ramelteon Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
	2355	196597-26-9

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: ramelteon rozerem TAK-375	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. The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Molecular weight: 259.35 Formula: C16H21NO2 CLOGP: 2.48 LIPINSKI: 0 HAC: 3 HDO: 1 TPSA: 38.33 ALOGS: -4.20 ROTB: 4 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

ramelteon
rozerem
TAK-375

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. The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle.

Molecular weight: 259.35
Formula: C16H21NO2
CLOGP: 2.48
LIPINSKI: 0
HAC: 3
HDO: 1
TPSA: 38.33
ALOGS: -4.20
ROTB: 4

Status: OFP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

None

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	1	Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine)	0.10 %	Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose)	0.44 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BA (Bioavailability)	1.80 %	Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
Vd (Volume of distribution)	1.05 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	13.10 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.20 %	Lombardo F, Berellini G, Obach RS
t_half (Half-life)	1.90 hours	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company	Orphan
July 22, 2005	FDA	TAKEDA PHARMS USA

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Initial insomnia	130.13	17.07	38	4813	4414	46676797
Abnormal dreams	124.61	17.07	45	4806	10234	46670977
Nightmare	110.28	17.07	47	4804	16551	46664660
Middle insomnia	109.16	17.07	40	4811	9475	46671736
Product dispensing error	67.50	17.07	28	4823	9205	46672006
Somnolence	64.13	17.07	80	4771	156441	46524770
Poor quality sleep	62.85	17.07	31	4820	15222	46665989
Insomnia	57.73	17.07	78	4773	164846	46516365
Altered state of consciousness	35.79	17.07	25	4826	23323	46657888
Hallucination	35.18	17.07	34	4817	49917	46631294
Hepatic function abnormal	31.21	17.07	27	4824	34394	46646817
Ovarian cancer recurrent	31.17	17.07	9	4842	1002	46680209
Restlessness	29.38	17.07	23	4828	25501	46655710
Somnambulism	29.30	17.07	13	4838	5024	46676187
Intentional overdose	27.81	17.07	34	4817	64910	46616301
Galactorrhoea	26.01	17.07	11	4840	3786	46677425
Hangover	24.82	17.07	8	4843	1287	46679924
Feeling abnormal	24.00	17.07	45	4806	125015	46556196
Anxiety	22.77	17.07	55	4796	181902	46499309
Hypersomnia	22.43	17.07	16	4835	15423	46665788
Drug eruption	19.88	17.07	17	4834	21312	46659899
Impulsive behaviour	19.73	17.07	7	4844	1508	46679703
Product administered to patient of inappropriate age	19.10	17.07	8	4843	2688	46678523

FDA Adverse Event Reporting System (Male)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Somnolence	69.28	18.86	69	3331	96694	29852384
Initial insomnia	69.01	18.86	21	3379	2568	29946510
Middle insomnia	52.53	18.86	21	3379	5752	29943326
Hangover	52.51	18.86	14	3386	1064	29948014
Nightmare	51.97	18.86	26	3374	12050	29937028
Abnormal dreams	48.80	18.86	22	3378	8093	29940985
Pneumonia aspiration	42.91	18.86	35	3365	37745	29911333
Poor quality sleep	38.42	18.86	18	3382	7223	29941855
Interstitial lung disease	32.47	18.86	37	3363	60160	29888918
Delirium	30.88	18.86	30	3370	40601	29908477
Cerebral infarction	26.95	18.86	23	3377	26350	29922728
Disseminated intravascular coagulation	24.02	18.86	20	3380	22151	29926927
Restlessness	23.68	18.86	20	3380	22579	29926499
Hepatic function abnormal	21.28	18.86	25	3375	41920	29907158
Enterocolitis	19.18	18.86	11	3389	6676	29942402

Pharmacologic Action:

Source	Code	Description
ATC	N05CH02	NERVOUS SYSTEM PSYCHOLEPTICS HYPNOTICS AND SEDATIVES Melatonin receptor agonists
FDA MoA	N0000000250	Melatonin Receptor Agonists
FDA EPC	N0000175743	Melatonin Receptor Agonist

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Initial insomnia	indication	59050008
Suicidal thoughts	contraindication	6471006
Alcoholism	contraindication	7200002
Depressive disorder	contraindication	35489007
Hepatic failure	contraindication	59927004
Sleep apnea	contraindication	73430006	DOID:0050847
Disease of liver	contraindication	235856003	DOID:409
Hyperprolactinemia	contraindication	237662005	DOID:12700
Sleep automatism	contraindication	247962006

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	13.14	acidic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Mechanism action	Bioact source	MoA source
Melatonin receptor type 1B	GPCR	P49286	MTR1B_HUMAN	AGONIST	Ki	10.39		WOMBAT-PK	CHEMBL
Melatonin receptor type 1A	GPCR	P48039	MTR1A_HUMAN	AGONIST	Ki	10.90		WOMBAT-PK	CHEMBL

External reference:

ID	Source
4024923	VUID
N0000171613	NUI
D02689	KEGG_DRUG
4024923	VANDF
C1565316	UMLSCUI
CHEBI:109549	CHEBI
JEV	PDB_CHEM_ID
CHEMBL1218	ChEMBL_ID
DB00980	DRUGBANK_ID
1356	IUPHAR_LIGAND_ID
C495910	MESH_SUPPLEMENTAL_RECORD_UI
8447	INN_ID
901AS54I69	UNII
208902	PUBCHEM_CID
596205	RXNORM
20324	MMSL
320752	MMSL
70325	MMSL
d05578	MMSL
010947	NDDF
419588002	SNOMEDCT_US
419878007	SNOMEDCT_US

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	0591-2191	TABLET	8 mg	ORAL	ANDA	27 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	0832-1250	TABLET, FILM COATED	8 mg	ORAL	ANDA	30 sections
Rozerem	HUMAN PRESCRIPTION DRUG LABEL	1	21695-183	TABLET, FILM COATED	8 mg	ORAL	NDA	30 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	42291-776	TABLET	8 mg	ORAL	ANDA	26 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	43598-741	TABLET	8 mg	ORAL	ANDA	25 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	50268-708	TABLET	8 mg	ORAL	ANDA	26 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	51407-375	TABLET	8 mg	ORAL	ANDA	26 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	52817-235	TABLET, FILM COATED	8 mg	ORAL	ANDA	28 sections
Rozerem	HUMAN PRESCRIPTION DRUG LABEL	1	54868-5649	TABLET, FILM COATED	8 mg	ORAL	NDA	18 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	55700-874	TABLET, FILM COATED	8 mg	ORAL	ANDA	28 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	63629-8264	TABLET	8 mg	ORAL	ANDA	28 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	63629-8531	TABLET	8 mg	ORAL	ANDA	26 sections
Rozerem	HUMAN PRESCRIPTION DRUG LABEL	1	64764-805	TABLET, FILM COATED	8 mg	ORAL	NDA	27 sections
Rozerem	HUMAN PRESCRIPTION DRUG LABEL	1	68151-4881	TABLET, FILM COATED	8 mg	ORAL	NDA	28 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	70010-028	TABLET	8 mg	ORAL	ANDA	26 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	70710-1344	TABLET	8 mg	ORAL	ANDA	27 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	70771-1495	TABLET	8 mg	ORAL	ANDA	1 sections
RAMELTEON	HUMAN PRESCRIPTION DRUG LABEL	1	72189-153	TABLET	8 mg	ORAL	ANDA	16 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	72319-005	TABLET, FILM COATED	8 mg	ORAL	ANDA	28 sections