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
Alopecia	2472.16	32.93	649	3825	21352	2332259
Diarrhoea	1081.15	32.93	490	3984	83074	2270537
Multiple sclerosis relapse	1028.84	32.93	283	4191	10660	2342951
Paraesthesia	754.48	32.93	263	4211	21825	2331786
Hypoaesthesia	718.29	32.93	248	4226	19967	2333644
Fatigue	514.79	32.93	301	4173	84572	2269039
Nausea	454.33	32.93	308	4166	111881	2241730
Headache	447.95	32.93	270	4204	79909	2273702
Gait disturbance	333.88	32.93	147	4327	22398	2331213
Fall	331.88	32.93	185	4289	46914	2306697
Multiple sclerosis	294.25	32.93	94	4380	5840	2347771
Rash	264.30	32.93	174	4300	59384	2294227
Product dose omission	262.85	32.93	148	4326	38109	2315502
Hepatic enzyme increased	248.06	32.93	94	4380	9708	2343903
Pain	239.19	32.93	166	4308	61691	2291920
Unevaluable event	238.53	32.93	89	4385	8802	2344809
Weight decreased	234.12	32.93	124	4350	28247	2325364
Condition aggravated	228.40	32.93	127	4347	31852	2321759
Exposure during pregnancy	201.67	32.93	108	4366	25111	2328500
Asthenia	193.02	32.93	131	4343	46795	2306816
Balance disorder	192.00	32.93	78	4396	9669	2343942
Muscular weakness	184.75	32.93	86	4388	14811	2338800
Pruritus	182.98	32.93	123	4351	43217	2310394
Pain in extremity	177.82	32.93	120	4354	42420	2311191
Dizziness	175.51	32.93	135	4339	58530	2295081
Drug ineffective	172.46	32.93	169	4305	101455	2252156
Abdominal discomfort	162.97	32.93	83	4391	17373	2336238
Depression	161.40	32.93	97	4377	28035	2325576
Hypertension	158.67	32.93	95	4379	27266	2326345
Abdominal pain upper	141.91	32.93	82	4392	22018	2331593
Memory impairment	139.95	32.93	68	4406	12855	2340756
Vomiting	138.08	32.93	128	4346	71474	2282137
Urinary tract infection	131.00	32.93	87	4387	29855	2323756
Burning sensation	125.05	32.93	54	4420	7774	2345837
Malaise	118.05	32.93	105	4369	55480	2298131
Alanine aminotransferase increased	117.31	32.93	62	4412	13970	2339641
Blood pressure increased	116.95	32.93	66	4408	16920	2336691
Abdominal pain	113.32	32.93	84	4390	34290	2319321
Neuropathy peripheral	111.38	32.93	56	4418	11376	2342235
Visual impairment	109.90	32.93	56	4418	11699	2341912
Central nervous system lesion	107.03	32.93	34	4440	2060	2351551
Dyspnoea	106.13	32.93	116	4358	78617	2274994
Feeling abnormal	104.22	32.93	69	4405	23512	2330099
Vision blurred	103.68	32.93	58	4416	14610	2339001
Breast cancer	102.85	32.93	50	4424	9445	2344166
Back pain	101.26	32.93	76	4398	31583	2322028
Insomnia	93.97	32.93	67	4407	25720	2327891
Contusion	91.46	32.93	51	4423	12759	2340852
Optic neuritis	89.41	32.93	28	4446	1618	2351993
Decreased appetite	84.97	32.93	66	4408	28825	2324786
Nasopharyngitis	79.62	32.93	57	4417	21999	2331612
Muscle spasms	78.46	32.93	56	4418	21510	2332101
Depressed mood	76.93	32.93	34	4440	5164	2348447
Gastrointestinal disorder	76.17	32.93	40	4434	8877	2344734
Lymphopenia	74.67	32.93	27	4447	2427	2351184
Magnetic resonance imaging abnormal	72.18	32.93	20	4454	751	2352860
Liver function test increased	72.05	32.93	28	4446	3073	2350538
Pyrexia	70.21	32.93	78	4396	53630	2299981
Limb discomfort	69.72	32.93	28	4446	3351	2350260
Erythema	66.49	32.93	54	4420	25105	2328506
Arthralgia	66.11	32.93	76	4398	54209	2299402
Hot flush	60.63	32.93	32	4442	7167	2346444
Urinary incontinence	60.42	32.93	27	4447	4206	2349405
Migraine	59.02	32.93	36	4438	10617	2342994
Loss of personal independence in daily activities	54.57	32.93	27	4447	5284	2348327
Dry skin	54.41	32.93	29	4445	6623	2346988
Cognitive disorder	54.24	32.93	27	4447	5354	2348257
Abortion spontaneous	53.71	32.93	37	4437	13408	2340203
Incontinence	51.84	32.93	18	4456	1436	2352175
Pneumonia	50.11	32.93	63	4411	49233	2304378
Chest pain	49.55	32.93	48	4426	28089	2325522
Hepatocellular injury	48.87	32.93	23	4451	4032	2349579
Blister	48.39	32.93	27	4447	6744	2346867
Influenza	47.84	32.93	34	4440	12944	2340667
Anxiety	47.82	32.93	48	4426	29311	2324300
Heart rate increased	47.78	32.93	32	4442	11073	2342538
Micturition urgency	46.53	32.93	16	4458	1240	2352371
Drug intolerance	46.15	32.93	34	4440	13683	2339928
JC polyomavirus test positive	45.20	32.93	11	4463	245	2353366
Product use issue	45.13	32.93	32	4442	12137	2341474
Palpitations	44.87	32.93	36	4438	16420	2337191
Skin exfoliation	43.88	32.93	24	4450	5766	2347845
Rash pruritic	43.10	32.93	26	4448	7509	2346102
Walking aid user	41.87	32.93	13	4461	729	2352882
Bronchitis	41.70	32.93	32	4442	13682	2339929
White blood cell count decreased	41.69	32.93	36	4438	18172	2335439
Hair texture abnormal	41.33	32.93	12	4462	534	2353077
Cough	41.31	32.93	47	4427	33070	2320541
Influenza like illness	40.68	32.93	30	4444	12084	2341527
Neuralgia	40.26	32.93	18	4456	2804	2350807
Aspartate aminotransferase increased	39.60	32.93	30	4444	12582	2341029
Mobility decreased	39.37	32.93	26	4448	8784	2344827
Pollakiuria	38.30	32.93	19	4455	3737	2349874
Decreased interest	38.09	32.93	11	4463	480	2353131
Hypersensitivity	37.35	32.93	38	4436	23555	2330056
Hemiparesis	36.81	32.93	18	4456	3432	2350179
Lipase increased	36.81	32.93	14	4460	1448	2352163
Peripheral swelling	36.69	32.93	33	4441	17564	2336047
Liver function test abnormal	35.65	32.93	23	4451	7467	2346144
Tooth abscess	35.32	32.93	15	4459	2064	2351547
Acne	35.17	32.93	17	4457	3159	2350452
Flatulence	34.96	32.93	19	4455	4506	2349105
Lymphocyte count decreased	34.25	32.93	17	4457	3346	2350265
Myalgia	34.09	32.93	36	4438	23297	2330314
Pancreatitis	34.07	32.93	23	4451	8056	2345555
Speech disorder	33.64	32.93	21	4453	6443	2347168
Vertigo	33.23	32.93	24	4450	9360	2344251

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	444.20	39.72	95	1043	3005	1742638
Diarrhoea	256.00	39.72	121	1017	53731	1691912
Alopecia	230.70	39.72	58	1080	3695	1741948
Hypoaesthesia	143.81	39.72	50	1088	9785	1735858
Gait disturbance	135.08	39.72	51	1087	12619	1733024
Paraesthesia	125.74	39.72	46	1092	10405	1735238
Fatigue	119.62	39.72	72	1066	50709	1694934
Multiple sclerosis	116.16	39.72	30	1108	2102	1743541
Product dose omission	106.95	39.72	51	1087	22389	1723254
Fall	97.62	39.72	51	1087	27163	1718480
Asthenia	94.05	39.72	54	1084	34616	1711027
Headache	89.11	39.72	52	1086	34324	1711319
Drug ineffective	81.44	39.72	62	1076	63739	1681904
Unevaluable event	66.51	39.72	25	1113	6041	1739602
Weight decreased	65.69	39.72	37	1101	22716	1722927
Pain	60.24	39.72	37	1101	26620	1719023
Rash	56.72	39.72	41	1097	38652	1706991
Alanine aminotransferase increased	55.51	39.72	27	1111	12251	1733392
Depression	50.46	39.72	28	1110	16641	1729002
Memory impairment	50.37	39.72	21	1117	6642	1739001
Balance disorder	49.66	39.72	20	1118	5792	1739851
Nausea	48.61	39.72	42	1096	51154	1694489
Muscular weakness	47.69	39.72	23	1115	10226	1735417
Pain in extremity	45.15	39.72	27	1111	18445	1727198
Hepatic enzyme increased	40.59	39.72	18	1120	6603	1739040

Pharmacologic Action:

Source	Code	Description
ATC	L04AA31	ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS IMMUNOSUPPRESSANTS IMMUNOSUPPRESSANTS Selective immunosuppressants
CHEBI has role	CHEBI:35475	non-steroidal anti-inflammatory drug
FDA EPC	N0000185502	Pyrimidine Synthesis Inhibitor
FDA MoA	N0000185501	Dihydroorotate Dehydrogenase 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)

None

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
Dihydroorotate dehydrogenase (quinone), mitochondrial	Enzyme		PYRD_RAT		IC50	8.05	CHEMBL
Dihydroorotate dehydrogenase	Unclassified		Q54A96_PLAFA		Ki	4.66	CHEMBL
Dihydroorotate dehydrogenase (quinone), mitochondrial	Enzyme		PYRD_MOUSE		IC50	7.16	CHEMBL

External reference:

ID	Source
D10172	KEGG_DRUG
C3497721	UMLSCUI
1C058IKG3B	UNII
7761	INN_ID
CHEMBL973	ChEMBL_ID
DB08880	DRUGBANK_ID
CHEBI:68540	CHEBI
54684141	PUBCHEM_CID
6844	IUPHAR_LIGAND_ID
C527525	MESH_SUPPLEMENTAL_RECORD_UI
703786007	SNOMEDCT_US
1310520	RXNORM
28846	MMSL
d07905	MMSL
014643	NDDF
4031717	VANDF
703785006	SNOMEDCT_US

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Aubagio	HUMAN PRESCRIPTION DRUG LABEL	1	58468-0210	TABLET, FILM COATED	14 mg	ORAL	NDA	20 sections
Aubagio	HUMAN PRESCRIPTION DRUG LABEL	1	58468-0211	TABLET, FILM COATED	7 mg	ORAL	NDA	20 sections
teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	68462-311	TABLET, FILM COATED	7 mg	ORAL	ANDA	19 sections
teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	68462-312	TABLET, FILM COATED	14 mg	ORAL	ANDA	19 sections
Teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	69238-1303	TABLET, FILM COATED	7 mg	ORAL	ANDA	19 sections
Teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	69238-1304	TABLET, FILM COATED	14 mg	ORAL	ANDA	19 sections
Teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	69539-032	TABLET, FILM COATED	7 mg	ORAL	ANDA	19 sections
Teriflunomide	HUMAN PRESCRIPTION DRUG LABEL	1	69539-033	TABLET, FILM COATED	14 mg	ORAL	ANDA	19 sections