Leflunomide
|
|
| Systematic (IUPAC) name |
| 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide |
| Clinical data |
| Trade names |
Arava, Arabloc, Lunava, Repso, Elafra |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a600032 |
| Licence data |
EMA:Link, US FDA:link |
|
Pregnancy
category
|
- AU: X (High risk)
- US: X (Contraindicated)
|
|
Legal status
|
- AU: Prescription Only (S4)
- CA: ℞-only
- UK: Prescription-only (POM)
- US: ℞-only
|
|
Routes of
administration
|
Oral (tablets) |
| Pharmacokinetic data |
| Bioavailability |
80%[1] |
|
Protein binding
|
>99%[1] |
| Metabolism |
GI mucosa and liver[1] |
|
Biological half-life
|
14–18 days[1] |
| Excretion |
Faeces (48%), urine (43%)[1] |
| Identifiers |
|
CAS Registry Number
|
75706-12-6 Y |
|
ATC code
|
L04AA13 |
| PubChem |
CID: 3899 |
| IUPHAR/BPS |
6825 |
| DrugBank |
DB01097 Y |
| ChemSpider |
3762 Y |
| UNII |
G162GK9U4W Y |
| KEGG |
D00749 Y |
| ChEBI |
CHEBI:6402 Y |
| ChEMBL |
CHEMBL960 Y |
| Chemical data |
| Formula |
C12H9F3N2O2 |
|
Molecular mass
|
270.207 g/mol |
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) Y
Key:VHOGYURTWQBHIL-UHFFFAOYSA-N Y
|
| Y (what is this?) (verify) |
Leflunomide (original brand name Arava) is an immunosuppressive disease-modifying antirheumatic drug (DMARD),[2] used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.[3]
Bottle of Leflunomide (Arava) and tablet
Contents
- 1 Medical use
- 2 Side effects
- 2.1 Contraindications
- 2.2 Interactions
- 3 Mechanism of action
- 4 Pharmacokinetics
- 5 Leflunomide metabolism and controversial similarity with teriflunomide
- 6 References
- 7 External links
Medical use
Rheumatoid arthritis and psoriatic arthritis are the only indications that have received regulatory approval.[1][4] Clinical studies regarding the following diseases have been conducted:[5]
- Polyoma BK Virus Nephropathy[6]
- Kimura's disease[7]
- Systemic lupus erythematosus[8]
- Felty's syndrome [9]
- Takayasu arteritis[10]
- Granulomatosis with polyangiitis[9]
- Ankylosing spondylitis[11]
- Crohn's disease[12][13]
- Sarcoidosis[14]
- Uveitis[15]
- Still's disease[16]
- Prostate cancer[17]
- Pemphigoid[18]
- Prevention of organ transplant rejection[19]
Side effects
Its principle dose-limiting side effects are liver damage, lung disease and immunosuppression.[19] The most common side effects (occurring in >1% of those treated with it) are, in approximately descending order of frequency:[1][4][20][21][22][23][24] diarrhoea, 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:[4] constipation, oral thrush, stomatitis, taste disturbance, thrombocytopenia and hives. Rarely (in 0.1% of those treated with it) it can cause:[4] 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.
Contraindications
Contraindications include:[1]
- 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.[1] 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.[1]
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.[25] However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.[25]
Mechanism of action
Leflunomide is an immunomodulatory drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) (abbreviation DHODH), which plays a key role in the de novo (from scratch) synthesis of the uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA, hence leflunomide inhibits the reproduction of rapidly dividing cells, especially lymphocytes.[19] 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).[26] Teriflunomide also inhibits several tyrosine kinases.[19] 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.[26] 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.[19]
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%).[1][19][20]
Leflunomide metabolism and controversial similarity with teriflunomide
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. 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.[27]
A77 1726, more commonly known as
teriflunomide (brand name Aubagio
®) is the
one and only active metabolite of leflunomide, completely responsive to all 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.
[28][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.”[27] Because of this, EMA had not considered teriflunomide being a new active substance.[30]
References
- ^ a b c d e f g h i j k "Arava (leflunomide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 11 March 2014.
- ^ 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.
- ^ Pinto P, Dougados M (2006). "Leflunomide in clinical practice" (PDF). Acta reumatológica portuguesa 31 (3): 215–24. PMID 17094333.
- ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- ^ http://clinicaltrials.gov/ct2/results?term=Leflunomide
- ^ Blanckaert, K; De Vriese, AS (23 September 2006). "Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients" (PDF). Nephrology Dialysis Transplantation 21 (12): 3364–3367. doi:10.1093/ndt/gfl404. PMID 16998219.
- ^ 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.
- ^ 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.
- ^ a b Sanders, S; Harisdangkul, V (2002). "Leflunomide for the treatment of rheumatoid arthritis and autoimmunity". American Journal of Medical Sciences 323 (4): 190–3. doi:10.1097/00000441-200204000-00004. PMID 12003373.
- ^ 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.
- ^ Haibel, H; Rudwaleit, M; Braun, J; Sieper, J (January 2005). "Six months open label trial of leflunomide in active ankylosing spondylitis." (PDF). Annals of the Rheumatic Diseases 64 (1): 124–6. doi:10.1136/ard.2003.019174. PMC 1755172. PMID 15608310.
- ^ 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.
- ^ 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.
- ^ Panselinas, E; Judson, MA (October 2012). "Acute pulmonary exacerbations of sarcoidosis." (PDF). Chest 142 (4): 827–36. doi:10.1378/chest.12-1060. PMID 23032450.
- ^ Roy, M (August 2007). "Early clinical experience with leflunomide in uveitis.". Canadian Journal of Ophthalmology 42 (4): 634. doi:10.3129/canjophthalmol.i07-085. PMID 17641721.
- ^ 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.
- ^ "Mitoxantrone and Prednisone With or Without Leflunomide in Treating Patients With Stage IV Prostate Cancer". ClinicalTrials.gov. National Institute of Health. September 2012. Retrieved 11 March 2014.
- ^ "Leflunomide Associated With Topical Corticosteroids for Bullous Pemphigoid (ARABUL)". ClinicalTrials.gov. National Institute of Health. December 2008. Retrieved 11 March 2014.
- ^ a b c d e f 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.
- ^ a b "PRODUCT INFORMATION ARAVA®" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. 7 August 2012. Retrieved 11 March 2014.
- ^ "Arava : EPAR - Product Information" (PDF). European Medicines Agency. Sanofi-Aventis Deutschland GmbH. 21 November 2013. Retrieved 11 March 2014.
- ^ "Data Sheet Arava®" (PDF). Medsafe. sanofi-aventis new zealand limited. 29 June 2012. Retrieved 11 March 2014.
- ^ "ARAVA (leflunomide) tablet, film coated [sanofi-aventis U.S. LLC]". DailyMed. sanofi-aventis U.S. LLC. November 2012. Retrieved 11 March 2014.
- ^ "Arava 100mg Tablets - Summary of Product Characteristic". electronic Medicines Compendium. SANOFI. 21 February 2014. Retrieved 11 March 2014.
- ^ a b Lee, S.; Park, Y.; Park, J.; Kang, Y.; Nam, E.; Kim, S.; Lee, J.; Yoo, W.; Lee, S. (2009). "Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis". Scandinavian journal of rheumatology 38 (1): 11–14. doi:10.1080/03009740802360632. PMID 19191187. edit
- ^ a b Fox, RI; Herrmann, ML; Frangou, CG; Wahl, GM; Morris, RE; Strand, V; Kirschbaum, BJ (December 1999). "Mechanism of action for leflunomide in rheumatoid arthritis.". Clinical Immunology 93 (3): 198–208. doi:10.1006/clim.1999.4777. PMID 10600330.
- ^ a b Melchiorri, Daniela; Barbara, van Zwieten-Boot; Romaldas, Maciulaitis; Nela, Vilceanu; Karsten, Bruins Slot; Ian, Hudson; Robert, Hemmings; Harald, Enzmann; Pierre, Demolis. "Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000" (PDF). European Medicines Agency. European Medicines Agency. p. 119. Retrieved 5 June 2015.
- ^ Rozman, B (2002). "Clinical Pharmacokinetics of Leflunomide.". Clinical pharmacokinetics 41 (6): 421–30. PMID 12074690.
- ^ Tandon, Ph.D., Veneeta. "Clinical Pharmacology/Biopharmaceutics Review of ARAVA™ (leflunomide tablets)" (PDF). http://www.accessdata.fda.gov. Center for Drug Evaluation and Research. Application Number: NDA 20-905 (ORIG). Retrieved 5 June 2015.
- ^ European Medicines Agency. Committee for Medicinal Products for Human Use. (27 June 2013). "Summary of Opinion (Initial Authorisation of Aubagio /teriflunomide/)" (PDF). European Medicines Agency (http://www.ema.europa.eu/ema/). Retrieved 5 June 2015.
External links
- ARAVA® (leflunomide) 14 mg tablets — Arava HCP website
- National Rheumatoid Arthritis Society (NRAS) Information about Disease Modifying drugs such as Leflunomide
- http://www.rheuma-online.de/medikamente/leflunomid-arava/studien-zu-leflunomid-arava/gibt-es-untersuchungen-zu-leflunomid-in-weiteren-einsatzgebieten.html (in German, regarding potential indications)
- http://www.arznei-telegramm.de/register/0204507.pdf (in German, regarding discontinuation of the drug)
- http://www.emea.europa.eu/pdfs/human/press/pus/561101en.pdf (warning as of 2001 regarding hepatotoxicity) (URL DEAD 16 Oct 2010)
- The safety of leflunomide Australian Prescriber
|
Immunosuppressive drugs / Immunosuppressants (L04)
|
|
Intracellular
(initiation) |
| Antimetabolites |
- purine synthesis inhibitors: Azathioprine
- Mycophenolic acid
- pyrimidine synthesis inhibitors: Leflunomide
- Teriflunomide
|
|
Macrolides/
other IL-2 inhibitors |
- FKBP/Cyclophilin/Calcineurin: Tacrolimus
- Ciclosporin
- Pimecrolimus
|
|
| IMiDs |
- Lenalidomide
- Pomalidomide
- Thalidomide
|
|
|
Intracellular
(reception) |
| IL-1 receptor antagonists |
|
|
| mTOR |
- Sirolimus
- Everolimus
- Ridaforolimus
- Temsirolimus
- Umirolimus
- Zotarolimus
|
|
|
| Extracellular |
| Antibodies |
| Monoclonal |
Serum target
(noncellular) |
- Complement component 5 (Eculizumab)
- TNF (Adalimumab
- Afelimomab
- Certolizumab pegol
- Golimumab
- Infliximab
- Nerelimomab)
- Interleukin 5 (Mepolizumab)
- Immunoglobulin E (Omalizumab)
- IL-12 and IL-23 (Lebrikizumab
- Ustekinumab)
|
|
| Cellular target |
- CD3 (Muromonab-CD3
- Otelixizumab
- Teplizumab
- Visilizumab)
- CD4 (Clenoliximab
- Keliximab
- Zanolimumab)
- CD11a (Efalizumab)
- CD18 (Erlizumab)
- CD20 (Obinutuzumab
- Rituximab
- Ocrelizumab
- Pascolizumab)
- CD23 (Gomiliximab
- Lumiliximab)
- CD40 (Teneliximab
- Toralizumab)
- CD62L/L-selectin (Aselizumab)
- CD80 (Galiximab)
- CD147/Basigin (Gavilimomab)
- CD154 (Ruplizumab)
- BLyS (Belimumab
- Blisibimod)
- CTLA-4 (Ipilimumab
- Tremelimumab)
- CAT (Bertilimumab
- Lerdelimumab
- Metelimumab)
- Integrin (Natalizumab)
- Interleukin-6 receptor (Tocilizumab)
- LFA-1 (Odulimomab)
- IL-2 receptor/CD25 (Basiliximab
- Daclizumab
- Inolimomab)
- T-lymphocyte (Zolimomab aritox)
|
|
| Unsorted |
- Atorolimumab
- Cedelizumab
- Fontolizumab
- Maslimomab
- Morolimumab
- Pexelizumab
- Reslizumab
- Rovelizumab
- Siplizumab
- Talizumab
- Telimomab aritox
- Vapaliximab
- Vepalimomab
|
|
|
| Polyclonal |
- Anti-thymocyte globulin
- Anti-lymphocyte globulin
|
|
|
| -cept (Fusion) |
- CTLA-4 (Abatacept
- Belatacept)
- TNF inhibitor (Etanercept
- Pegsunercept)
- Aflibercept
- Alefacept
- Rilonacept
|
|
|
|
Index of the immune system
|
|
| Description |
- Physiology
- cells
- autoantigens
- autoantibodies
- complement
- surface antigens
- IG receptors
|
|
| Disease |
- Allergies
- Immunodeficiency
- Immunoproliferative immunoglobulin disorders
- Hypersensitivity and autoimmune disorders
- Neoplasms and cancer
|
|
| Treatment |
- Procedures
- Drugs
- antihistamines
- immunostimulants
- immunosuppressants
- monoclonal antibodies
|
|
|
|
Specific antirheumatic products / DMARDs (M01C)
|
|
| Quinolines |
|
|
| Gold preparations |
- Sodium aurothiomalate
- Sodium aurothiosulfate
- Auranofin
- Aurothioglucose
- Aurotioprol
|
|
| Other |
- Penicillamine #/Bucillamine
- Chloroquine #/Hydroxychloroquine
- Leflunomide
- Sulfasalazine #
- antifolate (Methotrexate #)
- thiopurine (Azathioprine) #
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
|
|
Index of joint
|
|
| Description |
- Anatomy
- head and neck
- cranial
- arms
- torso and pelvis
- legs
- bursae and sheathes
- Physiology
|
|
| Disease |
- Arthritis
- acquired
- back
- childhood
- soft tissue
- Congenital
- Injury
- Symptoms and signs
- Examination
|
|
| Treatment |
- Procedures
- Drugs
- rheumatoid arthritis
- gout
- topical analgesics
|
|
|
