|Systematic (IUPAC) name|
|Trade names||Arabloc, Arava, Lunava, Repso|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||X (AU) X (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Metabolism||GI mucosa and liver|
|Excretion||Faeces (48%), urine (43%)|
|Mol. mass||270.207 g/mol|
|(what is this?)|
Leflunomide (brand names: Arabloc, Arava, Lunava, Repso) 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.
- Polyoma BK Virus Nephropathy
- Kimura's disease
- Systemic lupus erythematosus
- Felty's syndrome 
- Takayasu arteritis
- Wegener's granulomatosis
- Ankylosing spondylitis
- Crohn's disease
- Still's disease
- Prostate cancer
- Prevention of organ transplant rejection
Its principle 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: 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: 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.
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- 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 (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. 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.
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%).
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- National Rheumatoid Arthritis Society (NRAS) Information about Disease Modifying drugs such as Leflunomide
- http://www.arava.com/professional/home.do (full prescribing information)
- 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