Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Teriflunomide: Difference between pages

{{Short description|Drug used in treatment of multiple sclerosis}}

{{Use dmy dates|date=June 2024}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 470602409

| image2 = Teriflunomide 3D ball.png

| alt2 = Ball-and-stick model of the teriflunomide molecule

<!-- Clinical data -->

| pronounce =

| tradename = Aubagio

| Drugs.com = {{drugs.com|monograph|teriflunomide}}

| MedlinePlus = a613010

| DailyMedID = Teriflunomide

| pregnancy_AU = X

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Teriflunomide (Aubagio) Use During Pregnancy | website=Drugs.com | date=11 September 2019 | url=https://www.drugs.com/pregnancy/teriflunomide.html | access-date=2 March 2020}}</ref>

| pregnancy_category = Contraindicated<ref name="Drugs.com pregnancy" />

| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = L04

| ATC_suffix = AK02

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment =

| 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=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| 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 = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Aubagio FDA label">{{cite web | title=Aubagio- teriflunomide tablet, film coated | website=DailyMed | date=21 November 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4650d12c-b9c8-4525-b07f-a2d773eca155 | access-date=13 June 2024}}</ref>

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Aubagio EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->

| legal_UN_comment =

| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->

| excretion = [[Bile duct]]/[[fecal]], [[kidney]]

<!-- Identifiers -->

| IUPHAR_ligand = 6844

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 163451-81-8

| PubChem = 54684141

| DrugBank = DB08880

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 68540

| UNII_Ref = {{fdacite|correct|FDA}}

| KEGG = D10172

| KEGG_Ref = {{keggcite|changed|kegg}}

| synonyms = A77 1726

<!-- Chemical and physical data -->

| IUPAC_name = (2''Z'')-2-cyano-3-hydroxy-''N''-[4-(trifluoromethyl)phenyl]but-2-enamide

| SMILES = O=C(Nc1ccc(cc1)C(F)(F)F)C(/C#N)=C(/C)O

'''Teriflunomide''', sold under the brand name '''Aubagio''', is the [[active metabolite]] of [[leflunomide]].<ref name="pmid17122964">{{cite journal | vauthors = Magne D, Mézin F, Palmer G, Guerne PA | title = The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha | journal = Inflammation Research | volume = 55 | issue = 11 | pages = 469–75 | date = November 2006 | pmid = 17122964 | doi = 10.1007/s00011-006-5196-x | s2cid = 47034503 }}</ref> Teriflunomide was investigated in the [[Phase III clinical trial]] TEMSO as a medication for [[multiple sclerosis]] (MS). The study was completed in July 2010.<ref>{{ClinicalTrialsGov|NCT00134563|Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)}}</ref> 2-year results were positive.<ref>{{cite news |url=http://www.genengnews.com/gen-news-highlights/sanofi-aventis-teriflunomide-comes-up-trumps-in-two-year-phase-iii-ms-trial/81244075/ |title=Sanofi-Aventis' Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial |date=15 October 2010 | work = Genetic Engineering & Biotechnology News }}</ref> However, the subsequent TENERE head-to-head comparison trial reported that "although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with [[interferon beta-1a]], relapses were more common with teriflunomide."<ref name="medpage">{{cite web | url=http://www.medpagetoday.com/MeetingCoverage/CMSC-ACTRIMS/33059 | title=Teriflunomide Modest Help but Safe for MS | work=medpage | date=4 June 2012 | access-date=4 June 2012 | vauthors = Gever J| publisher=Joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis }}</ref> The drug was approved for use in the United States in September 2012<ref>{{cite web | title=Drug Approval Package: Aubagio (teriflunomide) Tablets NDA #202992 | website=U.S. [[Food and Drug Administration]] (FDA) | date=5 November 2012 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000TOC.cfm | access-date=1 March 2020}}</ref><ref>{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm319277.htm |archive-url=https://web.archive.org/web/20120913084145/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm319277.htm |url-status=dead |archive-date=13 September 2012 |title=FDA approves new multiple sclerosis treatment Aubagio |publisher=U.S. [[Food and Drug Administration]] (FDA)|access-date=14 September 2012}}</ref> and for use in the European Union in August 2013.<ref name="Aubagio EPAR">{{cite web | title=Aubagio EPAR | website=[[European Medicines Agency]] (EMA) | date=26 August 2013 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/aubagio | access-date=13 June 2024}}</ref>

==Adverse effects==

{{See|leflunomide}}

The US [[Food and Drug Administration]]'s prescribing information warns of potential [[hepatotoxicity]] (liver injury including liver failure) and [[Teratogenicity#Humans|teratogenicity]] (birth defects).<ref name="FDA_PI">{{cite web |title=Highlights of Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202992s000lbl.pdf |publisher=US Food and Drug Association |access-date=24 February 2024}}</ref> Elavated [[Alanine transaminase|ALT]] enzyme levels is the most common side effect (≥10% and ≥2% over placebo).<ref name=FDA_PI/>

==Mechanisms of action==

Teriflunomide is an [[immunomodulatory]] drug inhibiting [[pyrimidine]] [[de novo synthesis]] by blocking the enzyme [[dihydroorotate dehydrogenase]]. It is uncertain whether this explains its effect on MS lesions.<ref>{{cite journal | vauthors = Spreitzer H | date = 13 March 2006 | title = Neue Wirkstoffe - Teriflunomid | journal = Österreichische Apothekerzeitung | issue = 6/2006 | language = German }}</ref>

Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system.<ref>{{cite journal | vauthors = Vollmer T | date = 28 May 2009 | title = MS Therapies in the Pipeline: Teriflunomide | journal = EMS News | issue = 28 May 2009 }}</ref>

It has been found that teriflunomide blocks the transcription factor [[NF-κB]]. It also inhibits [[tyrosine kinase]] enzymes, but only in high doses not clinically used.<ref>{{cite journal | vauthors = Breedveld FC, Dayer JM | title = Leflunomide: mode of action in the treatment of rheumatoid arthritis | journal = Annals of the Rheumatic Diseases | volume = 59 | issue = 11 | pages = 841–9 | date = November 2000 | pmid = 11053058 | pmc = 1753034 | doi = 10.1136/ard.59.11.841 }}</ref>

==Activation of leflunomide to teriflunomide==

The branded drug teriflunomide is the main active ''[[in vivo]]'' metabolite of the [[Generic drug|generically]] available leflunomide. Upon administration of leflunomide, 70% of the drug administered converts into teriflunomide. The only difference between the molecules is the opening of the isoxazole ring. This is considered a simple structural modification and a technically simple one-step synthetic transformation. 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, Romaldas M, Nela V, Karsten BS, Ian H, Robert H, Harald E, Pierre D|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>

[[File:Activation of leflunomide.svg|thumb|center|425px|'''Teriflunomide''' is the only active metabolite of [[leflunomide]], completely responsible for its therapeutic actions. It results from the reaction of isoxazole ring opening, which occurs ''[[in vivo]]''. Teriflunomide then can interconvert between the [[E-Z notation|''E'' and ''Z'']] [[enol]]ic forms (and the corresponding keto-amide), 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]] (FDA) |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, [[European Medicines Agency|EMA]] initially had not considered teriflunomide being 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}}

{{Demyelinating diseases of CNS}}

{{Immunosuppressants}}

{{Portal bar | Medicine}}

{{Authority control}}

[[Category:CYP1A2 inducers]]

[[Category:Anilides]]

[[Category:Enols]]

[[Category:Human drug metabolites]]

[[Category:Immunosuppressants]]

[[Category:Nitriles]]

[[Category:Sanofi]]

[[Category:Trifluoromethyl compounds]]