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	127.71	17.48	38	5067	5117	53338844
Abnormal dreams	126.86	17.48	45	5060	10556	53333405
Nightmare	114.30	17.48	48	5057	17703	53326258
Middle insomnia	107.76	17.48	40	5065	10668	53333293
Product dispensing error	66.92	17.48	28	5077	10212	53333749
Somnolence	66.58	17.48	81	5024	167653	53176308
Poor quality sleep	61.53	17.48	31	5074	17292	53326669
Insomnia	59.57	17.48	81	5024	186991	53156970
Altered state of consciousness	36.26	17.48	25	5080	24811	53319150
Ovarian cancer recurrent	35.10	17.48	10	5095	1153	53342808
Hallucination	33.51	17.48	33	5072	53805	53290156
Hepatic function abnormal	31.51	17.48	27	5078	36872	53307089
Somnambulism	29.46	17.48	13	5092	5389	53338572
Intentional overdose	29.12	17.48	34	5071	67171	53276790
Restlessness	29.11	17.48	23	5082	28064	53315897
Galactorrhoea	26.35	17.48	11	5094	3984	53339977
Hangover	24.48	17.48	8	5097	1460	53342501
Feeling abnormal	24.11	17.48	45	5060	135256	53208705
Hypersomnia	22.78	17.48	16	5089	16339	53327622
Drug eruption	22.73	17.48	19	5086	25075	53318886
Impulsive behaviour	20.25	17.48	7	5098	1517	53342444
Blood pressure decreased	19.94	17.48	27	5078	61842	53282119
Anxiety	19.77	17.48	52	5053	196652	53147309
Hallucination, visual	18.61	17.48	15	5090	18817	53325144
Interstitial lung disease	18.01	17.48	25	5080	58597	53285364

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	67.33	18.87	70	3599	103727	32406130
Initial insomnia	65.59	18.87	21	3648	3051	32506806
Hangover	52.32	18.87	14	3655	1085	32508772
Middle insomnia	50.28	18.87	21	3648	6463	32503394
Nightmare	49.99	18.87	26	3643	13140	32496717
Abnormal dreams	47.78	18.87	22	3647	8542	32501315
Pneumonia aspiration	42.50	18.87	36	3633	41120	32468737
Interstitial lung disease	37.05	18.87	41	3628	64960	32444897
Poor quality sleep	36.65	18.87	18	3651	8056	32501801
Hepatic function abnormal	34.05	18.87	33	3636	44807	32465050
Delirium	30.81	18.87	31	3638	44015	32465842
Disseminated intravascular coagulation	29.68	18.87	23	3646	23153	32486704
Cerebral infarction	28.17	18.87	24	3645	27590	32482267
Upper respiratory tract inflammation	24.60	18.87	9	3660	1948	32507909
Restlessness	22.12	18.87	20	3649	24861	32484996
Insomnia	19.43	18.87	38	3631	100310	32409547

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 1A	GPCR	P48039	MTR1A_HUMAN	AGONIST	Ki	10.90		WOMBAT-PK	CHEMBL
Melatonin receptor type 1B	GPCR	P49286	MTR1B_HUMAN	AGONIST	Ki	10.39		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
8447	INN_ID
C495910	MESH_SUPPLEMENTAL_RECORD_UI
208902	PUBCHEM_CID
1356	IUPHAR_LIGAND_ID
901AS54I69	UNII
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	71205-918	TABLET	8 mg	ORAL	ANDA	26 sections
Ramelteon	HUMAN PRESCRIPTION DRUG LABEL	1	71335-1853	TABLET	8 mg	ORAL	ANDA	27 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