leflunomide leflunomide leflunomide, sold under the brand name arava among others, is an immunosuppressive disease-modifying antirheumatic drug (dmard), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. it is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase. bottle of leflunomide (arava) and tablet leflunomideclinical datatrade namesarava, lefumide, arabloc, othersahfs/drugs.commonographmedlineplusa600032license data eu ema: by inn us dailymed: leflunomide pregnancycategory au: x (high risk) routes ofadministrationby mouthatc codel04aa13 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only eu: rx-only pharmacokinetic databioavailability80%protein binding>99%metabolismgi mucosa and liverelimination half-life14–18 daysexcretionfaeces (48%), urine (43%)identifiers iupac name 5-methyl-n--isoxazole-4-carboxamide cas number75706-12-6 ypubchem cid3899iuphar/bps6825drugbankdb01097 ychemspider3762 yuniig162gk9u4wkeggd00749 ychebichebi:6402 ychemblchembl960 ycomptox dashboard (epa)dtxsid9023201 echa infocard100.123.883 chemical and physical dataformulac12h9f3n2o2molar mass270.211 g·mol−13d model (jsmol)interactive image smiles o=c(nc1ccc(cc1)c(f)(f)f)c2c(onc2)c inchi inchi=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) ykey:vhogyurtwqbhil-uhfffaoysa-n y (verify) medical use rheumatoid arthritis and psoriatic arthritis are the only indications that have received regulatory approval. 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: there has been reports on potential re-purposing of leflunomide for treatment of solid tumors with tumor suppressor, pten, loss. in pten negative tumors, leflunomide causes synthetic lethality potentially due to increased demand on pyrimidines in these faster growing cells. polyoma bk virus nephropathy kimura's disease systemic lupus erythematosus felty's syndrome takayasu arteritis granulomatosis with polyangiitis ankylosing spondylitis crohn's disease sarcoidosis uveitis still's disease prostate cancer pemphigoid prevention of organ transplant rejection side effects the dose-limiting side effects are liver damage, lung disease and immunosuppression. the most common side effects (occurring in >1% of those treated with it) are, in approximately descending order of frequency: 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: constipation, oral thrush, stomatitis, taste disturbance, thrombocytopenia and hives. rarely (in 0.1% of those treated with it) it can cause: 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. though not reported elsewhere, 80 cases of interstitial pneumonitis involving leflunomide have been reported in japan between 2003 and 2006. one such case resulting in a death was reported in a 2006 article from japan and the authors suggest "an inter-racial difference" for the interstitial pneumonitis. contraindications contraindications include: pregnancy, women of childbearing potential (unless contraception used) liver disease, hepatitis b/c seropositive active serious infections hypersensitivity 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. 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. 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. 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. 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. 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. 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. 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%). 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. teriflunomide is the active metabolite of leflunomide, 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 and z enolic forms (and the corresponding keto-amide), with the z-enol being the most stable and therefore most predominant form. "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.