Leflunomide

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Leflunomide
Systematic (IUPAC) name
5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide
Clinical data
Trade namesArava
AHFS/Drugs.commonograph
MedlinePlusa600032
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.X (contraindicated)
Legal statusRx only
Routesoral (tablets)
Pharmacokinetic data
Bioavailability80%
Protein binding>99.3%
Half-life2 weeks
ExcretionBiliar, renal
Identifiers
CAS number75706-12-6 YesY
ATC codeL04AA13
PubChemCID 3899
DrugBankDB01097
ChemSpider3762 YesY
UNIIG162GK9U4W YesY
KEGGD00749 YesY
ChEBICHEBI:6402 YesY
ChEMBLCHEMBL960 YesY
Chemical data
FormulaC12H9F3N2O2 
Mol. mass270.207 g/mol
 YesY (what is this?)  (verify)
 
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Leflunomide
Systematic (IUPAC) name
5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide
Clinical data
Trade namesArava
AHFS/Drugs.commonograph
MedlinePlusa600032
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.X (contraindicated)
Legal statusRx only
Routesoral (tablets)
Pharmacokinetic data
Bioavailability80%
Protein binding>99.3%
Half-life2 weeks
ExcretionBiliar, renal
Identifiers
CAS number75706-12-6 YesY
ATC codeL04AA13
PubChemCID 3899
DrugBankDB01097
ChemSpider3762 YesY
UNIIG162GK9U4W YesY
KEGGD00749 YesY
ChEBICHEBI:6402 YesY
ChEMBLCHEMBL960 YesY
Chemical data
FormulaC12H9F3N2O2 
Mol. mass270.207 g/mol
 YesY (what is this?)  (verify)

Leflunomide is a disease-modifying antirheumatic drug (DMARD),[1] used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.[2]

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.[3] Arava was approved by U.S., Canadian, European and other regulatory agencies in 1998.

Bottle of Leflunomide (Arava) and 20mg tablet

Mechanism of action[edit]

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).[4] 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.[5] 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.

Pharmacokinetics[edit]

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[edit]

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[6]). 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.[citation needed] 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.

Regular indications[edit]

In the US Arava is indicated in adults for the treatment of active moderate to severe rheumatoid arthritis and psoriatic arthritis

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.[6][7]

Orphan drug status[edit]

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[edit]

Clinical studies regarding the following diseases have been conducted:[8]

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.[citation needed]

Leflunomide has also been utilized for the treatment of Relapsing Polychondritis, but only case reports exist in the literature regarding this usage.[citation needed]

Contraindications and precautions[edit]

Leflunomide has a great number of absolute and relative contraindications, in part associated with its mode of action:

Malignancies[edit]

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.[citation needed]

Side-effects[edit]

The side-effects of Arava affect quite a number of organ systems, are frequent and at times severe or even fatal.

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.

Interactions[edit]

Dosage regimen[edit]

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[edit]

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.

If used concomitantly with immunosuppressants such as methotrexate, chronic monitoring should be monthly.

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.

Patient counselling[edit]

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[edit]

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.[citation needed]

References[edit]

  1. ^ 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. 
  2. ^ Pinto P, Dougados M (2006). "Leflunomide in clinical practice". Acta reumatológica portuguesa 31 (3): 215–24. PMID 17094333. 
  3. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020905s025lbl.pdf
  4. ^ 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. 
  5. ^ "Clin Immunol. 1999 Dec;93(3):198-208.". 
  6. ^ 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
  7. ^ 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
  8. ^ http://clinicaltrials.gov/ct2/results?term=Leflunomide
  9. ^ Nephrology Dialysis Transplantation, Oxford Journals
  10. ^ http://clinicaltrials.gov/ct2/show/NCT00637819 Phase II study of Leflunomide in Systemic Lupus Erythematosus
  11. ^ a b 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. 
  12. ^ http://clinicaltrials.gov/ct2/show/NCT00001863 Phase II trial of Leflunomide to Treat Uveitis
  13. ^ 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)
  14. ^ http://clinicaltrials.gov/ct2/show/NCT00802243 Phase II study of Leflunomide Associated With Topical Corticosteroids for Bullous Pemphigoid (ARABUL)
  15. ^ 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.

External links[edit]