Leflunomide

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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 chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide.

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 FDA and in many other countries (e.g., Canada, Europe) in 1999.

Mechanism of Action

Arava® is an immunomodulatory drug inhibiting dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) (abbreviation DHODH). Genuine antiproliferative activity has been proven. Additionally, 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

Relative to an oral solution, Arava® tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 (the main metabolite, see below) plasma levels. Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (internal reference of Aventis - hereafter referred to as M1) which is responsible for essentially all of the drug's activity in vivo. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite M1. 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. M1 is metabolized in the liver at cytosolic and microsomal sites and further excreted as well renally and billary.

Absorption and Need for Loading Dose: After oral administration, peak plasma levels of the active metabolite, M1, occurred between 6 - 12 hours after dosing. Due to the very long half-life of M1 (approx. 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to reach steady-state levels of M1 quickly. Without a loading dose, it is estimated that steady-state plasma concentrations would require nearly two months of dosing to be reached. The resulting plasma levels following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional. M1 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 of M1 from the body is warranted, an eleven day scheme with cholestyramine or the use of activated charcoal is indicated and will soon decrease M1 plasma levels below the critical limit of 0.02mg/l. Limited experience shows that M1 is not dialysable.

Regular Indications

Arava® is indicated in adults for the treatment of active moderate to severe rheumatoid arthritis and psoriasis 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.

Particular the concomitant use of methotrexate may lead to severe or even fatal liver- or hepatotoxicity. Seventy five per cent of all cases of severe liver damage reported until early 2001 were seen under combined drug therapy Arava® plus methotrexate.

Prescribers are reminded that Arava® should only be prescribed 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 transplations when co-administered with commonly used first line agents (USA only). Most experience exists with liver and renal transplations. It should be noted, that the efficacy and safety of leflunomide has not been completely assessed so far in well controlled and adequate studies.

Interestingly, M1 shows additionally 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, but these have to be reviewed critically, before approval can be given:

• Systemic lupus erythematosus;
• Felty's syndrome;
• Takayasu arteritis;
• Wegener's granulomatosis;
• Ankylosing spondylitis;
• Crohn's disease;
• Sarcoidosis;
• Uveitis;
• Still's disease;
• 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. So far JRA is not an approved indication for Arava®.

Leflunamide 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. Finally, 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).

• Combination with methotrexate, other DMARDs and alcohol.

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, M1 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 Regime

Usually, an oral loading dose of 100mg is followed by a once-a-day administration of 10 to 20mg 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 particular 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, 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 myelosupression, 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®.

External Links and References

• AHFS Database online
• Arzneimittel Datenbank (in German) (also regarding estimations of frequency of severe liver damage)
• 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 hepatoxicity)