Asenapine

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Asenapine
Asenapine Structural Formulae V.2.svg
Asenapine3Dan.gif
Systematic (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
Clinical data
Trade names Saphris, Sycrest
AHFS/Drugs.com monograph
MedlinePlus a610015
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes sublingual
Pharmacokinetic data
Bioavailability 35% (sublingual), <2% (Oral)[1][2][3][4]
Protein binding 95%[1][2][3][4]
Metabolism hepatic (glucurinodation by UGT1A4 and oxidative metabolism by CYP1A2)[1][2][3][4]
Half-life 24 hours[1][2][3][4]
Excretion Renal (50%), Faecal (40%; ~5-16% as unchanged drug in faeces)[1][2][3][4]
Identifiers
CAS number 65576-45-6 N
ATC code N05AH05
PubChem CID 163091
IUPHAR ligand 22
ChemSpider 2300725 YesY
UNII JKZ19V908O YesY
ChEBI CHEBI:71253 N
ChEMBL CHEMBL1201756 N
Chemical data
Formula C17H16ClNO 
Mol. mass 285.77 g/mol
 N (what is this?)  (verify)

Asenapine (USAN, rINNM and BANM;[5] trade names Saphris (AU, US), Sycrest (EU, UK)) is an atypical antipsychotic developed for the treatment of schizophrenia and acute mania associated with bipolar disorder by Schering-Plough after its November 19, 2007 merger with Organon International. Development of the drug, through Phase III trials, began while Organon was still a part of Akzo Nobel.[6] Preliminary data indicate that it has minimal anticholinergic and cardiovascular side effects, as well as minimal weight gain. Over 3000 patients have participated in clinical trials of asenapine, and the FDA accepted the manufacturer's NDA on November 26, 2007 for standard review.[7]

It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.[8]

Medical uses[edit]

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.[9] In Australia asenapine's approved (and also listed on the PBS) indications include the following:[10]

  • 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 UK asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.[3][4]

Absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed.[11] It appears to less efficacious than other antipsychotics in the treatment of schizophrenia,[12] although its all-cause discontinuation rate is moderate.[12] 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[edit]

Adverse effect incidence[1][2][3][4]
Note: The discussion below these lists provides some more context into the frequency and severity of these adverse effects.

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 according to a recent meta-analysis it produces 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).[12] Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis.[12] 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.[12] Being a second-generation (atypical) antipsychotic its liability for causing extrapyramidal side effect is comparatively low compared to first-generation antipsychotics such as haloperidol as is supported by the aforementioned meta-analysis (although this meta-analysis did reveal it had a relatively high EPS liability for an atypical antipsychotic drug).[12]

Pharmacology[edit]

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.[16] At all other targets Asenapine is an antagonist.[17] As of November 2010 Asenapine is also in clinical trials at UC Irvine to treat stuttering.

Receptor Affinity (pKi)[17] Affinity (Ki (nM))[9]
5-HT1A 8.6 2.5
5-HT1B 8.4 4.0
5-HT2A 10.2 0.06
5-HT2B 9.8 0.16
5-HT2C 10.5 0.03
5-HT5A 8.8 1.6
5-HT6 9.5 0.25
5-HT7 9.9 0.13
α1-Adrenergic 8.9 1.2
α2A-Adrenergic 8.9 1.2
α2B-Adrenergic 9.5 0.32
α2C-Adrenergic 8.9 1.2
D1 8.9 1.4
D2 8.9 1.3
D3 9.4 0.42
D4 9.0 1.1
H1 9.0 1.0
H2 8.2 6.2
mACh < 5 8,128

Synthesis[edit]

Asenapine scheme.png

J. van der Burg, U.S. Patent 4,145,434.

Reduction step is sodium in liquid ammonia.

References[edit]

  1. ^ a b c d e f "PRODUCT INFORMATION SAPHRIS® (asenapine maleate)" (PDF). TGA eBusiness Services. Merck Sharp & Dohme (Australia) Pty Limited. 14 January 2013. Retrieved 23 October 2013. 
  2. ^ a b c d e f "SAPHRIS (asenapine maleate) tablet [Organon Pharmaceuticals USA]". DailyMed. Organon Pharmaceuticals USA. March 2013. Retrieved 23 October 2013. 
  3. ^ a b c d e f g "Sycrest 5mg and 10mg sublingual tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Lundbeck Limited. 18 April 2013. Retrieved 23 October 2013. 
  4. ^ a b c d e f g "Product information 21/02/2013 Sycrest -EMEA/H/C/001177 -II/0012" (PDF). European Medicines Agency. N.V. Organon. 21 February 2013. Retrieved 23 October 2013. 
  5. ^ Truven Health Analytics, Inc. MARTINDALE - The Complete Drug Reference (Internet) [cited 2013 Sep 30]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  6. ^ "Bipolar Disorder". Clinical Trials Update (Genetic Engineering & Biotechnology News). 2007-06-15. pp. 52, 55. 
  7. ^ "Schering-Plough Announces Asenapine NDA Accepted for Filing by the U.S. FDA" (Press release). Schering-Plough. 2007-11-26. Retrieved 2008-12-29. 
  8. ^ Minassian, A; Young, JW (August 2010). "Evaluation of the clinical efficacy of asenapine in schizophrenia". Expert Opinion on Pharmacology 11 (12): 2107–2115. doi:10.1517/14656566.2010.506188. PMC 2924192. PMID 20642375. 
  9. ^ a b "Saphris (asenapine) prescribing information" (PDF). Schering Corporation. 2009-08-01. Retrieved 2009-09-05. 
  10. ^ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  11. ^ 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. 
  12. ^ a b c d e f 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.  edit
  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.  edit
  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. ^ Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry (in English). West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.  edit
  16. ^ http://cat.inist.fr/?aModele=afficheN&cpsidt=21237275
  17. ^ a b 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. 

External links[edit]