Leflunomide

Last updated

Leflunomide
Leflunomide.svg
Leflunomide ball-and-stick model.png
Clinical data
Trade names Arava, Lefumide, Arabloc, others
AHFS/Drugs.com Monograph
MedlinePlus a600032
License data
Pregnancy
category
  • AU:X (High risk)
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80% [7]
Protein binding >99% [7]
Metabolism GI mucosa and liver [7]
Metabolites Teriflunomide
Elimination half-life 14–18 days [7]
Excretion Faeces (48%), urine (43%) [7]
Identifiers
  • 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.123.883 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H9F3N2O2
Molar mass 270.211 g·mol−1
3D model (JSmol)
  • O=C(Nc1ccc(cc1)C(F)(F)F)c2c(onc2)C
  • 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) Yes check.svgY
  • Key:VHOGYURTWQBHIL-UHFFFAOYSA-N Yes check.svgY
   (verify)

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), [8] used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase. [9]

Contents

Bottle of Leflunomide (Arava) and tablet Arava20mg.jpg
Bottle of Leflunomide (Arava) and tablet

Medical use

Rheumatoid arthritis and psoriatic arthritis are the only indications that have received regulatory approval. [7] [10] 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: [11] There has been reports on potential re-purposing of leflunomide for treatment of solid tumors with tumor suppressor, PTEN, loss. [12] [13] In PTEN negative tumors, leflunomide causes synthetic lethality potentially due to increased demand on pyrimidines in these faster growing cells. [13]

Contraindications

Contraindications include: [7]

Adverse effects

The dose-limiting side effects are liver damage, lung disease and immunosuppression. [27] The most common side effects (occurring in >1% of those treated with it) are, in approximately descending order of frequency: [7] [10] [1] [28] [29] [5] [3] 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: [10] constipation, oral thrush, stomatitis, taste disturbance, thrombocytopenia and hives. Rarely (in 0.1% of those treated with it) it can cause: [10] 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. [7] 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. [7]

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. [30] However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone. [30]

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. [27]

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). [31] Teriflunomide also inhibits several tyrosine kinases. [27] 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. [31] 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. [27]

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%). [7] [27] [1]

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. [32]

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. Activation of leflunomide.svg
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." [32] Because of this, the European Medicines Agency (EMA) initially had not considered teriflunomide to be a new active substance. [35]

Related Research Articles

<span class="mw-page-title-main">Rheumatoid arthritis</span> Type of autoimmune arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves, and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

<span class="mw-page-title-main">Methotrexate</span> Chemotherapy and immunosuppressant medication

Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.

<span class="mw-page-title-main">Disease-modifying antirheumatic drug</span> Category of drugs

Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal anti-inflammatory drugs and steroids.

<span class="mw-page-title-main">Psoriatic arthritis</span> Long-term inflammatory arthritis

Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. This often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Hydroxychloroquine</span> Antimalarial medication

Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken by mouth, often in the form of hydroxychloroquine sulfate.

Lymphomatoid granulomatosis (LYG or LG) is a very rare lymphoproliferative disorder first characterized in 1972. Lymphomatoid means lymphoma-like and granulomatosis denotes the microscopic characteristic of the presence of granulomas with polymorphic lymphoid infiltrates and focal necrosis within it.

Biological response modifiers (BRMs) are substances that modify immune responses. They can be endogenous or exogenous, and they can either enhance an immune response or suppress it. Some of these substances arouse the body's response to an infection, and others can keep the response from becoming excessive. Thus they serve as immunomodulators in immunotherapy, which can be helpful in treating cancer and in treating autoimmune diseases, such as some kinds of arthritis and dermatitis. Most BRMs are biopharmaceuticals (biologics), including monoclonal antibodies, interleukin 2, interferons, and various types of colony-stimulating factors. "Immunotherapy makes use of BRMs to enhance the activity of the immune system to increase the body's natural defense mechanisms against cancer", whereas BRMs for rheumatoid arthritis aim to reduce inflammation.

<span class="mw-page-title-main">Golimumab</span> Pharmaceutical drug

Golimumab, sold under the brand name Simponi, is a human monoclonal antibody which is used as an immunosuppressive medication. Golimumab targets tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory molecule and hence is a TNF inhibitor. Profound reduction in C-reactive protein (CRP) levels, interleukin (IL)-6, intercellaular adhesion molecules (ICAM)-1, matrix metalloproteinase (MMP)-3, and vascular endothelial growth factor (VEGF) demonstrates golimumab as an effective modulator of inflammatory markers and bone metabolism. Golimumab is given via subcutaneous injection.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID‑19. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

<span class="mw-page-title-main">Dihydroorotate dehydrogenase</span> Class of enzymes

Dihydroorotate dehydrogenase (DHODH) is an enzyme that in humans is encoded by the DHODH gene on chromosome 16. The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to orotate, in de novo pyrimidine biosynthesis. This protein is a mitochondrial protein located on the outer surface of the inner mitochondrial membrane (IMM). Inhibitors of this enzyme are used to treat autoimmune diseases such as rheumatoid arthritis.

<span class="mw-page-title-main">Rheumatoid nodule</span> Medical condition

A rheumatoid nodule is a lump of tissue, or an area of swelling, that appears on the exterior of the skin usually around the olecranon or the interphalangeal joints, but can appear in other areas. There are four different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules, and central nervous systems nodules. These nodules occur almost exclusively in association with rheumatoid arthritis. Very rarely do rheumatoid nodules occur as rheumatoid nodulosis in the absence of rheumatoid arthritis. Rheumatoid nodules can also appear in areas of the body other than the skin. Less commonly they occur in the lining of the lungs or other internal organs. The occurrence of nodules in the lungs of miners exposed to silica dust was known as Caplan’s syndrome. Rarely, the nodules occur at diverse sites on body.

<span class="mw-page-title-main">Teriflunomide</span> Drug used in treatment of multiple sclerosis

Teriflunomide, sold under the brand name Aubagio, is the active metabolite of leflunomide. Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010. 2-year results were positive. 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." The drug was approved for use in the United States in September 2012 and for use in the European Union in August 2013.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

<span class="mw-page-title-main">Tofacitinib</span> Medication

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.

Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it received US FDA approval on 22 May 2017 and European Medicines Agency approval on 23 June 2017.

<span class="mw-page-title-main">Filgotinib</span> Chemical compound

Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.

<span class="mw-page-title-main">Peficitinib</span> Chemical compound

Peficitinib is a pharmaceutical drug used for the treatment of rheumatoid arthritis. It belongs to the class of drugs known as Janus kinase inhibitors.

<span class="mw-page-title-main">Upadacitinib</span> Chemical compound (medication)

Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

References

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  2. ↑ Anvisa (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] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
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  4. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
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  6. ↑ "Arava EPAR". European Medicines Agency. 25 August 2023. Retrieved 26 August 2023.
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  8. ↑ Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, van Riel P (January 2005). "When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide?". Annals of the Rheumatic Diseases. 64 (1): 44–51. doi:10.1136/ard.2003.016709. PMC   1755199 . PMID   15271770.
  9. ↑ Pinto P, Dougados M (2006). "Leflunomide in clinical practice" (PDF). Acta Reumatologica Portuguesa. 31 (3): 215–24. PMID   17094333.
  10. 1 2 3 4 Rossi S, ed. (2013). Australian Medicines Handbook. Adelaide: The Australian Medicines Handbook Unit Trust. ISBN   978-0-9805790-9-3.[ page needed ]
  11. ↑ "Leflunomide Search". ClinicalTrials.gov. U.S. National Library of Medicine.
  12. ↑ Ozturk S, Mathur D, Zhou RW, Mulholland D, Parsons R (December 2020). "Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer". Prostate Cancer and Prostatic Diseases. 23 (4): 718–723. doi:10.1038/s41391-020-0251-1. PMC   7666085 . PMID   32661432.
  13. 1 2 Mathur D, Stratikopoulos E, Ozturk S, Steinbach N, Pegno S, Schoenfeld S, et al. (April 2017). "PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition". Cancer Discovery. 7 (4): 380–390. doi:10.1158/2159-8290.CD-16-0612. PMC   5562025 . PMID   28255082.
  14. ↑ Blanckaert K, De Vriese AS (December 2006). "Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients". Nephrology, Dialysis, Transplantation. 21 (12): 3364–7. doi: 10.1093/ndt/gfl404 . PMID   16998219.
  15. ↑ Dai L, Wei XN, Zheng DH, Mo YQ, Pessler F, Zhang BY (June 2011). "Effective treatment of Kimura's disease with leflunomide in combination with glucocorticoids". Clinical Rheumatology. 30 (6): 859–65. doi:10.1007/s10067-011-1689-2. PMID   21286771. S2CID   1914281.
  16. ↑ Wu GC, Xu XD, Huang Q, Wu H (February 2013). "Leflunomide: friend or foe for systemic lupus erythematosus?". Rheumatology International. 33 (2): 273–6. doi:10.1007/s00296-012-2508-z. PMID   22961090. S2CID   7202069.
  17. 1 2 Sanders S, Harisdangkul V (April 2002). "Leflunomide for the treatment of rheumatoid arthritis and autoimmunity". The American Journal of the Medical Sciences. 323 (4): 190–3. doi:10.1097/00000441-200204000-00004. PMID   12003373. S2CID   28479334.
  18. ↑ Unizony S, Stone JH, Stone JR (January 2013). "New treatment strategies in large-vessel vasculitis". Current Opinion in Rheumatology. 25 (1): 3–9. doi: 10.1097/BOR.0b013e32835b133a . PMID   23114585. S2CID   21101525.
  19. ↑ Haibel H, Rudwaleit M, Braun J, Sieper J (January 2005). "Six months open label trial of leflunomide in active ankylosing spondylitis". Annals of the Rheumatic Diseases. 64 (1): 124–6. doi:10.1136/ard.2003.019174. PMC   1755172 . PMID   15608310.
  20. ↑ Prajapati DN, Knox JF, Emmons J, Saeian K, Csuka ME, Binion DG (August 2003). "Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy". Journal of Clinical Gastroenterology. 37 (2): 125–8. doi:10.1097/00004836-200308000-00006. PMID   12869881. S2CID   21212960.
  21. ↑ Holtmann MH, Gerts AL, Weinman A, Galle PR, Neurath MF (April 2008). "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. doi:10.1007/s10620-007-9953-7. PMID   17934840. S2CID   29918308.
  22. ↑ Panselinas E, Judson MA (October 2012). "Acute pulmonary exacerbations of sarcoidosis". Chest. 142 (4): 827–836. doi: 10.1378/chest.12-1060 . PMID   23032450.
  23. ↑ Roy M (August 2007). "Early clinical experience with leflunomide in uveitis". Canadian Journal of Ophthalmology. 42 (4): 634. doi:10.3129/can.j.ophthalmol.i07-085. PMID   17641721.
  24. ↑ Pirildar T (May 2003). "Treatment of adult-onset Still's disease with leflunomide and chloroquine combination in two patients". Clinical Rheumatology. 22 (2): 157. doi:10.1007/s10067-002-0667-0. PMID   12740686. S2CID   41656726.
  25. ↑ Clinical trial number NCT00004071 for "Mitoxantrone and Prednisone With or Without Leflunomide in Treating Patients With Stage IV Prostate Cancer" at ClinicalTrials.gov
  26. ↑ Clinical trial number NCT00802243 for "Leflunomide Associated With Topical Corticosteroids for Bullous Pemphigoid (ARABUL)" at ClinicalTrials.gov
  27. 1 2 3 4 5 6 Teschner S, Burst V (September 2010). "Leflunomide: a drug with a potential beyond rheumatology". Immunotherapy. 2 (5): 637–50. doi:10.2217/imt.10.52. PMID   20874647.
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  29. ↑ "Data Sheet Arava" (PDF). Medsafe. sanofi-aventis new zealand limited. 29 June 2012. Retrieved 11 March 2014.
  30. 1 2 Lee SS, Park YW, Park JJ, Kang YM, Nam EJ, Kim SI, et al. (2009). "Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis". Scandinavian Journal of Rheumatology. 38 (1): 11–4. doi:10.1080/03009740802360632. PMID   19191187. S2CID   205543918.
  31. 1 2 Fox RI, Herrmann ML, Frangou CG, Wahl GM, Morris RE, Strand V, et al. (December 1999). "Mechanism of action for leflunomide in rheumatoid arthritis". Clinical Immunology. 93 (3): 198–208. doi:10.1006/clim.1999.4777. PMID   10600330.
  32. 1 2 Melchiorri D, van Zwieten-Boot B, Maciulaitis R, Vilceanu M, Bruins Slot K, Hudson I, et al. "Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000" (PDF). European Medicines Agency. p. 119. Archived from the original (PDF) on 17 July 2015. Retrieved 5 June 2015.
  33. ↑ Rozman B (2002). "Clinical pharmacokinetics of leflunomide". Clinical Pharmacokinetics. 41 (6): 421–30. doi:10.2165/00003088-200241060-00003. PMID   12074690. S2CID   33745823.
  34. ↑ "Clinical Pharmacology/Biopharmaceutics Review. Product: ARAVA (leflunomide tablets). Application Number: NDA 20905" (PDF). U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Retrieved 15 April 2016.
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