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
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
DescriptionCurator's Comment:: description was created based on several sources, including
https://www.takeda.com/news/2011/20111007_3902.html
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
Sources: https://www.takeda.com/news/2011/20111007_3902.html
Curator's Comment:: # Takeda
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2094268 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15494157 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | ROZEREM Approved UseROZEREM 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 Date1.12199034E12 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
25.9 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16432265 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
36.1 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16432265 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16432265 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
30% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16432265 |
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
Dose | Population | Adverse 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%) Sources: Malaise (1.6%) Dizziness (3.2%) Nasopharyngitis (4.8%) |
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%) Sources: Dizziness (0.5%) Nausea (0.3%) Fatigue (0.3%) Headache (0.3%) Insomnia (0.3%) |
160 mg single, oral Highest studied dose Dose: 160 mg Route: oral Route: single Dose: 160 mg Sources: |
unknown Health Status: unknown Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 60.0 |
inconclusive | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 11, 13 |
major | yes (co-administration study) Comment: fluvoxamine increased ramelteon AUC 190-fold and Cmax 70-fold; rifampin decreased total expsoure to ramelteon by 80% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 11, 13 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 11, 13 |
minor | yes (co-administration study) Comment: rifampin decreased total expsoure to ramelteon by 80% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 11, 13 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf 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% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 11, 13 |
||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 13.0 |
yes | yes (co-administration study) Comment: fluconazole increased AUC by 150% and Cmax by 150%; rifampin decreased total expsoure to ramelteon by 80% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_biopharmr.pdf Page: 13.0 |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021782s000_Rozerem_pharmr_CORRECTED_REVIEW.pdf Page: 53, 66 |
PubMed
Title | Date | PubMed |
---|---|---|
Depression and sleep: pathophysiology and treatment. | 2006 |
|
Pharmacologic management of insomnia: past, present, and future. | 2006 Dec |
|
Searching for new options for treating insomnia: are melatonin and ramelteon beneficial? | 2006 Jul |
|
Gateways to clinical trials. | 2006 Jul-Aug |
|
A new sleeping pill. | 2006 Oct |
|
Ramelteon for the treatment of insomnia. | 2006 Oct |
|
Clinically relevant pharmacology of neuropsychiatric drugs approved over the last three years: Part II. | 2006 Sep |
|
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 |
|
Role of the melatonin system in the control of sleep: therapeutic implications. | 2007 |
|
Update on the safety considerations in the management of insomnia with hypnotics: incorporating modified-release formulations into primary care. | 2007 |
|
Use of non-benzodiazepine hypnotics in the elderly: are all agents the same? | 2007 |
|
Putting insomnia to rest. | 2007 Apr |
|
Drug Insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon. | 2007 Apr |
|
Putting "sleepdriving" and new safety warning in perspective. | 2007 Aug |
|
Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. | 2007 Aug 15 |
|
Greater incidence of depression with hypnotic use than with placebo. | 2007 Aug 21 |
|
Therapeutic options for sleep-maintenance and sleep-onset insomnia. | 2007 Jan |
|
New perspectives for the treatment of disorders of sleep and arousal. | 2007 Jul |
|
[New hypnotics: perspectives from sleep physiology]. | 2007 Jul-Aug |
|
Will insomnia treatments produce overall cost savings to commercial managed-care plans? A predictive analysis in the United States. | 2007 Jun |
|
A 2-night, 3-period, crossover study of ramelteon's efficacy and safety in older adults with chronic insomnia. | 2007 May |
|
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 |
|
Ramelteon: a review of its use in insomnia. | 2008 |
|
Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders. | 2008 |
|
Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. | 2008 |
|
Melatonergic drugs in clinical practice. | 2008 |
|
Efficacy and clinical safety of ramelteon: an evidence-based review. | 2008 Aug |
|
Effect of ramelteon, a selective MT(1)/MT (2)-receptor agonist, on respiration during sleep in mild to moderate COPD. | 2008 Aug |
|
A review of ramelteon in the treatment of sleep disorders. | 2008 Feb |
|
[Drugs for insomnia and improving quality of life (QOL): research and development of ramelteon, an MT1/MT2-receptor agonist]. | 2008 Jan |
|
Jet lag: therapeutic use of melatonin and possible application of melatonin analogs. | 2008 Jan-Mar |
|
Ramelteon: a melatonin receptor agonist for the treatment of insomnia. | 2008 Jan-Mar |
|
Ramelteon 8 mg/d versus placebo in patients with chronic insomnia: post hoc analysis of a 5-week trial using 50% or greater reduction in latency to persistent sleep as a measure of treatment effect. | 2008 Jul |
|
Stimulatory effects of a melatonin receptor agonist, ramelteon, on BDNF in mouse cerebellar granule cells. | 2008 Jul 4 |
|
Melatonin and its agonists: an update. | 2008 Oct |
|
Selective activation of melatonin receptors with ramelteon improves liver function and hepatic perfusion after hemorrhagic shock in rat. | 2008 Oct |
|
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 |
|
Ramelteon: a novel approach in the treatment of insomnia. | 2008 Sep |
|
Acute sleep-promoting action of the melatonin agonist, ramelteon, in the rat. | 2008 Sep |
|
Melatonin receptor agonist ramelteon activates the extracellular signal-regulated kinase 1/2 in mouse cerebellar granule cells. | 2008 Sep 9 |
|
The effect of melatonergic and non-melatonergic antidepressants on sleep: weighing the alternatives. | 2009 |
|
The effects of ramelteon in a first-night model of transient insomnia. | 2009 Jan |
|
The effects of ramelteon on respiration during sleep in subjects with moderate to severe chronic obstructive pulmonary disease. | 2009 Mar |
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15695169
Curator's Comment:: Ramelteon inhibited forskolin-stimulated cAMP production in the CHO cells that express the human MT1 or MT2 receptors.
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N05CH02
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LIVERTOX |
831
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N0000000250
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QN05CH02
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N0000175743
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NCI_THESAURUS |
C47795
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C66504
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Ramelteon
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RAMELTEON
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196597-26-9
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596205
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7787
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CHEMBL1218
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M9489
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196597-26-9
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C495910
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DB00980
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ACTIVE MOIETY
METABOLITE (PARENT)
METABOLITE ACTIVE (PARENT)
METABOLITE ACTIVE (PARENT)
METABOLITE INACTIVE (PARENT)