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Revision as of 11:34, 23 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456808647 of page Leflunomide for the Chem/Drugbox validation project (updated: 'DrugBank').  Latest revision as of 17:11, 24 February 2024 edit Kimen8 (talk | contribs)Extended confirmed users5,112 editsm Cleaned up using AutoEd 
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{{Short description|Chemical compound}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use American English|date=August 2023}}
{{Drugbox
{{Use dmy dates|date=August 2023}}
| Verifiedfields = changed
{{cs1 config |name-list-style=vanc |display-authors=6}}
| verifiedrevid = 415315630
{{Infobox drug
| IUPAC_name = 5-methyl-''N''--isoxazole-4-carboxamide
| verifiedrevid = 462089809
| image = Leflunomide.svg | image = Leflunomide.svg
| alt =
| image2 = Leflunomide ball-and-stick model.png
| alt2 =


<!--Clinical data--> <!-- Clinical data -->
| tradename = Arava | pronounce =
| tradename = Arava, Lefumide, Arabloc, others
| Drugs.com = {{drugs.com|monograph|leflunomide}} | Drugs.com = {{drugs.com|monograph|leflunomide}}
| MedlinePlus = a600032 | MedlinePlus = a600032
| licence_EU = Arava | licence_EU = yes
| licence_US = Leflunomide | DailyMedID = Leflunomide
| pregnancy_AU = X
| pregnancy_category = X (contraindicated)
| pregnancy_AU_comment =
| legal_status = Rx only
| pregnancy_category =
| routes_of_administration = oral (tablets)
| routes_of_administration = ]
| class =
| ATCvet =
| ATC_prefix = L04
| ATC_suffix = AK01
| ATC_supplemental =


<!--Pharmacokinetic data--> <!-- Legal status -->
| bioavailability = 80% | legal_AU = S4
| legal_AU_comment = <ref name = TGA />
| protein_bound = >99.3%
| metabolism = | legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=] |language=pt-BR |publication-date=4 April 2023}}</ref>
| elimination_half-life = 2 weeks
| legal_CA = Rx-only
| excretion = Biliar, renal
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref name = "Arava SmPC" />
| legal_US = Rx-only
| legal_US_comment = <ref name = "Arava FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Arava EPAR">{{cite web | title=Arava EPAR | website=European Medicines Agency | date=25 August 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/arava | access-date=26 August 2023}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->


<!--Identifiers--> <!-- Pharmacokinetic data -->
| bioavailability = 80%<ref name = MSR>{{cite web|title=Arava (leflunomide) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=11 March 2014|url=http://reference.medscape.com/drug/arava-leflunomide-343203#showall}}</ref>
| CASNo_Ref = {{cascite|correct|CAS}}
| protein_bound = >99%<ref name = MSR/>
| metabolism = GI mucosa and liver<ref name = MSR/>
| metabolites = ]
| onset =
| elimination_half-life = 14–18 days<ref name = MSR/>
| duration_of_action =
| excretion = Faeces (48%), urine (43%)<ref name = MSR/>

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 75706-12-6 | CAS_number = 75706-12-6
| CAS_supplemental =
| ATC_prefix = L04
| ATC_suffix = AA13
| ATC_supplemental =
| PubChem = 3899 | PubChem = 3899
| IUPHAR_ligand = 6825
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01097 | DrugBank = DB01097
Line 39: Line 72:
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00749 | KEGG = D00749
| ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 6402 | ChEBI = 6402
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 960 | ChEMBL = 960
| NIAID_ChemDB =
| PDB_ligand =
| synonyms =


<!--Chemical data--> <!-- Chemical and physical data -->
| IUPAC_name = 5-methyl-''N''--isoxazole-4-carboxamide
| C=12 | H=9 | F=3 | N=2 | O=2
| C=12 | H=9 | F=3 | N=2 | O=2
| molecular_weight = 270.207 g/mol
| smiles = O=C(Nc1ccc(cc1)C(F)(F)F)c2c(onc2)C | SMILES = O=C(Nc1ccc(cc1)C(F)(F)F)c2c(onc2)C
| InChI = 1/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
| InChIKey = VHOGYURTWQBHIL-UHFFFAOYAS
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18) | StdInChI = 1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = VHOGYURTWQBHIL-UHFFFAOYSA-N | StdInChIKey = VHOGYURTWQBHIL-UHFFFAOYSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}

'''Leflunomide''', sold under the brand name '''Arava''' among others, is an immunosuppressive disease-modifying antirheumatic drug (]),<ref name="pmid15271770">{{cite journal | vauthors = Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, van Riel P | title = When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide? | journal = Annals of the Rheumatic Diseases | volume = 64 | issue = 1 | pages = 44–51 | date = January 2005 | pmid = 15271770 | pmc = 1755199 | doi = 10.1136/ard.2003.016709 }}</ref> used in active moderate-to-severe ] and ]. It is a ] that works by inhibiting ].<ref name="pmid17094333">{{cite journal | vauthors = Pinto P, Dougados M | title = Leflunomide in clinical practice | journal = Acta Reumatologica Portuguesa | volume = 31 | issue = 3 | pages = 215–24 | year = 2006 | pmid = 17094333 | url = http://www.actareumatologica.pt/oldsite/conteudo/pdfs/ARP_2006_4_216_AR_-_Leflunomide.pdf }}</ref>

]

==Medical use==
] and ] are the only indications that have received regulatory approval.<ref name = MSR/><ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 }}{{pn|date=December 2020}}</ref> Arava was developed by ] and approved by the U.S. Food and Drug Administration in 1998. Clinical studies regarding the following diseases have been conducted:<ref>{{cite web | title = Leflunomide Search | url = http://clinicaltrials.gov/ct2/results?term=Leflunomide | work = ClinicalTrials.gov | publisher = U.S. National Library of Medicine }}</ref> <!-- hide the obvious ", but these have to be reviewed critically, before approval can be given:" -->There has been reports on potential re-purposing of leflunomide for treatment of solid tumors with tumor suppressor, PTEN, loss.<ref>{{cite journal | vauthors = Ozturk S, Mathur D, Zhou RW, Mulholland D, Parsons R | title = Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer | journal = Prostate Cancer and Prostatic Diseases | volume = 23 | issue = 4 | pages = 718–723 | date = December 2020 | pmid = 32661432 | pmc = 7666085 | doi = 10.1038/s41391-020-0251-1 }}</ref><ref name="Mathur et al 2017">{{cite journal | vauthors = Mathur D, Stratikopoulos E, Ozturk S, Steinbach N, Pegno S, Schoenfeld S, Yong R, Murty VV, Asara JM, Cantley LC, Parsons R | title = PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition | journal = Cancer Discovery | volume = 7 | issue = 4 | pages = 380–390 | date = April 2017 | pmid = 28255082 | pmc = 5562025 | doi = 10.1158/2159-8290.CD-16-0612 }}</ref> In PTEN negative tumors, leflunomide causes synthetic lethality potentially due to increased demand on pyrimidines in these faster growing cells.<ref name="Mathur et al 2017"/>
<!-- may be more useful to group by the latest phase they have started or reported on -->
{{div col|colwidth=22em}}
* Polyoma ] ]<ref>{{cite journal | vauthors = Blanckaert K, De Vriese AS | title = Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients | journal = Nephrology, Dialysis, Transplantation | volume = 21 | issue = 12 | pages = 3364–7 | date = December 2006 | pmid = 16998219 | doi = 10.1093/ndt/gfl404 | doi-access = free | title-link = doi }}</ref>
* ]<ref>{{cite journal | vauthors = Dai L, Wei XN, Zheng DH, Mo YQ, Pessler F, Zhang BY | title = Effective treatment of Kimura's disease with leflunomide in combination with glucocorticoids | journal = Clinical Rheumatology | volume = 30 | issue = 6 | pages = 859–65 | date = June 2011 | pmid = 21286771 | doi = 10.1007/s10067-011-1689-2 | s2cid = 1914281 }}</ref>
* ]<ref>{{cite journal | vauthors = Wu GC, Xu XD, Huang Q, Wu H | title = Leflunomide: friend or foe for systemic lupus erythematosus? | journal = Rheumatology International | volume = 33 | issue = 2 | pages = 273–6 | date = February 2013 | pmid = 22961090 | doi = 10.1007/s00296-012-2508-z | s2cid = 7202069 }}</ref>
* ]<ref name="pmid12003373">{{cite journal | vauthors = Sanders S, Harisdangkul V | title = Leflunomide for the treatment of rheumatoid arthritis and autoimmunity | journal = The American Journal of the Medical Sciences | volume = 323 | issue = 4 | pages = 190–3 | date = April 2002 | pmid = 12003373 | doi = 10.1097/00000441-200204000-00004 | s2cid = 28479334 }}</ref>
* ]<ref>{{cite journal | vauthors = Unizony S, Stone JH, Stone JR | title = New treatment strategies in large-vessel vasculitis | journal = Current Opinion in Rheumatology | volume = 25 | issue = 1 | pages = 3–9 | date = January 2013 | pmid = 23114585 | doi = 10.1097/BOR.0b013e32835b133a | s2cid = 21101525 | doi-access = free | title-link = doi }}</ref>
* ]<ref name="pmid12003373" />
* ]<ref>{{cite journal | vauthors = Haibel H, Rudwaleit M, Braun J, Sieper J | title = Six months open label trial of leflunomide in active ankylosing spondylitis | journal = Annals of the Rheumatic Diseases | volume = 64 | issue = 1 | pages = 124–6 | date = January 2005 | pmid = 15608310 | pmc = 1755172 | doi = 10.1136/ard.2003.019174 }}</ref>
* ]<ref>{{cite journal | vauthors = Prajapati DN, Knox JF, Emmons J, Saeian K, Csuka ME, Binion DG | title = Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy | journal = Journal of Clinical Gastroenterology | volume = 37 | issue = 2 | pages = 125–8 | date = August 2003 | pmid = 12869881 | doi = 10.1097/00004836-200308000-00006 | s2cid = 21212960 }}</ref><ref>{{cite journal | vauthors = Holtmann MH, Gerts AL, Weinman A, Galle PR, Neurath MF | title = Treatment of Crohn's disease with leflunomide as second-line immunosuppression : a phase 1 open-label trial on efficacy, tolerability and safety | journal = Digestive Diseases and Sciences | volume = 53 | issue = 4 | pages = 1025–32 | date = April 2008 | pmid = 17934840 | doi = 10.1007/s10620-007-9953-7 | s2cid = 29918308 }}</ref>
* ]<ref>{{cite journal | vauthors = Panselinas E, Judson MA | title = Acute pulmonary exacerbations of sarcoidosis | journal = Chest | volume = 142 | issue = 4 | pages = 827–836 | date = October 2012 | pmid = 23032450 | doi = 10.1378/chest.12-1060 | doi-access = free }}</ref>
* ]<ref>{{cite journal | vauthors = Roy M | title = Early clinical experience with leflunomide in uveitis | journal = Canadian Journal of Ophthalmology | volume = 42 | issue = 4 | pages = 634 | date = August 2007 | pmid = 17641721 | doi = 10.3129/can.j.ophthalmol.i07-085 }}</ref>
* ]<ref>{{cite journal | vauthors = Pirildar T | title = Treatment of adult-onset Still's disease with leflunomide and chloroquine combination in two patients | journal = Clinical Rheumatology | volume = 22 | issue = 2 | pages = 157 | date = May 2003 | pmid = 12740686 | doi = 10.1007/s10067-002-0667-0 | s2cid = 41656726 }}</ref>
* ]<ref>{{ClinicalTrialsGov|NCT00004071|Mitoxantrone and Prednisone With or Without Leflunomide in Treating Patients With Stage IV Prostate Cancer}}</ref>
* ]<ref>{{ClinicalTrialsGov|NCT00802243|Leflunomide Associated With Topical Corticosteroids for Bullous Pemphigoid (ARABUL)}}</ref>
* Prevention of organ transplant rejection<ref name = rh2010>{{cite journal | vauthors = Teschner S, Burst V | title = Leflunomide: a drug with a potential beyond rheumatology | journal = Immunotherapy | volume = 2 | issue = 5 | pages = 637–50 | date = September 2010 | pmid = 20874647 | doi = 10.2217/imt.10.52 }}</ref>
{{div col end}}

==Contraindications==
Contraindications include:<ref name = MSR/>
* Pregnancy, women of childbearing potential (unless contraception used)
* Liver disease, ]/] seropositive
* Active serious infections
* Hypersensitivity

==Adverse effects==
The dose-limiting side effects are liver damage, lung disease and immunosuppression.<ref name = rh2010/> The most common side effects (occurring in >1% of those treated with it) are, in approximately descending order of frequency:<ref name = MSR/><ref name = AMH/><ref name = TGA>{{cite web|title=Arava Product Information |work=TGA eBusiness Services|publisher=sanofi-aventis australia pty ltd|date=7 August 2012|access-date=11 March 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05926-3|format=PDF}}</ref><ref name = EMA>{{cite web|title=Arava : EPAR - Product Information|work=European Medicines Agency|publisher=Sanofi-Aventis Deutschland GmbH|date=21 November 2013|access-date=11 March 2014|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000235/WC500026289.pdf|archive-date=11 March 2014|archive-url=https://web.archive.org/web/20140311033136/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000235/WC500026289.pdf|url-status=dead}}</ref><ref name = MS>{{cite web|title=Data Sheet Arava|work=Medsafe|publisher=sanofi-aventis new zealand limited|date=29 June 2012|access-date=11 March 2014|url=http://www.medsafe.govt.nz/profs/datasheet/a/aravatab.pdf}}</ref><ref name = "Arava FDA label">{{cite web|title=Arava (leflunomide) tablet, film coated |work=DailyMed|publisher=sanofi-aventis U.S. LLC|date=November 2012|access-date=11 March 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=320f63f2-fac3-4aee-aff8-85724e00ef52}}</ref><ref name = "Arava SmPC">{{cite web|title=Arava 10mg Tablets - Summary of Product Characteristic|work=electronic Medicines Compendium|publisher=Sanofi|date=21 February 2014|access-date=11 March 2014|url=https://www.medicines.org.uk/emc/product/4056/smpc}}</ref> diarrhea, respiratory tract infections, hair loss, ], rash, nausea, bronchitis, headache, abdominal pain, abnormal ]s, back pain, ], urinary tract infection, dizziness, infection, joint disorder, itchiness, weight loss, loss of appetite, cough, gastroenteritis, ], ], ], vomiting, weakness, allergic reaction, chest pain, dry skin, eczema, ], ], ], ], ] and ]. Whereas uncommon side effects (occurring in 0.1–1% of those treated with the drug) include:<ref name = AMH/> constipation, ], ], taste disturbance, ] and ]. Rarely (in 0.1% of those treated with it) it can cause:<ref name = AMH/> ], ], ], ], ], ], ], ], ], ], cutaneous ], severe infection, ], ] and ].

== Interactions ==

Other immunomodulatory treatments should be avoided due to the potential for additive immunosuppressant effects, or in the case of immunostimulants like ] or ], reduced therapeutic effects.<ref name = MSR/> Likewise live vaccines (like ] vaccine and ] vaccines) should be avoided due to the potential for severe infection due to the immunosuppressive nature of the treatment.<ref name = MSR/>

The concomitant use of ], in particular, may lead to severe or even fatal liver-damage or hepatotoxicity. Seventy-five percent of all cases of severe liver damage reported until early 2001 were seen under combined drug therapy leflunomide plus methotrexate.<ref name = Lee/> However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.<ref name = Lee>{{cite journal | vauthors = Lee SS, Park YW, Park JJ, Kang YM, Nam EJ, Kim SI, Lee JH, Yoo WH, Lee SI | title = Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis | journal = Scandinavian Journal of Rheumatology | volume = 38 | issue = 1 | pages = 11–4 | year = 2009 | pmid = 19191187 | doi = 10.1080/03009740802360632 | s2cid = 205543918 }}</ref>

==Pharmacology==
===Mechanism of action===
Leflunomide is an ]y drug that achieves its effects by inhibiting the mitochondrial enzyme ] (DHODH), which plays a key role in the ''de novo'' synthesis of ] (rUMP), which is required for the synthesis of DNA and RNA. Hence, leflunomide inhibits the reproduction of rapidly dividing cells, especially ].<ref name = rh2010/>

The inhibition of human DHODH by ], the active metabolite of leflunomide, occurs at levels (approximately 600&nbsp;nM) that are achieved during treatment of ] (RA).<ref name = mech99/> Teriflunomide also inhibits several ].<ref name = rh2010/> Teriflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with their cell cycle progression while nonlymphoid cells are able to use another pathway to make their ribonucleotides by use of salvage pyrimidine pathway, which makes them less dependent on ''de novo'' synthesis.<ref name = mech99>{{cite journal | vauthors = Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, Kirschbaum BJ | title = Mechanism of action for leflunomide in rheumatoid arthritis | journal = Clinical Immunology | volume = 93 | issue = 3 | pages = 198–208 | date = December 1999 | pmid = 10600330 | doi = 10.1006/clim.1999.4777 }}</ref> Teriflunomide also has antiviral effects against numerous viruses including ], ] and the ], which it achieves by inhibiting viral replication by interfering with ] tegumentation and hence ] assembly.<ref name = rh2010/>

===Pharmacokinetics===
It has an oral ] of 80%, protein binding of >99%, metabolism sites of the GI mucosa and liver, ] (V<sub>d</sub>) of 0.13&nbsp;L/kg, ] of 14–18 days and excretion routes of faeces (48%) and urine (43%).<ref name = MSR/><ref name = rh2010/><ref name = TGA/>

===Leflunomide metabolism===
] is the main active ''in vivo'' metabolite of leflunomide. Upon administration of leflunomide, 70% of the drug administered converts into teriflunomide. The only difference between the molecules is the opening of the ] ring. Upon oral administration of leflunomide ''in vivo'', the isoxazole ring of leflunomide is opened and teriflunomide is formed.<ref name = "Melchiorri">{{cite web|vauthors=Melchiorri D, van Zwieten-Boot B, Maciulaitis R, Vilceanu M, Bruins Slot K, Hudson I, Hemmings R, Enzmann H, Demolis P|title=Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002514/WC500148684.pdf|website=European Medicines Agency|access-date=5 June 2015|page=119|archive-date=17 July 2015|archive-url=https://web.archive.org/web/20150717090028/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002514/WC500148684.pdf|url-status=dead}}</ref>
]''' is the ] of leflunomide, responsible for its therapeutic actions. It results from the reaction of isoxazole ring opening, which occurs '']''. Teriflunomide then can interconvert between the ] ]ic forms (and the corresponding keto-amide), with the ''Z''-enol being the most stable and therefore most predominant form.<ref>{{cite journal | vauthors = Rozman B | title = Clinical pharmacokinetics of leflunomide | journal = Clinical Pharmacokinetics | volume = 41 | issue = 6 | pages = 421–30 | date = 2002 | pmid = 12074690 | doi = 10.2165/00003088-200241060-00003 | s2cid = 33745823 }}</ref><ref>{{cite web|title=Clinical Pharmacology/Biopharmaceutics Review. Product: ARAVA (leflunomide tablets). Application Number: NDA 20905|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20905_ARAVA_BIOPHARMR.PDF|website=U.S. Food and Drug Administration|publisher=Center for Drug Evaluation and Research|access-date=15 April 2016}}</ref>]]

"Regardless of the substance administered (leflunomide or teriflunomide), it is the same molecule (teriflunomide)—the one exerting the pharmacological, immunological or metabolic action in view of restoring, correcting or modifying physiological functions, and does not present, in clinical use, a new chemical entity to patients."<ref name = "Melchiorri" /> Because of this, the ] (EMA) initially had not considered teriflunomide to be a new active substance.<ref>{{cite web|title=Summary of Opinion (Initial Authorisation): Aubagio (teriflunomide)|url=http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002514/WC500144913.pdf|publisher=European Medicines Agency|access-date=15 April 2016|archive-date=13 March 2016|archive-url=https://web.archive.org/web/20160313102850/http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002514/WC500144913.pdf|url-status=dead}}</ref>

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Shankaranarayana S, Barrett C, Kubler P | title=The safety of leflunomide | journal=Australian Prescriber | volume=36 | issue=1 | date=February 2013 | doi=10.18773/austprescr.2013.010 | pages=28–32 | doi-access = free | title-link = doi }}
{{refend}}

{{Immunosuppressants}}
{{Antirheumatic products}}
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