LEFLUNOMIDE- leflunomide tablet
Golden State Medical Supply, Inc.
PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH LEFLUNOMIDE. LEFLUNOMIDE IS CONTRAINDICATED IN PREGNANT WOMEN, OR WOMWN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTACEPTION. (SEE CONTRAINDICATIONS AND WARNINGS). PREGNANCY MUST BE AVOIDED DURING LEFLUNOMIDE TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINAT PROCEDURE AFTER LEFLUNOMIDE TREATMENT.
SEVERE LIVER INJURY, INCLUDING FATAL LIVER FAILURE, HAS BEEN REPORTED IN SOME PATIENTS TREATED WITH LEFLUNOMIDE. PATIENTS WITH PRE-EXISTING ACUTE OR CHRONIC LIVER DISEASE, OR THOSE WITH SERUM ALANINE AMINOTRANSFERADE (ALT) >2xULN BEFORE INITIATING TREATMENT, SHOULD NOT BE TREATED WITH LEFLUNOMIDE. USE CAUTION WHEN LEFLUNOMIDE IS GIVEN WITH OTHER POTENTIALLY HEPATOTOXIC DRUGS.
MONITORING OF ALT LEVELS IS RECOMMENDED AT LEAST MONTHLY FOR SIX MONTHS AFTER STARTING LEFLUNOMIDE, AND THEREAFTER EVERY SIX TO EIGHT WEEKS. IF ALTELEVATION > 3 FOLD ULN OCCURS, INTERRUPT LEFLUNOMIDE THERAPY WHILE INVESTIGATING THE PROBABLE CAUSE OF THE ALT ELEVATION BY CLOSE OBSERVATION AND ADDITIONAL TESTS. IF LIKELY LEFLUNOMIDE-INDUCED, START CHOLESTYRAMINE WASHOUT AND MONITOR LIVER TESTS WEEKLY UNTIL NORMALIZED. IF LEFLUNOMIDE-INDUCED LIVER INJURY IS UNLIKELY BECAUSE SOME OTHER PROBABLE CAUSE HAS BEEN FOUND, RESUMPTION OF LEFLUNOMIDE THERAPY MAY BE CONSIDERED. (SEE WARNINGS –HEPATOTOXICITY).
Leflunomide is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12 H9 F3 N2 O2 , a molecular weight of 270.2 and the following structural formula:
Leflunomide is available for oral administration as tablets containing 10 or 20 mg of active drug. Each Leflunomide Tablet, USP contains anhydrous lactose, colloidal silicon dioxide, crospovidone, and magnesium stearate.
Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite.
Following oral administration, peak levels of the active metabolite, M1, occurred between 6 to 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.
|Maintenance (Loading) Dose|
|Parameter||5 mg (50 mg)||10 mg (100 mg)||25 mg (100 mg)|
|C24 (Day 1) (mcg/mL)1||4.0 ± 0.6||8.4 ± 2.1||8.5 ± 2.2|
|C24 (ss) (mcg/mL)2||8.8 ± 2.9||18 ± 9.6||63 ± 36|
|t1/2 (DAYS)||15 ± 3||14 ± 5||18 ± 9|
|1 Concentration at 24 hours after loading dose |
2 Concentration at 24 hours after maintenance doses at steady state
Relative to an oral solution, leflunomide tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.
M1 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. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.
Leflunomide is metabolized to one primary (M1) 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. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism.
The active metabolite M1 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. Subsequent analysis of the samples revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr.
In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from >1 week to approximately 1 day (see PRECAUTIONS — General — Need for Drug Elimination), Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable.
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