|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||X (contraindicated)|
|Legal status||Rx only|
|Mol. mass||270.207 g/mol|
|(what is this?)|
It is sold under the brand name Arava by Sanofi-Aventis. It is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Arava was approved by U.S., Canadian, European and other regulatory agencies in 1998.
- 1 Mechanism of action
- 2 Pharmacokinetics
- 3 Regular indications
- 4 Orphan drug status
- 5 Other potential indications
- 6 Contraindications and precautions
- 7 Malignancies
- 8 Side-effects
- 9 Interactions
- 10 Dosage regimen
- 11 Necessary laboratory examinations
- 12 Patient counselling
- 13 Summary and safety controversy
- 14 References
- 15 External links
Mechanism of action
Leflunomide is an immunomodulatory drug inhibiting mitochondrial enzyme dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) (abbreviation DHODH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA). Leflunomide 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. Genuine antiproliferative activity has been proven. In addition, several experimental models (both in vivo and in vitro) have demonstrated an anti-inflammatory effect. This double action is supposed to slow progression of the disease and to cause remission/relief of symptoms of rheumatoid arthritis and psoriatic arthritis such as joint tenderness and decreased joint and general mobility in human patients.
Arava tablets are 80% bioavailable. Co-administration with a high-fat meal did not have a significant impact on plasma levels of the active metabolite teriflunomide. Following oral administration, leflunomide is metabolized to teriflunomide, which is responsible for all of the drug's activity in vivo. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of teriflunomide. Plasma levels of unchanged leflunomide are occasionally detected, but at very low levels. Some minor metabolites have been noticed to occur in human plasma, which do not account for the beneficial drug effects. Teriflunomide is metabolized in the liver at cytosolic and microsomal sites and further excreted as well renally and billiary.
Absorption and need for loading dose
After oral administration, peak plasma levels of teriflunomide occurred between 6 and 12 hours after dosing. Due to its very long half-life (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to reach steady-state levels quickly. Without a loading dose, it is estimated that steady-state plasma concentrations would require nearly two months of dosing to be reached (nevertheless, one study showed fewer adverse effects and good efficacy if no loading dose is used at the beginning of treatment with leflunomide of patients with rheumatoid arthritis). The resulting plasma levels following both loading doses and continued clinical dosing indicate that plasma levels are dose proportional. Teriflunomide can be found as late as 2 years after termination of therapy in human plasma in sufficient levels to cause severe harm to pregnant women or to cause significant interactions. If quick removal from the body is necessary, an eleven-day scheme with cholestyramine or the use of activated charcoal is indicated and will soon decrease plasma levels below the critical limit of 0.02 mg/l. Limited experience shows that teriflunomide is not dialysable.
In the US Arava is indicated in adults for the treatment of active moderate to severe rheumatoid arthritis and psoriatic arthritis
- to reduce signs and symptoms
- to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing
- to improve physical function.
The onset of clinical improvement can be expected after 4 to 6 weeks of continued therapy.
Aspirin, or other nonsteroidal anti-inflammatory agents (NSAR), and/or low-dose corticosteroids may be continued during treatment with leflunomide. The combined use of leflunomide with antimalarials, intramuscular or oral gold, D-penicillamine, azathioprine, or methotrexate has not been adequately studied and is, therefore, contraindicated.
Especially the concomitant use of methotrexate 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 Arava 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.
Orphan drug status
Leflunomide has recently been assigned orphan drug status for the prevention of solid-organ rejection after allograft transplantations when co-administered with commonly used first-line agents (USA only). Most experience exists with liver and renal transplantations. The efficacy and safety of leflunomide has not been completely assessed so far in well-controlled and adequate studies.
Teriflunomide shows, in addition to the expected profound immunosuppressive potency, limited antiviral activity against CMV (cytomegalovirus). CMV infections endanger eyesight (retinitis) or even the lives of transplant patients (systemic infections) under conventional immunosuppressive therapy regimes.
Other potential indications
Clinical studies regarding the following diseases have been conducted:
- Polyoma BK Virus Nephropathy
- Systemic lupus erythematosus
- Felty's syndrome 
- Takayasu arteritis
- Wegener's granulomatosis 
- Ankylosing spondylitis
- Crohn's disease
- Sarcoidosis
- Still's disease
- Prostate cancer
One study has been made in pediatric patients with juvenile rheumatoid arthritis (JRA). In these, patient group clinical efficacy, side-effect profile, and pharmacokinetic data have been comparable to adult patients with rheumatoid arthritis on Arava alone. The results, however, have been somewhat inferior to the active control group, possibly reflecting a relative underdosing in the lower age of patients group.
Contraindications and precautions
Leflunomide has a great number of absolute and relative contraindications, in part associated with its mode of action:
- Hypersensitivity to the drug or to inactive ingredients.* Important contraindications are "preexisting pregnancy", or women of childbearing potential not using reliable anticonceptive methods. Women should not become pregnant before 2 years after termination of therapy have elapsed or undergo a rapid wash-out procedure as stated above. Men wishing to father a child should discontinue leflunomide after consultation with their prescribing physician and also undergo the wash-out procedure.Animal studies with leﬂunomide showed an increase in teratogenicity and embryonic death, leflunomide is contraindicated in pregnancy. Men taking leflunomide should avoid getting their partner pregnant while taking leflunomide and for up to 64 days after therapy (at least one cycle of spermatogenesis).
- Preexisting significant liver or renal disease and moderate to severe diseases of the bone marrow or immune system preclude the use of Leflunomide.
- Moderate to severe bacterial, fungal or viral infections (e.g., AIDS, latent HIV-Infection, pneumonia, active tuberculosis).
Due to its potent immunosuppression, leflunomide has the potential to promote myeloid/lymphatic malignancies or solid cancers. In postmarketing reports some cases of lymphoma have been noticed, the absolute number of cases and the case/patient ratio is unknown. In rheumatoid arthritis patients a several-fold increase of lymphoma is already found in those patients not treated with any DMARD.
The side-effects of Arava affect quite a number of organ systems, are frequent and at times severe or even fatal.
- Most serious is symptomatic liver damage ranging from jaundice to hepatitis, which can be fulminant, severe liver necrosis, and liver cirrhosis. Fatalities are known. Liver function studies may or may not precede the outbreak of clinical disease. The total incidence of severe liver damage is estimated to be as high as 0.5%, according to an internal report of the FDA. The EMEA, the European pendant to FDA, has in 2001 reported 296 cases of hepatotoxicity in 104,000 patient years, with 129 considered as serious, 2 cases of liver cirrhosis, and 15 cases of liver failure. Nine of the patients died. EMEA findings are that liver damage is typically seen within the first 6 months of therapy and is partially depending on cofactors, because of the serious cases 101 (78%) were concomitantly treated with other hepatotoxic drugs; 58% of those with asymptomatic elevations of liver function studies were cotreated with certain NSARs and/or methotrexate (see contraindications). In addition, 33% (=27 patients) of the patients with serious damage had other risk factors (history of alcohol abuse, liver function disturbance, acute heart failure, severe pulmonary disease or pancreatic carcinoma). Analysis of the data suggested that monitoring of liver function studies and wash-out periods may have not been fully adhered to. In case of any question, please refer to the procedures suggested in the EMEA statement as listed in section external links and references.
- Also very important is a relatively high incidence of myelosuppression with leukopenia, and/or hypoplastic anemia, and/or thrombocytopenia. Infections, sometimes as severe as development of active tuberculosis, pneumonia, PCP, and severe viral or mycotical infections, possibly leading to sepsis, death or permanent damage have been seen. Anemia or bleeding episodes may also lead to serious complications.
- Interstitial lung disease may occasionally be noticed and is recognized by progressive dyspnea and typical X-ray findings. This disease may or may not be reversible upon treatment and may lead to permanent disability or death.
- Other sites are: GIT, skin reactions up to life-threatening forms (Stevens–Johnson syndrome and toxic epidermal necrolysis), heart problems, alopecia (17%), CNS troubles etc.
If severe side-effects are encountered, teriflunomide can be readily removed from the body with oral cholestyramine or activated charcoal (see above) to slow or reverse the noted side-effects.
- Alcohol, other DMARDs including chloroquine/hydroxychloroquine, live virus vaccines, tegafur, some tuberculostatics (rifampin and/or isoniazid), tolbutamide and warfarin should not be given concomitantly.
Usually, an oral loading dose of 100 mg is followed by a once-a-day administration of 10 to 20 mg as determined by a specialized clinician. He/she will also determine the total duration of treatment. Experience regarding the duration of treatment has been gained in 2 studies, in one study treatment has been continued for 1 year, in the other for 2 years. After termination of treatment, beneficial effects may last for some years.
Necessary laboratory examinations
- Hematologic Monitoring
Patients taking Arava should have platelet count, white blood cell count, and hemoglobin or hematocrit monitored before initiation of treatment (baseline values), monthly for six months following initiation of therapy, and every 6 to 8 weeks thereafter.
- Bone Marrow Suppression Monitoring for Combination Therapy with Immunosuppressants
If used concomitantly with immunosuppressants such as methotrexate, chronic monitoring should be monthly.
- Liver Enzyme Monitoring
ALT (SGPT) values must be obtained at baseline and monitored at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month.
Patients should be carefully informed as to report immediately any subjective early signs of liver damage, bone marrow damage, serious infection, life-threatening skin reactions, and interstitial lung disease to their physician. This is particularly important for the interval between laboratory examinations. When counselling, firstly identify yourself to the patient and ensure that the name of the medication they are using is provided. Then state the purpose of the medication, common side effects and how to avoid or manage these side effects, the benefits of using therapy, any precautions, the correct dose and way to use a delivery device (if appropriate), ways to self monitor, storage and what to do if a dose is missed. Also be sure to check whether they are taking any other medications which may interact with this medication, whether prescription, OTC (over the counter) or alternative therapies. Actively listen to what the patient says and ensure that you summarise points to confirm that you have heard them correctly.
Summary and safety controversy
Arava is a potent drug comparing favourably with other DMARDs regarding the efficacy as measured by improvements on the ACR scale. Leflunomide met the ACR20 criteria in up to 56% of patients; most other drugs (e.g., methotrexate alone, sulfasalazine, TNF-inhibitors (infliximab, etanercept, and adalimumab), the latter drugs also in combination with methotrexate) reach values from 20% only up to approximately 50%. Arava was withdrawn in clinical studies in 36% of patients due to different reasons (intolerable side-effects, lack of efficacy, unspecified reasons); the incidence was not higher than observed in the methotrexate control group. However, postmarketing data regarding the high incidence of severe liver damage, serious myelosuppression, profound immunosuppression leading to serious or even fatal infections, the possibility that Arava is a human carcinogen, and the occurrence of interstitial lung disease has led to the forming of patient groups in the USA and Europe, for example, supported by safety aware physicians. These groups call for the local or worldwide ban or discontinuation of Arava.
- 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". Acta reumatológica portuguesa 31 (3): 215–24. PMID 17094333.
- Fukushima R, Kanamori S, Hirashiba M, et al. (2007). "Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice". Reprod. Toxicol. 24 (3-4): 310–6. doi:10.1016/j.reprotox.2007.05.006. PMID 17604599.
- "Clin Immunol. 1999 Dec;93(3):198-208.".
- 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.
- Kremer, Joel et al (2004) Combination Leflunomide and Methotrexate (MTX) Therapy for Patients with Active Rheumatoid Arthritis Failing MTX Monotherapy: Open-Label Extension of a Randomized, Double-Blind, Placebo Controlled Trial The Journal of Rheumatology, 31 (8): 1521-1531, accessed August 1, 2010
- Nephrology Dialysis Transplantation, Oxford Journals
- http://clinicaltrials.gov/ct2/show/NCT00637819 Phase II study of Leflunomide in Systemic Lupus Erythematosus
- Sanders S, Harisdangkul V (2002). "Leflunomide for the treatment of rheumatoid arthritis and autoimmunity". Am. J. Med. Sci. 323 (4): 190–3. doi:10.1097/00000441-200204000-00004. PMID 12003373.
- http://clinicaltrials.gov/ct2/show/NCT00001863 Phase II trial of Leflunomide to Treat Uveitis
- http://clinicaltrials.gov/ct2/show/NCT00004071 A pahse II/III study of Mitoxantrone and Prednisone With or Without Leflunomide in Treating Patients With Stage IV Prostate Cancer (COMPLETED)
- http://clinicaltrials.gov/ct2/show/NCT00802243 Phase II study of Leflunomide Associated With Topical Corticosteroids for Bullous Pemphigoid (ARABUL)
- Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 2001;63:106-12.
- 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