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

Stem definition	Drug id	CAS RN
	4634	163451-81-8

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: HMR1726 flucyamide aubagio teriflunomide	Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS. Molecular weight: 270.21 Formula: C12H9F3N2O2 CLOGP: 2.13 LIPINSKI: 0 HAC: 4 HDO: 2 TPSA: 73.12 ALOGS: -4.34 ROTB: 3 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

HMR1726
flucyamide
aubagio
teriflunomide

Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.

Molecular weight: 270.21
Formula: C12H9F3N2O2
CLOGP: 2.13
LIPINSKI: 0
HAC: 4
HDO: 2
TPSA: 73.12
ALOGS: -4.34
ROTB: 3

Status: OFP

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

Drug dosage:

Dose	Unit	Route
14	mg	O

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	4	Hosey CM, Chan R, Benet LZ
Vd (Volume of distribution)	0.16 L/kg	Lombardo F, Berellini G, Obach RS
CL (Clearance)	0.01 mL/min/kg	Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma)	0.01 %	Lombardo F, Berellini G, Obach RS
t_half (Half-life)	350 hours	Lombardo F, Berellini G, Obach RS

Approvals:

Date	Agency	Company	Orphan
Aug. 26, 2013	EMA
Sept. 12, 2012	FDA	SANOFI AVENTIS US

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
Multiple sclerosis relapse	1600.03	16.88	617	20451	44236	53283762
Alopecia	1183.56	16.88	869	20199	233714	53094284
Multiple sclerosis	732.27	16.88	306	20762	26847	53301151
Paraesthesia	426.76	16.88	373	20695	127142	53200856
Hypoaesthesia	409.25	16.88	371	20697	132624	53195374
Diarrhoea	228.81	16.88	649	20419	624897	52703101
Product dose omission issue	206.98	16.88	312	20756	191308	53136690
Gait disturbance	148.23	16.88	242	20826	158600	53169398
Balance disorder	129.54	16.88	152	20916	73055	53254943
Fall	98.67	16.88	338	20730	358102	52969896
Rheumatoid arthritis	97.41	16.88	7	21061	314524	53013474
Product dose omission in error	95.55	16.88	32	21036	1503	53326495
Optic neuritis	92.53	16.88	49	21019	7286	53320712
Unevaluable event	91.24	16.88	105	20963	49393	53278605
Memory impairment	91.22	16.88	138	20930	84619	53243379
Fatigue	88.56	16.88	540	20528	729966	52598032
Off label use	83.88	16.88	41	21027	472171	52855827
Muscular weakness	73.41	16.88	138	20930	100854	53227144
Bladder disorder	73.03	16.88	43	21025	7845	53320153
Depressed mood	65.74	16.88	77	20991	36887	53291111
JC polyomavirus test positive	64.54	16.88	22	21046	1091	53326907
Acute kidney injury	62.97	16.88	12	21056	253856	53074142
Drug hypersensitivity	60.79	16.88	15	21053	265227	53062771
Central nervous system lesion	60.67	16.88	42	21026	10120	53317878
Toxicity to various agents	59.80	16.88	8	21060	219590	53108408
Depression	58.62	16.88	182	20886	182870	53145128
Headache	57.44	16.88	385	20683	536436	52791562
Magnetic resonance imaging abnormal	56.61	16.88	26	21042	2843	53325155
Visual impairment	54.67	16.88	101	20967	72811	53255187
Limb discomfort	50.16	16.88	56	21012	25466	53302532
Exposure during pregnancy	48.45	16.88	133	20935	124727	53203271
Burning sensation	44.44	16.88	73	20995	47940	53280058
Completed suicide	42.94	16.88	3	21065	138198	53189800
Condition aggravated	42.43	16.88	230	20838	296904	53031094
Hepatic enzyme increased	39.92	16.88	125	20943	126070	53201928
Maternal exposure during pregnancy	39.33	16.88	7	21061	155632	53172366
Lymphopenia	38.44	16.88	40	21028	16803	53311195
Mobility decreased	37.63	16.88	89	20979	76182	53251816
Sensory disturbance	37.60	16.88	35	21033	12851	53315147
Urinary incontinence	35.72	16.88	52	21016	30769	53297229
COVID-19	35.37	16.88	57	21011	36831	53291167
Electric shock sensation	35.37	16.88	9	21059	157	53327841
Breast cancer	35.27	16.88	67	21001	49291	53278707
Cognitive disorder	33.51	16.88	62	21006	44716	53283282
Drug interaction	33.21	16.88	23	21045	219306	53108692
Therapeutic product effect decreased	33.20	16.88	5	21063	125650	53202348
Death	32.59	16.88	57	21011	357175	52970823
Micturition urgency	32.38	16.88	27	21041	8575	53319423
Hyponatraemia	31.95	16.88	3	21065	108604	53219394
Synovitis	31.69	16.88	3	21065	107890	53220108
Injection site pain	31.16	16.88	4	21064	113387	53214611
Incontinence	31.00	16.88	29	21039	10714	53317284
Hypotension	30.75	16.88	33	21035	254043	53073955
Overdose	29.12	16.88	4	21064	107732	53220266
Feeling abnormal	28.23	16.88	117	20951	135184	53192814
Muscle spasticity	28.17	16.88	35	21033	17803	53310195
Decreased interest	28.10	16.88	17	21051	3256	53324742
Weight decreased	27.10	16.88	172	20896	234776	53093222
Joint swelling	26.73	16.88	32	21036	234606	53093392
Lipase increased	26.45	16.88	25	21043	9353	53318645
Anaemia	26.28	16.88	43	21025	276675	53051323
Hair texture abnormal	25.20	16.88	17	21051	3925	53324073
Heteroplasia	23.31	16.88	4	21064	7	53327991
Liver function test increased	22.65	16.88	39	21029	26589	53301409
Walking aid user	22.50	16.88	19	21049	6139	53321859
Pneumonia	22.39	16.88	84	20984	407085	52920913
Systemic lupus erythematosus	22.01	16.88	11	21057	125403	53202595
Blood pressure increased	21.54	16.88	111	20957	140368	53187630
Vision blurred	21.07	16.88	78	20990	85526	53242472
Muscle spasms	20.31	16.88	106	20962	134689	53193309
Pain in extremity	20.10	16.88	186	20882	284864	53043134
Haemoglobin decreased	19.98	16.88	15	21053	137292	53190706
Nausea	19.87	16.88	413	20655	755678	52572320
Paternal exposure timing unspecified	19.58	16.88	4	21064	24	53327974
Abortion	19.57	16.88	12	21056	2354	53325644
Lower respiratory tract infection	19.21	16.88	6	21062	90975	53237023
Band sensation	18.95	16.88	8	21060	715	53327283
Respiratory failure	18.90	16.88	8	21060	100504	53227494
Pharyngeal abscess	18.84	16.88	6	21062	240	53327758
Cardiac failure congestive	18.07	16.88	7	21061	92750	53235248
Onychoclasis	18.05	16.88	16	21052	5517	53322481
Progressive multiple sclerosis	17.99	16.88	8	21060	811	53327187
Temperature intolerance	17.95	16.88	19	21049	8134	53319864
Therapeutic product effect incomplete	17.76	16.88	7	21061	91777	53236221
Dysstasia	17.61	16.88	29	21039	19070	53308928
Granuloma annulare	17.55	16.88	7	21061	541	53327457
Pancytopenia	17.48	16.88	7	21061	90921	53237077
Hypertension	17.37	16.88	150	20918	225281	53102717
Encephalitis autoimmune	17.32	16.88	9	21059	1287	53326711
Secondary progressive multiple sclerosis	17.09	16.88	9	21059	1323	53326675

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
Multiple sclerosis relapse	676.88	25.30	178	3976	11603	32497769
Multiple sclerosis	351.14	25.30	97	4057	7547	32501825
Alopecia	182.41	25.30	76	4078	20654	32488718
Product dose omission issue	89.55	25.30	86	4068	102489	32406883
Gait disturbance	86.89	25.30	76	4078	80332	32429040
Hypoaesthesia	85.80	25.30	66	4088	58287	32451085
Paraesthesia	78.72	25.30	63	4091	58881	32450491
Diarrhoea	69.70	25.30	147	4007	364655	32144717
Balance disorder	56.55	25.30	44	4110	39415	32469957
Product dose omission in error	47.75	25.30	11	4143	404	32508968
Fatigue	42.72	25.30	119	4035	350582	32158790
Fall	35.95	25.30	78	4076	196123	32313249
Headache	34.81	25.30	77	4077	196120	32313252
Memory impairment	31.58	25.30	32	4122	40447	32468925
Meningoencephalitis herpetic	30.80	25.30	9	4145	848	32508524
Visual impairment	27.49	25.30	27	4127	32861	32476511
Unevaluable event	27.02	25.30	27	4127	33559	32475813

Pharmacologic Action:

Source	Code	Description
ATC	L04AA31	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS IMMUNOSUPPRESSANTS IMMUNOSUPPRESSANTS Selective immunosuppressants
MeSH PA	D000700	Analgesics
MeSH PA	D018712	Analgesics, Non-Narcotic
MeSH PA	D000893	Anti-Inflammatory Agents
MeSH PA	D000894	Anti-Inflammatory Agents, Non-Steroidal
MeSH PA	D018501	Antirheumatic Agents
MeSH PA	D007155	Immunologic Factors
MeSH PA	D007166	Immunosuppressive Agents
MeSH PA	D018373	Peripheral Nervous System Agents
MeSH PA	D018689	Sensory System Agents
FDA MoA	N0000185501	Dihydroorotate Dehydrogenase Inhibitors
FDA EPC	N0000185502	Pyrimidine Synthesis Inhibitor
CHEBI has role	CHEBI:35475	non-steroidal anti-inflammatory drugs
CHEBI has role	CHEBI:38637	protein tyrosine kinase inhibitor
CHEBI has role	CHEBI:49103	drug metabolites
CHEBI has role	CHEBI:50908	agente hepatotoxico
CHEBI has role	CHEBI:68542	DHODH inhibitors

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Multiple sclerosis	indication	24700007	DOID:2377

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	5.59	acidic
pKa2	10.61	acidic

Orange Book patent data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Patent number	Patent expiration date	Patent use
14MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	6794410	Sept. 12, 2026	TREATMENT OF PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS
7MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	6794410	Sept. 12, 2026	TREATMENT OF PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS
14MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	9186346	Feb. 4, 2034	TREATMENT OF PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS WHILE MANAGING THE RISK OF TERIFLUNOMIDE AND ROSUVASTATIN INTERACTION BY LIMITING THE ROSUVASTATIN DOSE TO NO MORE THAN 10MG AND/OR ADMINISTERING ABOUT HALF THE NORMAL DOSE
7MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	9186346	Feb. 4, 2034	TREATMENT OF PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS WHILE MANAGING THE RISK OF TERIFLUNOMIDE AND ROSUVASTATIN INTERACTION BY LIMITING THE ROSUVASTATIN DOSE TO NO MORE THAN 10MG AND/OR ADMINISTERING ABOUT HALF THE NORMAL DOSE

Orange Book exclusivity data (new drug applications)

Formulation strength	Trade name	Applicant	Application number	Approval date	Type	Dose form	Route	Exclusivity date	Description
14MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	April 30, 2024	REVISIONS TO LABELING BASED ON DATA SUBMITTED IN RESPONSE TO PEDIATRIC WRITTEN REQUEST
7MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	April 30, 2024	REVISIONS TO LABELING BASED ON DATA SUBMITTED IN RESPONSE TO PEDIATRIC WRITTEN REQUEST
14MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	Oct. 30, 2024	PEDIATRIC EXCLUSIVITY
7MG	AUBAGIO	SANOFI AVENTIS US	N202992	Sept. 12, 2012	RX	TABLET	ORAL	Oct. 30, 2024	PEDIATRIC EXCLUSIVITY

Bioactivity Summary:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Dihydroorotate dehydrogenase (quinone), mitochondrial	Enzyme	Q02127	PYRD_HUMAN	INHIBITOR	Ki	7.52	CHEMBL	CHEMBL
Dihydrofolate reductase	Enzyme	P00374	DYR_HUMAN		IC50	6.41	CHEMBL
Dihydroorotate dehydrogenase (quinone), mitochondrial	Enzyme		PYRD_RAT		IC50	8.05	CHEMBL
Dihydroorotate dehydrogenase (quinone), mitochondrial	Enzyme		PYRD_MOUSE		IC50	7.16	CHEMBL
Dihydroorotate dehydrogenase	Enzyme		Q54A96_PLAFA		Ki	4.66	CHEMBL
Dihydroorotate dehydrogenase	Enzyme		G4VFD7_SCHMA		IC50	4.30	CHEMBL

External reference:

ID	Source
D10172	KEGG_DRUG
4031717	VANDF
CHEBI:68540	CHEBI
A26	PDB_CHEM_ID
CHEMBL973	ChEMBL_ID
C527525	MESH_SUPPLEMENTAL_RECORD_UI
6844	IUPHAR_LIGAND_ID
7761	INN_ID
DB08880	DRUGBANK_ID
1C058IKG3B	UNII
54684141	PUBCHEM_CID
1310520	RXNORM
193228	MMSL
28846	MMSL
d07905	MMSL
014643	NDDF
703785006	SNOMEDCT_US
703786007	SNOMEDCT_US
C1718383	UMLSCUI

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	0115-1565	TABLET, FILM COATED	14 mg	ORAL	ANDA	20 sections
Aubagio	HUMAN PRESCRIPTION DRUG LABEL	1	58468-0210	TABLET, FILM COATED	14 mg	ORAL	NDA	32 sections
Aubagio	HUMAN PRESCRIPTION DRUG LABEL	1	58468-0211	TABLET, FILM COATED	7 mg	ORAL	NDA	32 sections
teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	68462-311	TABLET, FILM COATED	7 mg	ORAL	ANDA	29 sections
teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	68462-312	TABLET, FILM COATED	14 mg	ORAL	ANDA	29 sections
Teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	69238-1303	TABLET, FILM COATED	7 mg	ORAL	ANDA	23 sections
Teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	69238-1304	TABLET, FILM COATED	14 mg	ORAL	ANDA	23 sections
Teriflunomide	Human Prescription Drug Label	1	69539-032	TABLET, FILM COATED	7 mg	ORAL	ANDA	27 sections
Teriflunomide	Human Prescription Drug Label	1	69539-033	TABLET, FILM COATED	14 mg	ORAL	ANDA	27 sections