Leflunomide Explained

Verifiedrevid:462089809
Tradename:Arava, Lefumide, Arabloc, others
Licence Eu:yes
Dailymedid:Leflunomide
Pregnancy Au:X
Routes Of Administration:By mouth
Atc Prefix:L04
Atc Suffix:AK01
Legal Au:S4
Legal Br:C1
Legal Br Comment:[1]
Legal Ca:Rx-only
Legal Uk:POM
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[2]
Bioavailability:80%[3]
Protein Bound:>99%
Metabolism:GI mucosa and liver
Metabolites:Teriflunomide
Elimination Half-Life:14–18 days
Excretion:Faeces (48%), urine (43%)
Cas Number:75706-12-6
Pubchem:3899
Iuphar Ligand:6825
Drugbank:DB01097
Chemspiderid:3762
Unii:G162GK9U4W
Kegg:D00749
Chebi:6402
Chembl:960
Iupac Name:5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide
C:12
H:9
F:3
N:2
O:2
Smiles:O=C(Nc1ccc(cc1)C(F)(F)F)c2c(onc2)C
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)
Stdinchikey:VHOGYURTWQBHIL-UHFFFAOYSA-N

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD),[4] used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.[5]

Medical use

Rheumatoid arthritis and psoriatic arthritis are the only indications that have received regulatory approval.[3] [6] Arava was developed by Sanofi Aventis and approved by the U.S. Food and Drug Administration in 1998. Clinical studies regarding the following diseases have been conducted:[7] There has been reports on potential re-purposing of leflunomide for treatment of solid tumors with tumor suppressor, PTEN, loss.[8] [9] In PTEN negative tumors, leflunomide causes synthetic lethality potentially due to increased demand on pyrimidines in these faster growing cells.[9]

Contraindications

Contraindications include:[3]

Adverse effects

The dose-limiting side effects are liver damage, lung disease and immunosuppression.[21] The most common side effects (occurring in >1% of those treated with it) are, in approximately descending order of frequency:[3] [6] [22] [23] [24] [25] [26] diarrhea, respiratory tract infections, hair loss, high blood pressure, rash, nausea, bronchitis, headache, abdominal pain, abnormal liver function tests, back pain, indigestion, urinary tract infection, dizziness, infection, joint disorder, itchiness, weight loss, loss of appetite, cough, gastroenteritis, pharyngitis, stomatitis, tenosynovitis, vomiting, weakness, allergic reaction, chest pain, dry skin, eczema, paraesthesia, pneumonia, rhinitis, synovitis, cholelithiasis and shortness of breath. Whereas uncommon side effects (occurring in 0.1–1% of those treated with the drug) include:[6] constipation, oral thrush, stomatitis, taste disturbance, thrombocytopenia and hives. Rarely (in 0.1% of those treated with it) it can cause:[6] anaphylaxis, angiooedema, anaemia, agranulocytosis, eosinophilia, leucopenia, pancytopenia, vasculitis, toxic epidermal necrolysis, Stevens–Johnson syndrome, cutaneous lupus erythematosus, severe infection, interstitial lung disease, cirrhosis and liver failure.

Interactions

Other immunomodulatory treatments should be avoided due to the potential for additive immunosuppressant effects, or in the case of immunostimulants like echinacea or astragalus, reduced therapeutic effects.[3] Likewise live vaccines (like haemophilus influenzae type b vaccine and yellow fever vaccines) should be avoided due to the potential for severe infection due to the immunosuppressive nature of the treatment.[3]

The concomitant use of methotrexate, 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. However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.[27]

Pharmacology

Mechanism of action

Leflunomide is an immunomodulatory drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA. Hence, leflunomide inhibits the reproduction of rapidly dividing cells, especially lymphocytes.[21]

The inhibition of human DHODH by teriflunomide, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA). Teriflunomide also inhibits several tyrosine kinases.[21] 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.[28] Teriflunomide also has antiviral effects against numerous viruses including CMV, HSV1 and the BK virus, which it achieves by inhibiting viral replication by interfering with nucleocapsid tegumentation and hence virion assembly.[21]

Pharmacokinetics

It has an oral bioavailability of 80%, protein binding of >99%, metabolism sites of the GI mucosa and liver, volume of distribution (Vd) of 0.13 L/kg, elimination half-life of 14–18 days and excretion routes of faeces (48%) and urine (43%).[3] [21] [22]

Leflunomide metabolism

Teriflunomide 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 isoxazole ring. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide is opened and teriflunomide is formed.[29]

"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." Because of this, the European Medicines Agency (EMA) initially had not considered teriflunomide to be a new active substance.[30]

Further reading

Notes and References

  1. Web site: Anvisa . Brazilian Health Regulatory Agency . 31 March 2023 . RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial . Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control. live . 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 . 3 August 2023 . 16 August 2023 . . pt-BR . 4 April 2023.
  2. Web site: Arava EPAR . European Medicines Agency . 25 August 2023 . 26 August 2023.
  3. Web site: Arava (leflunomide) dosing, indications, interactions, adverse effects, and more. Medscape Reference. WebMD. 11 March 2014.
  4. Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, van Riel P . When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide? . Annals of the Rheumatic Diseases . 64 . 1 . 44–51 . January 2005 . 15271770 . 1755199 . 10.1136/ard.2003.016709 .
  5. Pinto P, Dougados M . Leflunomide in clinical practice . Acta Reumatologica Portuguesa . 31 . 3 . 215–24 . 2006 . 17094333 .
  6. Book: Rossi S . 978-0-9805790-9-3 . Australian Medicines Handbook . Adelaide . The Australian Medicines Handbook Unit Trust . 2013 .
  7. Web site: Leflunomide Search . ClinicalTrials.gov . U.S. National Library of Medicine .
  8. Ozturk S, Mathur D, Zhou RW, Mulholland D, Parsons R . Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer . Prostate Cancer and Prostatic Diseases . 23 . 4 . 718–723 . December 2020 . 32661432 . 7666085 . 10.1038/s41391-020-0251-1 .
  9. Mathur D, Stratikopoulos E, Ozturk S, Steinbach N, Pegno S, Schoenfeld S, Yong R, Murty VV, Asara JM, Cantley LC, Parsons R . PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition . Cancer Discovery . 7 . 4 . 380–390 . April 2017 . 28255082 . 5562025 . 10.1158/2159-8290.CD-16-0612 .
  10. Blanckaert K, De Vriese AS . Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients . Nephrology, Dialysis, Transplantation . 21 . 12 . 3364–7 . December 2006 . 16998219 . 10.1093/ndt/gfl404 . free . doi .
  11. Dai L, Wei XN, Zheng DH, Mo YQ, Pessler F, Zhang BY . Effective treatment of Kimura's disease with leflunomide in combination with glucocorticoids . Clinical Rheumatology . 30 . 6 . 859–65 . June 2011 . 21286771 . 10.1007/s10067-011-1689-2 . 1914281 .
  12. Wu GC, Xu XD, Huang Q, Wu H . Leflunomide: friend or foe for systemic lupus erythematosus? . Rheumatology International . 33 . 2 . 273–6 . February 2013 . 22961090 . 10.1007/s00296-012-2508-z . 7202069 .
  13. Sanders S, Harisdangkul V . Leflunomide for the treatment of rheumatoid arthritis and autoimmunity . The American Journal of the Medical Sciences . 323 . 4 . 190–3 . April 2002 . 12003373 . 10.1097/00000441-200204000-00004 . 28479334 .
  14. Unizony S, Stone JH, Stone JR . New treatment strategies in large-vessel vasculitis . Current Opinion in Rheumatology . 25 . 1 . 3–9 . January 2013 . 23114585 . 10.1097/BOR.0b013e32835b133a . 21101525 . free . doi .
  15. Haibel H, Rudwaleit M, Braun J, Sieper J . Six months open label trial of leflunomide in active ankylosing spondylitis . Annals of the Rheumatic Diseases . 64 . 1 . 124–6 . January 2005 . 15608310 . 1755172 . 10.1136/ard.2003.019174 .
  16. Prajapati DN, Knox JF, Emmons J, Saeian K, Csuka ME, Binion DG . Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy . Journal of Clinical Gastroenterology . 37 . 2 . 125–8 . August 2003 . 12869881 . 10.1097/00004836-200308000-00006 . 21212960 .
  17. Holtmann MH, Gerts AL, Weinman A, Galle PR, Neurath MF . Treatment of Crohn's disease with leflunomide as second-line immunosuppression : a phase 1 open-label trial on efficacy, tolerability and safety . Digestive Diseases and Sciences . 53 . 4 . 1025–32 . April 2008 . 17934840 . 10.1007/s10620-007-9953-7 . 29918308 .
  18. Panselinas E, Judson MA . Acute pulmonary exacerbations of sarcoidosis . Chest . 142 . 4 . 827–836 . October 2012 . 23032450 . 10.1378/chest.12-1060 . free .
  19. Roy M . Early clinical experience with leflunomide in uveitis . Canadian Journal of Ophthalmology . 42 . 4 . 634 . August 2007 . 17641721 . 10.3129/can.j.ophthalmol.i07-085 .
  20. Pirildar T . Treatment of adult-onset Still's disease with leflunomide and chloroquine combination in two patients . Clinical Rheumatology . 22 . 2 . 157 . May 2003 . 12740686 . 10.1007/s10067-002-0667-0 . 41656726 .
  21. Teschner S, Burst V . Leflunomide: a drug with a potential beyond rheumatology . Immunotherapy . 2 . 5 . 637–50 . September 2010 . 20874647 . 10.2217/imt.10.52 .
  22. Web site: Arava Product Information . TGA eBusiness Services. sanofi-aventis australia pty ltd. 7 August 2012. 11 March 2014. PDF.
  23. Web site: Arava : EPAR - Product Information. European Medicines Agency. Sanofi-Aventis Deutschland GmbH. 21 November 2013. 11 March 2014. 11 March 2014. https://web.archive.org/web/20140311033136/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000235/WC500026289.pdf. dead.
  24. Web site: Data Sheet Arava. Medsafe. sanofi-aventis new zealand limited. 29 June 2012. 11 March 2014.
  25. Web site: Arava (leflunomide) tablet, film coated [sanofi-aventis U.S. LLC]]. DailyMed. sanofi-aventis U.S. LLC. November 2012. 11 March 2014.
  26. Web site: Arava 10mg Tablets - Summary of Product Characteristic. electronic Medicines Compendium. Sanofi. 21 February 2014. 11 March 2014.
  27. Lee SS, Park YW, Park JJ, Kang YM, Nam EJ, Kim SI, Lee JH, Yoo WH, Lee SI . Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis . Scandinavian Journal of Rheumatology . 38 . 1 . 11–4 . 2009 . 19191187 . 10.1080/03009740802360632 . 205543918 .
  28. Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, Kirschbaum BJ . Mechanism of action for leflunomide in rheumatoid arthritis . Clinical Immunology . 93 . 3 . 198–208 . December 1999 . 10600330 . 10.1006/clim.1999.4777 .
  29. Web site: Melchiorri D, van Zwieten-Boot B, Maciulaitis R, Vilceanu M, Bruins Slot K, Hudson I, Hemmings R, Enzmann H, Demolis P. Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000. European Medicines Agency. 5 June 2015. 119. 17 July 2015. https://web.archive.org/web/20150717090028/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002514/WC500148684.pdf. dead.
  30. Web site: Summary of Opinion (Initial Authorisation): Aubagio (teriflunomide). European Medicines Agency. 15 April 2016. 13 March 2016. 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. dead.

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