2107–2115. doi:10.1517/14656566.2010.506188. PMC 2924192. PMID 20642375.
  7. "Saphris (asenapine) prescribing information" (PDF). Schering Corporation. 2009-08-01. Archived from the original (PDF) on 2009-11-22. Retrieved 2009-09-05.
  8. "First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). Retrieved 13 February 2021.
  9. Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  10. Stoner, Steven (2012). "Asenapine: a clinical review of a second-generation antipsychotic". Clinical Therapeutics. 34 (5): 1023–40. doi:10.1016/j.clinthera.2012.03.002. PMID 22494521.
  11. Carrithers, Brennan; El-Mallakh, Rif S (18 March 2020). "Transdermal Asenapine in Schizophrenia: A Systematic Review". Patient Preference and Adherence. 14: 1541–1551. doi:10.2147/PPA.S235104. PMC 7468370. PMID 32943849.
  12. Hay, A; Byers, A; Sereno, M (2015). "Asenapine versus placebo for schizophrenia". Cochrane Database of Systematic Reviews. 2015 (11): CD011458.pub2. doi:10.1002/14651858.CD011458.pub2. PMC 6464872. PMID 26599405.
  13. Cipriani, A; Barbui, C; Salanti, G; Rendell, J; Brown, R; Stockton, S; Purgato, M; Spineli, LM; Goodwin, GM; Geddes, JR (October 2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". Lancet. 378 (9799): 1306–1315. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976. S2CID 25512763.
  14. Szegedi, A; Zhao, J; van Willigenburg, A; Nations, KR; Mackle, M; Panagides, J (June 2011). "Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials". BMC Psychiatry. 11: 101. doi:10.1186/1471-244X-11-101. PMC 3152513. PMID 21689438.
  15. Washington, Nicole B. (October 2012). "Which psychotropics carry the greatest risk of QTc prolongation?". Current Psychiatry. 11 (10): 36–39. Retrieved 14 April 2017.
  16. Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
  17. Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.
  18. Joint Formulary Committee, BMJ, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
  19. Haddad, Peter; Haddad, Peter M.; Dursun, Serdar; Deakin, Bill (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. p. 207–216. ISBN 9780198527480.
  20. Moncrieff J (July 2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. S2CID 6267180.
  21. Sacchetti, Emilio; Vita, Antonio; Siracusano, Alberto; Fleischhacker, Wolfgang (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797.
  22. Shahid M, Walker GB, Zorn SH, Wong EH (2009). "Asenapine: a novel psychopharmacologic agent with a unique human receptor signature". J. Psychopharmacol. 23 (1): 65–73. doi:10.1177/0269881107082944. PMID 18308814. S2CID 206489515.
  23. Ghanbari, Ramez; El Mansari, Mostafa; Shahid, Mohammed; Blier, Pierre (March 2009). "Electrophysiological characterization of the effects of asenapine at 5-HT1A, 5-HT2A, α2-adrenergic and D2 receptors in the rat brain". European Neuropsychopharmacology. 19 (3): 177–187. doi:10.1016/j.euroneuro.2008.11.001. PMID 19116183. S2CID 140204044.
  • "Asenapine". Drug Information Portal. U.S. National Library of Medicine.
  • "Asenapine maleate". Drug Information Portal. U.S. National Library of Medicine.
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