Leflunomide - Treatment Of Rheumatic Diseases

What is leflunomide?

Leflunomide is a drug selected from the group of immunosuppressants, which is used as a basic therapeutic in the treatment of rheumatic diseases.

Clinical Data

Applications (indications)
In Leflunomide is a long-acting anti-inflammatory drug, which as antirheumatic (eng. 'Disease-modifying antirheumatic drug' DMARD) is used in the treatment of rheumatoid arthritis and psoriatic arthritis. An improvement in the symptoms expected after about two to three weeks.

Interactions with other drugs
Concomitant treatment with other DMARDs (methotrexate, chloroquine, etc.) should be done under strict viewpoints and, like other therapies and base combinations are also possible started and controlled by appropriately experienced and trained specialists. Due to the (highly effective) combination of leflunomide with methotrexate, the risk may, inter alia, serious liver damage (eg, granulomatous hepatitis.) Or dangerous infections have increased; the risk of such combination therapy for long-term treatment is not yet sufficiently known. Nevertheless, the combination therapy with leflunomide and methotrexate in rheumatology now has a fairly wide practical significance.

Use during pregnancy and lactation
Use during pregnancy and lactation is strictly contraindicated. Leflunomide can cause severe birth defects in the unborn life. Pregnancy must therefore be absolutely excluded before starting treatment. Reliable contraception during the treatment period with leflunomide is also the prerequisite for therapy with this medication.

Adverse effects (side effects)
During treatment with leflunomide may cause itching, Schleimhautulcera, hair loss (alopecia), diarrhea and very rarely come to agranulocytosis and fatal hepatic necrosis, but it is well tolerated in general.

Sufferers who suffer from a severe immunodeficiency, such. As HIV-infected, leflunomide should not take. Even with all the diseases that have immunosuppression result, it should not be a treatment with leflunomide.

Pharmacological properties

Mechanism of action (pharmacodynamics)
Leflunomide leads to inhibition of dihydroorotate dehydrogenase, a key enzyme in the pyrimidine of particular importance in cell division of T lymphocytes. In addition, the leukocyte migration is inhibited.

Uptake and distribution in the body (pharmacokinetics)
Leflunomide is absorbed in the intestine after peroral intake to about 82-95%. Leflunomide is converted by the so-called first-pass metabolism into its active metabolite A771726 (Teriflunomid) in the wall of the intestine and the liver. It is metabolised by several enzymes in other active substances and has a half-life of 1 to 4 weeks in the body. The excretion of Leflunomide and its active metabolites via stool and urine.

The metabolite Teriflunomid - after phase III clinical development - has been approved in 2013 for an application in multiple sclerosis.

The symptoms of overdose correspond broadly to the adverse event profile (abdominal pain, nausea etc). In case of overdose or poisoning of leflunomide cholestyramine or activated charcoal is recommended to accelerate elimination.

Other Information

Leflunomide was developed by Hoechst. Its anti-rheumatic properties in 1985 first described. The first leflunomide-containing medicines Arava was approved in the US on 10 September 1998. On 2 September 1999, the approval was followed for the European Union.

In early 2001 warned the European Medicines Agency (EMA) prior to the occurrence of liver complications during treatment with leflunomide. The drug was especially from 2002, the focus of public interest, as the US consumer advocacy group Public Citizen urged the local health ministry said in a petition for withdrawal of approval for Arava. The petition was based on the comparison with other rheumatic agents increased incidence of fatal liver complications, hypertension and Stevens-Johnson syndrome. The petition also relied on the warning of the EMA. Although the Department of Drug Safety of the US Food and Drug Administration in an opinion joined the concerns of the petition end of 2002, the management of the Authority dismissed the petition in March 2004.

The active metabolite Teriflunomid shows efficacy in the treatment of the thrust-shaped form of multiple sclerosis. The drug is for 2013 - under the trade name Aubagio ® (manufacturer: Genzyme / sanofi) - approved. No additional benefit for Teriflunomid arises from the perspective of the drug Commission of the German medical profession (Akd├ä) - for lack of a superior efficacy and no difference in the potential for damage - total. However, the Federal Joint Committee (G-BA) takes decisions on the added value.

The annual relapse rate under the two Teriflunomid doses (7 and 14 mg daily) 0.37 compared to 0.54 among placebo was a large international placebo-controlled randomized study over two years. The difference was statistically significant with a relative risk reduction of 31%. As a progressive disability to determine (27.3% on placebo, 21.7% of 7 mg / d and 20.2% at 14 mg / d Teriflunomid) was far less, however there was slightly more serious infections.

Trade names

As original drug leflunomide is distributed in both the European Union and in Switzerland under the name Arava trade and Sanofi-Aventis. Since 2010, with the generic drug leflunomide in the European Union are allowed.

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