Leflunomide

Leflunomide

Systematic (IUPAC) name
5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide
Clinical data
Trade names	Arava
AHFS/Drugs.com	monograph
MedlinePlus	a600032
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	X (contraindicated)
Legal status	Rx only
Routes	oral (tablets)
Pharmacokinetic data
Bioavailability	80%
Protein binding	>99.3%
Half-life	2 weeks
Excretion	Biliar, renal
Identifiers
CAS number	75706-12-6 Y
ATC code	L04AA13
PubChem	CID 3899
DrugBank	APRD00205
ChemSpider	3762 Y
UNII	G162GK9U4W Y
KEGG	D00749 Y
ChEBI	CHEBI:6402 Y
ChEMBL	CHEMBL960 Y
Chemical data
Formula	C12H9F3N2O2
Mol. mass	270.207 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  (verify)

Leflunomide is a medication of the DMARD type, used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.

Basic chemical, pharmacological, and marketing data

Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous.

The substance 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 also contains some inactive ingredients, which could cause allergies or intolerances. Arava was approved by the U.S. Food and Drug Administration (FDA) and in many other countries (e.g., Canada, Europe) in 1998.

Bottle of Leflunomide (Arava) and 20mg tablet

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 with 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.

Pharmacokinetics

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.^{[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

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.

Prescribers are reminded that Arava should be prescribed only by specialists experienced in the treatment of rheumatic diseases.

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^{[citation needed]}
• Wegener's granulomatosis
• Ankylosing spondylitis^{[citation needed]}
• Crohn's disease^{[citation needed]}
• Sarcoidosis^{[citation needed]}
• Uveitis
• Still's disease^{[citation needed]}
• Prostate cancer
• Pemphigoid.

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

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 (e.g., lactose).

• 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.

• 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).

Malignancies

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.

Side-effects

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.

Interactions

• Alcohol, other DMARDs including chloroquine/hydroxychloroquine, live virus vaccines, tegafur, some tuberculostatics (rifampin and/or isoniazid), tolbutamide and warfarin should not be given concomitantly.

Dosage regimen

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.

Patient counselling

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.

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.^{[citation needed]}

External links

• 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)