U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C16H21NO2
Molecular Weight 259.344
Optical Activity ( - )
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of RAMELTEON

SMILES

CCC(=NCC[C@]1([H])CCc2ccc3c(CCO3)c21)O

InChI

InChIKey=YLXDSYKOBKBWJQ-LBPRGKRZSA-N
InChI=1S/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m0/s1

HIDE SMILES / InChI

Molecular Formula C16H21NO2
Molecular Weight 259.344
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment:: description was created based on several sources, including https://www.takeda.com/news/2011/20111007_3902.html

Ramelteon was approved by the United States (U.S.) in July 2005, and the Japanese Ministry of Health, Labour and Welfare in April 2010. It is currently available in the USA and Japan as ROZEREM and is indicated for the treatment of insomnia characterized by difficulty with sleep onset. In October 7, 2011, Takeda has decided to discontinue the development of ramelteon in Europe for the treatment of insomnia in order to best optimize Takeda’s resources for its research and development activities. Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the MT3 receptor. The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties since these receptors are acted upon by endogenous melatonin and are thought to be involved in the maintenance of the circadian rhythm underlying normal sleep-wake cycles. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates.

Originator

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ROZEREM

Approved Use

ROZEREM is indicated for the treatment of insomnia characterized by difficulty with sleep onset. The clinical trials performed in support of efficacy were up to 6 months in duration. The final formal assessments of sleep latency were performed after 2 days of treatment during the crossover study (elderly only), at 5 weeks in the 6-week studies (adults and elderly), and at the end of the 6-month study (adults and elderly) [see Clinical Studies (14)

Launch Date

1.12199034E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
25.9 ng/mL
64 mg single, oral
dose: 64 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RAMELTEON serum
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
36.1 ng × h/mL
64 mg single, oral
dose: 64 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RAMELTEON serum
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
1.9 h
64 mg single, oral
dose: 64 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RAMELTEON serum
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
30%
64 mg single, oral
dose: 64 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
RAMELTEON serum
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
32 mg 1 times / day multiple, oral
Highest studied dose
Dose: 32 mg, 1 times / day
Route: oral
Route: multiple
Dose: 32 mg, 1 times / day
Sources:
unhealthy, 42.8 years
n = 63
Health Status: unhealthy
Condition: chronic primary insomnia
Age Group: 42.8 years
Sex: M+F
Population Size: 63
Sources:
Other AEs: Somnolence, Malaise...
Other AEs:
Somnolence (12.7%)
Malaise (1.6%)
Dizziness (3.2%)
Nasopharyngitis (4.8%)
Sources:
40 mg 1 times / day multiple, oral
Overdose
Dose: 40 mg, 1 times / day
Route: oral
Route: multiple
Dose: 40 mg, 1 times / day
Sources:
unhealthy, 47 years
n = 1
Health Status: unhealthy
Condition: insomnia
Age Group: 47 years
Sex: F
Population Size: 1
Sources:
8 mg 1 times / day steady, oral
Recommended
Dose: 8 mg, 1 times / day
Route: oral
Route: steady
Dose: 8 mg, 1 times / day
Sources:
unhealthy, adult
n = 3594
Health Status: unhealthy
Condition: insomnia
Age Group: adult
Population Size: 3594
Sources:
Disc. AE: Somnolence, Dizziness...
AEs leading to
discontinuation/dose reduction:
Somnolence (0.8%)
Dizziness (0.5%)
Nausea (0.3%)
Fatigue (0.3%)
Headache (0.3%)
Insomnia (0.3%)
Sources:
160 mg single, oral
Highest studied dose
Dose: 160 mg
Route: oral
Route: single
Dose: 160 mg
Sources:
unknown
AEs

AEs

AESignificanceDosePopulation
Malaise 1.6%
32 mg 1 times / day multiple, oral
Highest studied dose
Dose: 32 mg, 1 times / day
Route: oral
Route: multiple
Dose: 32 mg, 1 times / day
Sources:
unhealthy, 42.8 years
n = 63
Health Status: unhealthy
Condition: chronic primary insomnia
Age Group: 42.8 years
Sex: M+F
Population Size: 63
Sources:
Somnolence 12.7%
32 mg 1 times / day multiple, oral
Highest studied dose
Dose: 32 mg, 1 times / day
Route: oral
Route: multiple
Dose: 32 mg, 1 times / day
Sources:
unhealthy, 42.8 years
n = 63
Health Status: unhealthy
Condition: chronic primary insomnia
Age Group: 42.8 years
Sex: M+F
Population Size: 63
Sources:
Dizziness 3.2%
32 mg 1 times / day multiple, oral
Highest studied dose
Dose: 32 mg, 1 times / day
Route: oral
Route: multiple
Dose: 32 mg, 1 times / day
Sources:
unhealthy, 42.8 years
n = 63
Health Status: unhealthy
Condition: chronic primary insomnia
Age Group: 42.8 years
Sex: M+F
Population Size: 63
Sources:
Nasopharyngitis 4.8%
32 mg 1 times / day multiple, oral
Highest studied dose
Dose: 32 mg, 1 times / day
Route: oral
Route: multiple
Dose: 32 mg, 1 times / day
Sources:
unhealthy, 42.8 years
n = 63
Health Status: unhealthy
Condition: chronic primary insomnia
Age Group: 42.8 years
Sex: M+F
Population Size: 63
Sources:
Fatigue 0.3%
Disc. AE
8 mg 1 times / day steady, oral
Recommended
Dose: 8 mg, 1 times / day
Route: oral
Route: steady
Dose: 8 mg, 1 times / day
Sources:
unhealthy, adult
n = 3594
Health Status: unhealthy
Condition: insomnia
Age Group: adult
Population Size: 3594
Sources:
Headache 0.3%
Disc. AE
8 mg 1 times / day steady, oral
Recommended
Dose: 8 mg, 1 times / day
Route: oral
Route: steady
Dose: 8 mg, 1 times / day
Sources:
unhealthy, adult
n = 3594
Health Status: unhealthy
Condition: insomnia
Age Group: adult
Population Size: 3594
Sources:
Insomnia 0.3%
Disc. AE
8 mg 1 times / day steady, oral
Recommended
Dose: 8 mg, 1 times / day
Route: oral
Route: steady
Dose: 8 mg, 1 times / day
Sources:
unhealthy, adult
n = 3594
Health Status: unhealthy
Condition: insomnia
Age Group: adult
Population Size: 3594
Sources:
Nausea 0.3%
Disc. AE
8 mg 1 times / day steady, oral
Recommended
Dose: 8 mg, 1 times / day
Route: oral
Route: steady
Dose: 8 mg, 1 times / day
Sources:
unhealthy, adult
n = 3594
Health Status: unhealthy
Condition: insomnia
Age Group: adult
Population Size: 3594
Sources:
Dizziness 0.5%
Disc. AE
8 mg 1 times / day steady, oral
Recommended
Dose: 8 mg, 1 times / day
Route: oral
Route: steady
Dose: 8 mg, 1 times / day
Sources:
unhealthy, adult
n = 3594
Health Status: unhealthy
Condition: insomnia
Age Group: adult
Population Size: 3594
Sources:
Somnolence 0.8%
Disc. AE
8 mg 1 times / day steady, oral
Recommended
Dose: 8 mg, 1 times / day
Route: oral
Route: steady
Dose: 8 mg, 1 times / day
Sources:
unhealthy, adult
n = 3594
Health Status: unhealthy
Condition: insomnia
Age Group: adult
Population Size: 3594
Sources:
Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer







Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no (co-administration study)
Comment: theophylline AUC increased 40% and Cmax increased 35%
Page: 11, 13
no
no (co-administration study)
Comment: dextromethorphan AUC and Cmax did not change
Page: 11, 13
no
no (co-administration study)
Comment: ramelteon decreased digoxin exposure by 3%
Page: 11, 60, 63
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
inconclusive
major
yes (co-administration study)
Comment: fluvoxamine increased ramelteon AUC 190-fold and Cmax 70-fold; rifampin decreased total expsoure to ramelteon by 80%
Page: 11, 13
minor
yes (co-administration study)
Comment: rifampin decreased total expsoure to ramelteon by 80%
Page: 11, 13
minor
yes (co-administration study)
Comment: ketaconazole increased ramelteon AUC by 84% and Cmax 36%; rifampin decreased total expsoure to ramelteon by 80%
Page: 11, 13
yes
yes (co-administration study)
Comment: fluconazole increased AUC by 150% and Cmax by 150%; rifampin decreased total expsoure to ramelteon by 80%
Page: 13.0
Tox targets

Tox targets

Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Gateways to clinical trials.
2003 Nov
Gateways to clinical trials.
2004 Jul-Aug
Sleep and aging: prevalence of disturbed sleep and treatment considerations in older adults.
2005
Ramelteon.
2005
Gateways to clinical trials.
2005 Apr
Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist.
2005 Feb
Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment.
2005 Mar
Use of sleep-promoting medications in nursing home residents : risks versus benefits.
2006
New drugs 06, part II.
2006 Aug
Treating insomnia: Current and investigational pharmacological approaches.
2006 Dec
An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia.
2006 Jan
New drugs: ramelteon, tipranavir, nepafenac, and deferasirox.
2006 Jan-Feb
Searching for new options for treating insomnia: are melatonin and ramelteon beneficial?
2006 Jul
Gateways to clinical trials.
2006 Jul-Aug
Ramelteon for the treatment of insomnia.
2006 Oct
Associated Professional Sleep Societies--SLEEP 2006 20th Anniversary Meeting. 17-22 June 2006, Salt Lake City, UT, USA.
2006 Sep
Treatment of sleep dysfunction and psychiatric disorders.
2006 Sep
Eszopiclone for late-life insomnia.
2007
Update on the safety considerations in the management of insomnia with hypnotics: incorporating modified-release formulations into primary care.
2007
[Melatonin, melatonin receptor agonists and tryptophan as sleep aids].
2007
Use of non-benzodiazepine hypnotics in the elderly: are all agents the same?
2007
Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia.
2007 Aug 15
[Recent and potential drugs for treatment of insomnia].
2007 Jan
Hypnotic sedative drugs.
2007 Jun
In search of novel and therapeutically significant melatoninergic ligands.
2007 Nov
Gateways to clinical trials.
2007 Oct
Safety of ramelteon in individuals with mild to moderate obstructive sleep apnea.
2007 Sep
Melatonergic drugs in clinical practice.
2008
A review of ramelteon in the treatment of sleep disorders.
2008 Feb
Jet lag: therapeutic use of melatonin and possible application of melatonin analogs.
2008 Jan-Mar
Circadian phase-shifting effects of repeated ramelteon administration in healthy adults.
2008 Oct 15
Possibility that certain hypnotics might cause cancer in skin.
2008 Sep
Hypnotics and skin cancer: hint at drug carcinogenesis, coincidence, or benefit of more sleep?
2008 Sep
Sleep dysfunction in heart failure.
2008 Sep
Acute sleep-promoting action of the melatonin agonist, ramelteon, in the rat.
2008 Sep
The effects of ramelteon in a first-night model of transient insomnia.
2009 Jan
Patents

Sample Use Guides

The recommended dose 8 mg taken within 30 minutes of going to bed. It is recommended that drug not be taken with or immediately after a high fat meal.
Route of Administration: Oral
In Vitro Use Guide
Curator's Comment:: Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors.
Unknown
Substance Class Chemical
Created
by admin
on Fri Jun 25 21:28:27 UTC 2021
Edited
by admin
on Fri Jun 25 21:28:27 UTC 2021
Record UNII
901AS54I69
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
RAMELTEON
HSDB   INN   JAN   MART.   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
RAMELTEON [JAN]
Common Name English
RAMELTEON [VANDF]
Common Name English
ROZEREM
Brand Name English
TAK375
Code English
(-)-N-(2-(((8S)-1,6,7,8-TETRAHYDRO-2H-INDENO(5,4-.BETA.)FURAN-8-YL)ETHYL)PROPANAMIDE
Common Name English
RAMELTEON [HSDB]
Common Name English
RAMELTEON [MART.]
Common Name English
RAMELTEON [ORANGE BOOK]
Common Name English
RAMELTEON [USAN]
Common Name English
TAK-375
Code English
RAMELTEON [WHO-DD]
Common Name English
RAMELTEON [MI]
Common Name English
PROPANAMIDE, N-(2-((8S)-1,6,7,8-TETRAHYDRO-2H-INDENO(5,4-.BETA.)FURAN-8-YL)ETHYL)-
Common Name English
RAMELTEON [INN]
Common Name English
Classification Tree Code System Code
WHO-ATC N05CH02
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
LIVERTOX 831
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
NDF-RT N0000000250
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
WHO-VATC QN05CH02
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
NDF-RT N0000175743
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
NCI_THESAURUS C47795
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
Code System Code Type Description
NCI_THESAURUS
C66504
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
LACTMED
Ramelteon
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
WIKIPEDIA
RAMELTEON
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
FDA UNII
901AS54I69
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
CAS
196597-26-9
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
RXCUI
596205
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY RxNorm
HSDB
7787
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
ChEMBL
CHEMBL1218
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
DRUG CENTRAL
2355
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
EVMPD
SUB21315
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
MERCK INDEX
M9489
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY Merck Index
INN
8447
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
EPA CompTox
196597-26-9
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
MESH
C495910
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
PUBCHEM
208902
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
IUPHAR
1356
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
DRUG BANK
DB00980
Created by admin on Fri Jun 25 21:28:27 UTC 2021 , Edited by admin on Fri Jun 25 21:28:27 UTC 2021
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
MINOR
EXCRETED UNCHANGED
FECAL; URINE
METABOLIC ENZYME -> SUBSTRATE
MINOR
TARGET -> AGONIST
AGONIST
Ki
METABOLIC ENZYME -> SUBSTRATE
MAJOR
TARGET -> AGONIST
HUMAN RECEPTOR IN CHO CELLS
Ki
BINDER->LIGAND
independent of concentration
BINDING
METABOLIC ENZYME -> SUBSTRATE
Related Record Type Details
METABOLITE INACTIVE -> PARENT
METABOLITE ACTIVE -> PARENT
metabolite M-II, has a longer half-life and greater systemic exposure than ramelteon. Hence, M-II may contribute significantly to the hypnotic benefits of ramelteon. S-ISOMER represents 94% of M-II.
METABOLITE -> PARENT
METABOLITE ACTIVE -> PARENT
major isozyme metabolizes to S-isomer
MAJOR
PLASMA
METABOLITE ACTIVE -> PARENT
minor isozyme
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC Elimination
PHARMACOKINETIC
Tmax PHARMACOKINETIC FASTED ORAL ADMINISTRATION

ORAL BIOAVAILABILITY PHARMACOKINETIC
Volume of Distribution PHARMACOKINETIC