Chemical compound
Lemborexant
Trade names Dayvigo Other names E-2006
License data
Pregnancy category
Routes of administration
By mouth
[3]
Drug class
Orexin receptor antagonist ;
Hypnotic ;
Sedative
ATC code
Legal status
Bioavailability Good (≥87%)
[5]
[6]
Protein binding 94%
[3]
Metabolism
Liver (major:
CYP3A4 , minor:
CYP3A5 )
[3]
Metabolites M10
[3]
Elimination half-life 17–19 hours or 55 hours
[3]
[7]
Excretion
Feces : 57.4%
[3]
Urine : 29.1%
[3]
(1R ,2S )-2-[(2,4-Dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N -(5-fluoropyridin-2-yl)cyclopropane-1-carboxamide
CAS Number
PubChem
CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (
EPA )
Formula C 22 H 20 F 2 N 4 O 2
Molar mass 410.425 g·mol−1 3D model (
JSmol )
CC1=NC(=NC=C1OC[C@]2(C[C@H]2C(=O)NC3=NC=C(C=C3)F)C4=CC(=CC=C4)F)C
InChI=1S/C22H20F2N4O2/c1-13-19(11-25-14(2)27-13)30-12-22(15-4-3-5-16(23)8-15)9-18(22)21(29)28-20-7-6-17(24)10-26-20/h3-8,10-11,18H,9,12H2,1-2H3,(H,26,28,29)/t18-,22+/m0/s1
Key:MUGXRYIUWFITCP-PGRDOPGGSA-N
Lemborexant , sold under the brand name Dayvigo , is an
orexin antagonist medication which is used in the treatment of
insomnia .
[3]
[8] It is indicated specifically for the treatment of insomnia characterized by difficulties with
sleep onset and/or
maintenance in adults.
[3]
[8] The medication is taken
by mouth .
[3]
[8]
Side effects of lemborexant include
somnolence ,
fatigue ,
headache , and
abnormal dreams .
[3]
[8] The medication is a
dual orexin receptor antagonist (DORA).
[3]
[8] It acts as a
selective dual
antagonist of the
orexin receptors
OX1 and
OX2 .
[3]
[8] Lemborexant has a long
elimination half-life of 17 to 55 hours and a
time to peak of about 1 to 3 hours.
[3]
[8] It is not a
benzodiazepine or
Z-drug and does not interact with
GABA receptors , instead having a distinct
mechanism of action .
[3]
[8]
Lemborexant was approved for medical use in the United States in December 2019.
[9]
[10]
[11] It is a
schedule IV
controlled substance in the United States and may have a low
potential for misuse .
[3]
[8] Besides lemborexant, other orexin receptor antagonists including
suvorexant and
daridorexant have also been introduced.
[12]
[13]
Medical uses
Lemborexant is used in the treatment of
insomnia in adults.
[3]
A major
systematic review and
network meta-analysis of medications for the treatment of insomnia published in 2022 found that lemborexant had an
effect size (
standardized mean difference (SMD)) against
placebo for treatment of insomnia at 4 weeks of 0.36 (95%
CI Tooltip confidence interval 0.08 to 0.63) and at 3 months of 0.41 (95%
CI 0.04 to 0.78).
[14] Lemborexant had similar effect sizes at 4 weeks as the other evaluated and marketed orexin receptor antagonists
suvorexant (SMD 0.31, 95% CI 0.01 to 0.62) and
daridorexant (SMD 0.23, 95% CI –0.01 to 0.48), whereas
benzodiazepines and
Z-drugs generally showed larger effect sizes (e.g., SMDs of 0.45 to 0.83) than lemborexant and the other orexin receptor antagonists.
[14] However, the review concluded that lemborexant and
eszopiclone among all of the insomnia medications assessed had the best profiles overall in terms of
efficacy ,
tolerability , and
acceptability .
[14]
Compared to
benzodiazepines , there is a low risk of developing
tolerance and
dependence .
[15]
Memory and
attention are not affected the next morning when taking lemborexant.
[16]
Available forms
Lemborexant is available in the form of 5 and 10 mg
oral
film-coated
tablets .
[3]
Side effects
Side effects of lemborexant include
somnolence or
fatigue (combined preferred terms of somnolence,
lethargy , fatigue, and
sluggishness ) (6.9% at 5 mg and 9.6% at 10 mg vs. 1.3% for
placebo ),
headache (5.9% at 5 mg and 4.5% at 10 mg vs. 3.4% for placebo), and
nightmares or
abnormal dreams (0.9% at 5 mg and 2.2% at 10 mg vs. 0.9% for placebo).
[3] Less common side effects include
sleep paralysis (1.3% at 5 mg and 1.6% at 10 mg vs. 0% for placebo) and
hypnagogic hallucinations (0.1% at 5 mg and 0.7% at 10 mg vs. 0% for placebo).
[3]
Lemborexant at doses of 10, 20, and 30 mg produces
drug-liking responses similar to those of
zolpidem (30 mg) and
suvorexant (40 mg) in recreational sedative drug users.
[3] It is a
controlled substance in the United States and is considered to have a low
misuse potential .
[3]
[17]
Pharmacology
Pharmacodynamics
Lemborexant is a dual
antagonist of the
orexin
OX1 and
OX2
receptors .
[18]
[19]
[20] It associates and dissociates from the orexin receptors more rapidly than certain other orexin receptor antagonists, such as
suvorexant , and this may cause it to have a shorter
duration of action .
[12]
Pharmacokinetics
The
bioavailability of lemborexant is good and is at least 87%.
[5]
[6] The
time to peak levels of lemborexant is 1 to 3 hours.
[3] A high-fat and high-calorie meal has been found to delay the time to peak levels by 2 hours.
[3] Its
plasma protein binding
in vitro is 94%.
[3] Lemborexant is
metabolized primarily by
CYP3A4 and to a lesser extent by
CYP3A5 .
[3] The
"effective" half-life of lemborexant is 17 to 19 hours while its
terminal elimination half-life is 55 hours.
[3]
[7]
[8] The medication is
excreted in
feces (57%) and to a lesser extent
urine (29%).
[3]
Peak-normalized concentrations (% of
Cmax ) of the orexin receptor antagonists suvorexant (SUV; 20 mg) and lemborexant (LEM; 10 mg) with administration at
steady state in humans.
[21]
Although lemborexant has a longer
terminal elimination half-life than suvorexant, it appears to be more rapidly
cleared than suvorexant in the earlier phases of
elimination .
[21]
[7] In addition, lemborexant dissociates from the orexin receptors more rapidly than does suvorexant.
[21] These differences may allow for comparatively reduced next-day effects such as daytime somnolence with lemborexant.
[21]
[7]
History
In June 2016,
Eisai initiated Phase III
clinical trials in the United States, France, Germany, Italy, Japan, Poland, Spain and the UK.
[22]
In December 2019, lemborexant was approved for use in the United States based on results from the SUNRISE 1 and SUNRISE 2 Phase III clinical trials.
[11]
[23]
Society and culture
Names
Lemborexant is the
generic name of the drug and its
INN Tooltip International Nonproprietary Name while E-2006 was its developmental code name. Lemborexant is sold under the brand name Dayvigo.
[3]
Availability
Lemborexant is marketed in the United States,
Canada ,
Australia , and
Japan .
[24]
[25]
[26]
[27] It is not approved by the
European Medicines Agency (EMA) for use in the
European Union or by the
Medicines and Healthcare products Regulatory Agency (MHRA) in the
United Kingdom .
[28]
[29]
Research
Lemborexant is under development for the treatment of
circadian rhythm sleep disorders ,
sleep apnea , and
chronic obstructive pulmonary disease .
[30] As of February 2022, it is in
phase 2
clinical trials for circadian rhythm sleep disorders and
phase 1 trials for sleep apnea and chronic obstructive pulmonary disease.
[30]
References
^
a
b
"Dayvigo" . Therapeutic Goods Administration (TGA) . 23 July 2021. Retrieved 5 September 2021 .
^
"Updates to the Prescribing Medicines in Pregnancy database" . Therapeutic Goods Administration (TGA) . 12 May 2022. Retrieved 13 May 2022 .
^
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
z
aa
ab
ac
ad
"Dayvigo- lemborexant tablet, film coated" . DailyMed . Retrieved 17 June 2021 .
^
"Summary Basis of Decision (SBD) for Dayvigo" . Health Canada . 23 October 2014. Retrieved 29 May 2022 .
^
a
b Hoyer D, Jacobson LH (2018). "Lemborexant. Dual orexin receptor antagonist, Treatment of insomnia". Drugs of the Future . 43 (10): 715.
doi :
10.1358/dof.2018.043.10.2828699 .
ISSN
0377-8282 .
^
a
b Lalovic B, Majid O, Aluri J, Landry I, Moline M, Hussein Z (December 2020).
"Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder" . Journal of Clinical Pharmacology . 60 (12): 1642–1654.
doi :
10.1002/jcph.1683 .
PMC
7689791 .
PMID
32666570 .
^
a
b
c
d Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J (November 2020). "Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders". Expert Opinion on Drug Metabolism & Toxicology . 16 (11): 1063–1078.
doi :
10.1080/17425255.2020.1817380 .
PMID
32901578 .
S2CID
221572078 .
^
a
b
c
d
e
f
g
h
i
j Waters K (February 2022). "Review of the Efficacy and Safety of Lemborexant, a Dual Receptor Orexin Antagonist (DORA), in the Treatment of Adults With Insomnia Disorder". The Annals of Pharmacotherapy . 56 (2): 213–221.
doi :
10.1177/10600280211008492 .
PMID
34078141 .
S2CID
235321467 .
^
"Novel Drug Approvals for 2019" . U.S.
Food and Drug Administration (FDA) . 2 January 2020. Retrieved 10 January 2020 . This article incorporates text from this source, which is in the
public domain .
^
"FDA-Approved Drugs: Lemborexant" . U.S.
Food and Drug Administration (FDA) . Retrieved 10 January 2020 .
^
a
b
"FDA Approves Dayvigo (lemborexant) for the Treatment of Insomnia in Adult Patients" . Drugs.com . 23 December 2019. Retrieved 10 January 2020 .
^
a
b Jacobson LH, Hoyer D, de Lecea L (May 2022). "Hypocretins (orexins): The ultimate translational neuropeptides". Journal of Internal Medicine . 291 (5): 533–556.
doi :
10.1111/joim.13406 .
PMID
35043499 .
S2CID
248119793 .
^ Markham A (April 2022).
"Daridorexant: First Approval" . Drugs . 82 (5): 601–607.
doi :
10.1007/s40265-022-01699-y .
PMC
9042981 .
PMID
35298826 .
^
a
b
c De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, et al. (July 2022).
"Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis" . Lancet . 400 (10347): 170–184.
doi :
10.1016/S0140-6736(22)00878-9 .
hdl :
11380/1288245 .
PMID
35843245 .
S2CID
250536370 .
^ Suzuki H, Hibino H (18 August 2021).
"The effect of lemborexant for insomnia disorder" . SAGE Open Medicine . 9 : 20503121211039098.
doi :
10.1177/20503121211039098 .
PMC
8377315 .
PMID
34422270 .
^ Murphy P, Kumar D, Zammit G, Rosenberg R, Moline M (May 2020).
"Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening" . Journal of Clinical Sleep Medicine . 16 (5): 765–773.
doi :
10.5664/jcsm.8294 .
PMC
7849806 .
PMID
32022664 .
^ Asakura S, Shiotani M, Gauvin DV, Fujiwara A, Ueno T, Bower N, et al. (December 2021).
"Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant" . Regulatory Toxicology and Pharmacology . 127 : 105053.
doi :
10.1016/j.yrtph.2021.105053 .
PMID
34619288 .
S2CID
238476630 .
^ Christopher JA (2014). "Small-molecule antagonists of the orexin receptors". Pharmaceutical Patent Analyst . 3 (6): 625–638.
doi :
10.4155/ppa.14.46 .
PMID
25489915 .
^ Boss C, Roch C (August 2015). "Recent trends in orexin research--2010 to 2015". Bioorganic & Medicinal Chemistry Letters . 25 (15): 2875–2887.
doi :
10.1016/j.bmcl.2015.05.012 .
PMID
26045032 .
^ Boss C (December 2014). "Orexin receptor antagonists--a patent review (2010 to August 2014)". Expert Opinion on Therapeutic Patents . 24 (12): 1367–1381.
doi :
10.1517/13543776.2014.978859 .
PMID
25407283 .
S2CID
21106711 .
^
a
b
c
d Kishi T, Nishida M, Koebis M, Taninaga T, Muramoto K, Kubota N, et al. (December 2021).
"Evidence-based insomnia treatment strategy using novel orexin antagonists: A review" . Neuropsychopharmacology Reports . 41 (4): 450–458.
doi :
10.1002/npr2.12205 .
PMC
8698673 .
PMID
34553844 .
^
"Lemborexant" . Specialist Pharmacy Service . Archived from
the original on 7 November 2017. Retrieved 5 November 2017 .
^
"Drug Trials Snapshot: Dayvigo" . U.S.
Food and Drug Administration (FDA) . 20 December 2019. Retrieved 24 January 2020 . This article incorporates text from this source, which is in the
public domain .
^
"Micromedex Products: Please Login" .
^
"Drug Product Database: Access the database" . 18 March 2010.
^
"Dayvigo" . 23 July 2021.
^
"EISAI TO LAUNCH IN-HOUSE DEVELOPED NEW ANTI-INSOMNIA DRUG DAYVIGO® (LEMBOREXANT) WITH INDICATION FOR INSOMNIA IN JAPAN | News Release:2020 | Eisai Co., Ltd" .
^
"Medicines" . European Medicines Agency .
^
"Products" . Medicines and Healthcare products Regulatory Agency (MHRA) .
^
a
b
"Lemborexant - Eisai - AdisInsight" .
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