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 as well as the medium to long-term management of bipolar disorder.^[4][10]

Asenapine

Clinical data
Trade names	Saphris, Sycrest, Secuado
Other names	ORG-5222
AHFS/Drugs.com	Monograph
MedlinePlus	a610015
License data	EU EMA: by INN US DailyMed: Asenapine US FDA: Asenapine
Pregnancy category	AU: C
Routes of administration	Sublingual, transdermal
Drug class	Atypical antipsychotic
ATC code	N05AH05 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances)[1] UK: POM (Prescription only)[2] US: WARNING[3]Rx-only EU: Rx-only[4]
Pharmacokinetic data
Bioavailability	35% (sublingual), <2% (oral),[5][6][2][7] transdermal bioavailability is significantly higher than sublingual[8][9]
Protein binding	95%[5][6][2][7]
Metabolism	hepatic (glucurinodation by UGT1A4 and oxidative metabolism by CYP1A2)[5][6][2][7]
Elimination half-life	24 hours (sublingual),[5][6][2][7] 30 hours (transdermal),[8] 33.9 hours (transdermal)[9]
Excretion	Kidney (50%), Faecal (40%; ~5–16% as unchanged drug in faeces)[5][6][2][7]
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	65576-45-6 N as salt: 85650-56-2
PubChem CID	163091 as salt: 6917875
IUPHAR/BPS	22
DrugBank	DB06216 as salt: DBSALT000010
ChemSpider	2300725 Y as salt: 5293095
UNII	JKZ19V908O as salt: CU9463U2E2
KEGG	D11769 as salt: D02995
ChEBI	CHEBI:71253 N as salt: CHEBI:71245
ChEMBL	ChEMBL1201756 N as salt: ChEMBL2040684
ECHA InfoCard	100.059.828
Chemical and physical data
Formula	C17H16ClNO
Molar mass	285.77 g·mol−1
3D model (JSmol)	Interactive image
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.^[11]

It was initially approved in the United States in 2009^[12] and approved as a generic medication in 2020.^[13]

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.^[12] In Australia asenapine's approved (and also listed on the PBS) indications include the following:^[14]

• 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.^[2][7][4]

Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed.^[15] A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado.^[8]

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.^[16]

Bipolar disorder

For the medium-term and long-term management and control of both depressive and manic features of bipolar disorder asenapine was found to be equally effective as olanzapine, but with a substantially superior side effect profile.^[10]

In acute mania, asenapine was found to be significantly superior to placebo.^[10] 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 such as risperidone and olanzapine (with the exception of ziprasidone). Drop-out rates (in clinical trials) were also unusually high with asenapine.^[17] 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.^[18]

Adverse effects

Adverse effect incidence^[5][6][2][7]

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

• Somnolence

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

• Weight gain^†
• Increased appetite
• Extrapyramidal side effects (EPS; such as dystonia, akathisia, dyskinesia, muscle rigidity, parkinsonism)
• Sedation
• Dizziness
• Dysgeusia (altered taste)
• Oral hypoaesthesia (numbness), only when taken sublingually. Transdermal asenapine was shown to eliminate this side effect.^[8]
• Increased alanine aminotransferase
• Dyspepsia, stomach discomfort, and/or vomiting^[a]
• Fatigue

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

• Hyperglycaemia — elevated blood glucose (sugar)
• Syncope
• Seizure
• Dysarthria
• sinus bradycardia
• Bundle branch block
• QTc interval prolongation (has a relatively low risk for causing QTc interval prolongation.^[19][20])
• sinus tachycardia
• Orthostatic hypotension
• Hypotension
• Swollen tongue
• Dysphagia (difficulty swallowing)
• Glossodynia
• Oral paraesthesia

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

• Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate)
• Tardive dyskinesia
• Speech disturbance
• Rhabdomyolysis
• Angioedema
• Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia
• Accommodation disorder^{[clarification needed]}
• Pulmonary embolism
• Gynaecomastia
• Galactorrhoea

Unknown incidence adverse effects

• Allergic reaction
• Restless legs syndrome
• 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).^[21] Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis.^[21] 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.^[21] 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.^[21]

Discontinuation

For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing to avoid acute withdrawal syndrome or rapid relapse.^[22] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.^[23] Other symptoms may include restlessness, increased sweating, and trouble sleeping.^[23] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.^[23] Symptoms generally resolve after a short period of time.^[23]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a transient withdrawal symptom.^[24] It may also result in recurrence of the condition that is being treated.^[25] Rarely tardive dyskinesia can occur when the medication is stopped.^[23]

Pharmacology

Pharmacodynamics

See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications

Asenapine^[26][12]

Site	pKi	Ki (nM)	Action
5-HT1A	8.6	2.5	Partial agonist
5-HT1B	8.4	4.0	Antagonist
5-HT2A	10.2	0.06	Antagonist
5-HT2B	9.8	0.16	Antagonist
5-HT2C	10.5	0.03	Antagonist
5-HT5A	8.8	1.6	Antagonist
5-HT6	9.5	0.25	Antagonist
5-HT7	9.9	0.13	Antagonist
α1	8.9	1.2	Antagonist
α2A	8.9	1.2	Antagonist
α2B	9.5	0.32	Antagonist
α2C	8.9	1.2	Antagonist
D1	8.9	1.4	Antagonist
D2	8.9	1.3	Antagonist
D3	9.4	0.42	Antagonist
D4	9.0	1.1	Antagonist
H1	9.0	1.0	Antagonist
H2	8.2	6.2	Antagonist
mACh	<5	8128	Antagonist

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT_1A (8.6), 5-HT_1B (8.4), 5-HT_2A (10.2), 5-HT_2B (9.8), 5-HT_2C (10.5), 5-HT_5A (8.8), 5-HT₆ (9.5), and 5-HT₇ (9.9) receptors, the adrenergic α₁ (8.9), α_2A (8.9), α_2B (9.5), and α_2C (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-HT_1A receptors.^[27] At all other targets asenapine is an antagonist.^[26]

Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT_2A, 5-HT_2C, 5-HT₆, and 5-HT₇ receptors, and very high affinity for the α₂ and H₁ receptors.^[26]

Notes

1. The Phase III trials used for FDA approval in the US used lists of "elicited side effects", asking all subjects about each side effect on the list, and "nausea" was not included. The elicited side effects list included the related symptoms of "dyspepsia", "stomach discomfort", and "vomiting", and the incidence of each was higher than placebo and in the range of 1 to 10% of asenapine-treated subjects.^[6]

References

1. Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
2. "Sycrest 5mg sublingual tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 9 September 2020.
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4. "Sycrest EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 9 September 2020.
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10. Vita A, De Peri L, Siracusano A, Sacchetti E (September 2013). "Efficacy and tolerability of asenapine for acute mania in bipolar I disorder: meta-analyses of randomized-controlled trials". International Clinical Psychopharmacology. 28 (5): 219–227. doi:10.1097/YIC.0b013e32836290d2. PMID 23719049. S2CID 20871442.
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17. Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. (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.
18. 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.
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22. Joint Formulary Committee B, 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.
23. Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN 9780198527480.
24. 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.
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27. Ghanbari R, El Mansari M, Shahid M, Blier P (March 2009). "Electrophysiological characterization of the effects of asenapine at 5-HT(1A), 5-HT(2A), alpha(2)-adrenergic and D(2) receptors in the rat brain". European Neuropsychopharmacology. 19 (3): 177–187. doi:10.1016/j.euroneuro.2008.11.001. PMID 19116183. S2CID 140204044.

External links

• "Asenapine". Drug Information Portal. U.S. National Library of Medicine.
• "Asenapine maleate". Drug Information Portal. U.S. National Library of Medicine.