DESCRIPTION
Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2

PHARMACOLOGICAL ACTION
Pharmacodynamics
Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase and has antiproliferative activity.

Pharmacokinetics
Absorption
Following oral administration, peak levels of the active metabolite, occurred between 6 - 12 hours after dosing. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on active metabolite plasma levels.
Distribution
Active metabolite has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound (>99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations.
Metabolism
Leflunomide is metabolized to one primary active metabolite and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of leflunomide metabolism is unknown
Elimination
The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion.

DOSAGE AND ADMINISTRATION
Due to the long half-life in patients with RA and recommended dosing interval (24 hours) Leflunomide therapy is to be initiated with a loading dose of 100 mg (as a single dose) per day for 3 days, to be followed by a daily recommended dose of 20 mg for the treatment of patients with RA. If leflunomide 20 mg/day is not well tolerated clinically, the dose may be reduced to 10 mg daily. The total daily dose should not exceed 20 mg/day.
Liver enzymes are advised to be monitored and dose adjustments may be required. As the half-life of the active metabolite of leflunomide is long, patients need to be carefully observed after dose reduction, as it may take a few weeks for metabolite levels to decline.

CONTRAINDICATIONS
leflunomide is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of leflunomide.

ADVERSE EFFECTS
Body as a Whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain
Cardiovascular: angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation
Gastrointestinal: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder
Endocrine: diabetes mellitus, hyperthyroidism
Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis
Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema
Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture
Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo
Respiratory System: asthma, dyspnea, epistaxis, lung disorder
Skin and Appendages: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin
Special Senses: blurred vision, cataract, conjunctivitis, eye disorder, taste perversion
Urogenital System: albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis

WARNINGS AND PRECAUTIONS
Pregnancy
Pregnancy Category X
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers
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 to initiate treatment with leflunomide, taking into account the importance of the drug to the mother.

Renal Impairment
There is no clinical experience in the use of leflunomide in patients with renal impairment. Caution should be used when administering this drug in the said population.

Hepatic Impairment
The use of leflunomide is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses.

INTERACTIONS
No significant drug interaction have been reported with hepatotoxic drugs, NSAIDs and Tolbutamide.
Cholestyramine and Charcoal:
Administration of cholestyramine or activated charcoal in patients, resulted in a rapid and significant decrease in plasma active metabolite.
Rifampin:
Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, active metabolite peak levels were increased (~40%) over those seen when leflunomide was given alone. Because of the potential for leflunomide levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide and rifampin.

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

STORAGE
Store at room temperature.
Protect from light, heat and moisture.
Keep all medicines out of the reach of children.

PRESENTATION
Lefanor 10 mg tablet Alu Alu blister of 30s
Lefanor 20 mg tablet Alu Alu blister of 30s