Agomelatine

Source: Wikipedia, the free encyclopedia.
Agomelatine
Clinical data
Trade namesMelitor, Thymanax, Valdoxan, others
Other namesAGO-178; AGO178C; S-20098; S-20098-F55
AHFS/Drugs.comInternational Drug Names
License data
Pregnancy
category
  • AU: B1
Dependence
liability		Low[1]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability1%[2]
Protein binding95%[2]
MetabolismLiver (90% CYP1A2 and 10% CYP2C9)[2]
Elimination half-life1–2 hours[2]
ExcretionKidney (80%, mostly as metabolites)[2]
Identifiers
  • N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide
JSmol)
  • O=C(NCCc1c2c(ccc1)ccc(OC)c2)C
  • InChI=1S/C15H17NO2/c1-11(17)16-9-8-13-5-3-4-12-6-7-14(18-2)10-15(12)13/h3-7,10H,8-9H2,1-2H3,(H,16,17) checkY
  • Key:YJYPHIXNFHFHND-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder.[7] One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects.[7][8] Another review also found it was similarly effective to many other antidepressants.[9]

Common side effects include weight gain, fatigue,

liver problems, nausea, headaches, and anxiety.[10][11] Due to potential liver problems ongoing blood tests are recommended.[12] Its use is not recommended in people with dementia or over the age of 75.[10] There is tentative evidence that it may have fewer side effects than some other antidepressants.[7] It acts by blocking certain serotonin receptors and activating melatonin receptors.[12]

Agomelatine was approved for medical use in Europe in 2009 and Australia in 2010.

Servier.[12]

Medical uses

Major depressive disorder

Agomelatine is used for the treatment of

SMDTooltip standardized mean difference) of 0.24.[8][14]

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed agomelatine to be one of the most effective and one of only two medications found to be more tolerable than placebo.[15]

A

major depression.[17] A 2018 meta-study comparing 21 antidepressants found agomelatine was one of the more tolerable, yet effective antidepressants.[9]

However, the body of research on agomelatine has been substantially affected by publication bias, prompting analyses which take into account both published and unpublished studies.[8][18][19] These have confirmed that agomelatine is approximately as effective as more commonly used antidepressants (e.g. SSRIs), but some qualified this as "marginally clinically relevant",[19] being only slightly above placebo.[18][19] According to a 2013 review, agomelatine did not seem to provide an advantage in efficacy over other antidepressants for the acute-phase treatment of major depression.[20]

Generalized anxiety disorder

Agomelatine has been found more effective than placebo in the treatment of

placebo-controlled studies and in long term relapse prevention.[21][22][23][24][25]

Use in special populations

It is not recommended in Europe for use in

adolescents below 18 years of age due to a lack of data on safety and efficacy.[13] However, a recent 12 week study first reported in September 2020, and published in 2022 showed greater efficacy vs. placebo for agomelatine 25 mg per day in youth age 7–17 years and an acceptable tolerability profile with similar efficacy to fluoxetine.[26][27] Only limited data is available on use in elderly people ≥ 75 years old with major depressive episodes.[13]

It is not recommended during pregnancy or breastfeeding.[10]

Contraindications

Agomelatine is contraindicated in patients with kidney or

renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.[13]

Adverse effects

Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without modification of REM (rapid eye movement) sleep amount or REM latency.[29] Agomelatine also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.[2][13]

Agomelatine appears to cause fewer

sexual side effects and discontinuation effects than paroxetine.[2]

Common (1–10% incidence) adverse effects include[2][13][30][31]
  • Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature)
  • Abdominal pain
  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation
  • Back pain
  • Fatigue
  • Increased ALAT and ASAT (liver enzymes)
  • Headache
  • Dizziness
  • Somnolence
  • Insomnia
  • Migraine
  • Anxiety
Uncommon (0.1–1%) adverse effects include[2][13][30][31]
  • Paraesthesia
    (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves)
  • Blurred vision
  • Eczema
  • Pruritus
    (itching)
  • Urticaria
  • Agitation
  • Irritability
  • Restlessness
  • Aggression
  • Nightmares
  • Abnormal dreams
Rare (0.01–0.1%) adverse effects include[2][13][30][31]

Dependence and withdrawal

No dosage tapering is needed on treatment discontinuation.

abuse potential as measured in healthy volunteer studies.[2][13]

Overdose

Agomelatine is expected to be relatively safe in overdose.[33]

Interactions

Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressant fluvoxamine, reduce its clearance and can lead to an increase in agomelatine exposure, and possibly serotonin syndrome .[2][30] There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity.[2][30]

Pharmacology

Pharmacodynamics

Agomelatine is a

serotonin receptors.[13]

Agomelatine resynchronizes

frontal cortex. Therefore, it is sometimes classified as a norepinephrine–dopamine disinhibitor. However, the clinical significance of 5-HT2C antagonism by agomelatine is disputed.[37] Unlike clinically significant 5-HT2C antagonists, clinically relevant doses of agomelatine fail to acutely increase slow wave sleep in humans.[38][39]

Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin onset.[13]

Chemistry

Structure

melatonin
(top) vs. agomelatine (bottom).

The

melatonin. Where melatonin has an indole ring system, agomelatine has a naphthalene bioisostere instead.[40]

Synthesis

Agomelatine-synthesis:[41][42] and structure-activity studies:[43][44]

History

Agomelatine was discovered and developed by the

phase III trials in the European Union
.

In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) under the trade names Valdoxan and Thymanax.[45] On 27 July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorisation. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about side effects.[45] In September 2007, Servier submitted a new marketing application to the EMA.[46]

In March 2006,

Servier announced it had sold the rights to market agomelatine in the United States to Novartis.[47] It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012.[48] However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available.[49]

It received approval from the European Medicines Agency (EMA) for marketing in the European Union in February 2009[13] and approval from the Therapeutic Goods Administration (TGA) for marketing in Australia in August 2010.[2]

Research

Circadian rhythm sleep disorders

Agomelatine has been investigated for its effects on sleep regulation due its actions as a melatonin receptor agonist.[50] Studies report various improvements in general quality of sleep metrics, as well as benefits in circadian rhythm sleep disorders.[50][8][36][51] However, research is very limited (e.g., case reports) and agomelatine is not approved for use in the treatment of sleep disorders.[50]

Seasonal affective disorder

A 2019

Cochrane review suggested no recommendations of agomelatine in support of, or against, its use to treat individuals with seasonal affective disorder.[52]

References

  1. PMID 36632077
    .
  2. ^ a b c d e f g h i j k l m n o "Valdoxan Product Information" (PDF). TGA eBusiness Services. Servier Laboratories Pty Ltd. 2013-09-23. Archived from the original on 2017-03-24. Retrieved 2013-10-14.
  3. ^ 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 2023-08-03.
  4. ^ "Valdoxan 25 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 13 July 2020. Archived from the original on 17 January 2021. Retrieved 14 January 2021.
  5. ^ "Thymanax EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 26 February 2021. Retrieved 14 January 2021.
  6. ^ "Valdoxan EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 28 February 2021. Retrieved 14 January 2021.
  7. ^
    PMID 24343836
    .
  8. ^
    PMID 24647162
    .
  9. ^
    PMID 29477251
    .
  10. ^
    ISBN 9780857113382
    .
  11. ^ "Product Information: Valdoxan, INN-agomelatine" (PDF). www.ema.europa.eu. European Medicines Agency. 13 November 2013. Archived (PDF) from the original on 29 October 2014. Retrieved 27 February 2016.
  12. ^
    S2CID 73421269
    .
  13. ^ a b c d e f g h i j k l m n o p q "Summary of Product Characteristics" (PDF). European Medicine Agency. Archived (PDF) from the original on 2014-10-29. Retrieved 2013-10-14.
  14. S2CID 8142581. Archived
    from the original on 2023-03-07. Retrieved 2023-01-24.
  15. PMID 29477251
    .
  16. S2CID 21796064
    .
  17. PMID 21859514
    .
  18. ^
    PMID 23999482
    .
  19. ^
    S2CID 21808090
    .
  20. PMID 24343836
    .
  21. S2CID 40152863
    .
  22. S2CID 24860538
    .
  23. PMID 33537871
    .
  24. S2CID 5569226
    .
  25. S2CID 5569226
    .
  26. S2CID 245167558
    .
  27. ^ "Agomelatine Effective for Children, Adolescents With Depression". dgnews.docguide.com. Archived from the original on 2021-12-06. Retrieved 2020-09-21.
  28. ^ "Information about Valdoxan for patients". Servier. Archived from the original on 2012-12-10. Retrieved 2012-12-10.
  29. S2CID 5997517
    .
  30. ^
    ISBN 9780980579093
    .
  31. ^
    ISBN 978-0857110848. Archived
    from the original on 2023-01-14. Retrieved 2018-07-24.
  32. S2CID 41069663
    .
  33. ISBN 978-0-470-97948-8. Archived
    from the original on 2023-01-14. Retrieved 2018-07-24.
  34. S2CID 84678381
    .
  35. S2CID 18753440
    .
  36. ^
    S2CID 29745284
    .
  37. ISSN 1432-2072
    .
  38. S2CID 253752682
    .
  39. S2CID 5997517
    .
  40. doi:10.1107/S0108270193012922
    .
  41. ^ EP application 447285, Andrieux J, Houssin R, Yous S, Guardiola B, Lesieur D, "Naphthalene derivatives, procedure for their preparation and pharmaceutical compositions containing them.", published 1991-09-18, assigned to Adir 
  42. ^ US granted 5225442, Andrieux J, Houssin R, Yous S, Guardiola B, Lesieur D, "Compounds having a naphthalene structure", issued 6 July 1993, assigned to Adir 
  43. PMID 1315395
    .
  44. PMID 7932550
    .
  45. ^ a b "Questions and Answers on Recommendation for Refusal of Marketing Authorisation". European Medicines Agency. 18 November 2006. Archived from the original (PDF) on 6 August 2010. Retrieved 6 July 2009.
  46. ^ "CHMP Assessment Report for Valdoxan" (PDF). European Medicines Agency. 20 November 2008. Archived (PDF) from the original on 24 April 2011. Retrieved 6 July 2009.
  47. ^ Bentham C (2006-03-29). "Servier and Novartis sign licensing agreement for agomelatine, a novel treatment for depression". Servier UK. Archived from the original on 16 April 2009. Retrieved 2009-05-15.
  48. ^ "Clinical trials for agomelatine". ClinicalTrials.gov. National Institutes of Health. Archived from the original on 4 October 2011. Retrieved 6 July 2009.
  49. ^ Malone E (25 October 2011). "Novartis drops future blockbuster agomelatine". Scrip Intelligence. Archived from the original on 11 November 2011.
  50. ^
    PMID 27500861
    .
  51. ^ "Valdoxan: A New Approach to The Treatment of Depression". Medical News Today. MediLexicon International Ltd. 2005-04-05. Archived from the original on 15 April 2009. Retrieved 14 May 2009.
  52. PMID 31206585
    .

External links
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