Leflunomide

Uses

Leflunomide is used for adults for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms and to retard structural damage as manifested by x-ray erosions and joint space narrowing .

Leflunomide is also used to associated treatment for these conditions: Juvenile Idiopathic Arthritis (JIA), Rheumatoid Arthritis

How Leflunomide works

Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells.

Dosage

Leflunomide dosage

Leflunomide once-daily oral dosing for rheumatoid arthritis patients. After a loading dose of 100 mg once daily for 3 days, the maintenance dose is 20 mg once daily. Leflunomide does not require step wise dose increment over time. The dose may be decreased to 10 mg daily if tolerability issues arise.

Side Effects

Adverse reactions associated with the use of leflunomide include diarrhea, nausea, vomiting, abdominal pain, headache, respiratory infection, bronchitis, elevated liver enzymes, aggravation of pre-existing hypertension, alopecia, and rash.

Toxicity

LD₅₀=100-250 mg/kg (acute oral toxicity)

Precaution

Caution should be taken for those female with child bearing potential who are not using reliable contraception and for the subject of renal insufficiency. Leflunomide should be stopped before becoming pregnant. Liver function should be monitored before starting treatment.

Interaction

Cholestyramine and activated charcoal may decrease plasma concentration of active metabolite. Concurrent use of methotrexate and other hepatotoxic drugs may increase the risk of hepatotoxicity. Rifampicin increases serum levels of the active metabolite.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

[Moderate] GENERALLY AVOID: The consumption of alcohol during therapy with leflunomide may potentiate the risk of liver injury.

Leflunomide has been associated with hepatotoxicity, including elevated liver transaminases, hepatitis, jaundice
MANAGEMENT: Patients should be advised to avoid excessive alcohol use during leflunomide treatment.

Leflunomide Hypertension interaction

[Moderate] Hypertension was reported as an adverse reaction in patients on leflunomide.

Blood pressure should be monitored during treatment and periodically thereafter as this agent can increase the blood pressure in these patients.

Leflunomide Drug Interaction

Major: duloxetine, duloxetine, etanercept, etanercept, adalimumab, adalimumab, hydroxychloroquine, hydroxychloroquineUnknown: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, pregabalin, pregabalin, levothyroxine, levothyroxine, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Leflunomide Disease Interaction

Major: immunosuppression, liver disease, peripheral neuropathy, pulmonary toxicity, renal dysfunction, tuberculosisModerate: hypertension

Volume of Distribution

• 0.13 L/kg

Elimination Route

Well absorbed, peak plasma concentrations appear 6-12 hours after dosing

Half Life

2 weeks

Elimination Route

The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide.

Pregnancy & Breastfeeding use

Pregnancy: Leflunomide is not recommended for pregnant women. Pregnancy must be avoided during leflunomide treatment or prior to the completion of the drug elimination procedure after leflunomide treatment.

Nursing Mother: Leflunomide should not be used by nursing mothers. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk and there is a potential for serious adverse reactions in nursing infants from leflunomide. Therefore, a decision should be made whether to proceed with nursing or initiate treatment with leflunomide, taking into account the importance of the drug to the mother.

Contraindication

Leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide, hepatic impairment, severe uncontrolled infections and bone marrow dysplasia.

Acute Overdose

There is no human experience regarding leflunomide over dosage. In the event of a significant overdose or toxicity, cholestyramine or charcoal administration is recommended to accelerate elimination.

Storage Condition

Store at 25°C.

Innovators Monograph

You find simplified version here Leflunomide