LEFUMIDE

Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous.

Leflunomide was approved by

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

For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease.

Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use.

Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA).

RA is an auto-immune disease characterized by high T-cell activity.

T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis.

At rest, T lymphocytes meet their metabolic requirements by the salvage pathway.

Activated lymphocytes need to expand their pyrimidine pool 7.

• to 8-fold, while the purine pool is expanded only 2.

• to 3-fold.

To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis.

Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.

Dihydroorotate dehydrogenase (quinone), mitochondrial Inhibitor Protein-tyrosine kinase 2-beta Antagonist.

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

Primarily hepatic.

Leflunomide is converted to its active form following oral intake.

Hover over products below to view reaction partners Leflunomide A771726.

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.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

There have been reports of chronic overdose in patients taking leflunomide at daily dose up to five times the recommended daily dose and reports of acute overdose in adults and children.

Adverse events were consistent with the safety profile for leflunomide.

The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.

In the event of a significant overdose or toxicity, perform an accelerated drug elimination procedure to accelerate elimination.

Studies with both hemodialysis and

CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide, the primary metabolite of leflunomide, is not dialyzable.

Leflunomide tablets are contraindicated in

Pregnant women.

Leflunomide may cause fetal harm.

If a woman becomes pregnant while taking this drug, stop leflunomide, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure.

Patients with severe hepatic impairment.

Patients with known hypersensitivity to leflunomide or any of the other components of leflunomide tablets.

Known reactions include anaphylaxis.

Patients being treated with teriflunomide.

Severe hepatic impairment.

Hypersensitivity to leflunomide tablet or any of its inactive components.

Current teriflunomide treatment.

Loading dosage for patients at low risk for leflunomide -associated hepatotoxicity and leflunomide -associated myelosuppression: 100 mg daily for 3 days.

Maintenance dosage: 20 mg daily.

Maximum recommended daily dosage: 20 mg once daily.

If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily.

Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting leflunomide tablets. 2.1 Recommended Dosage The recommended dosage of Leflunomide is 20 mg once daily.

Treatment may be initiated with or without a loading dose, depending upon the patient's risk of leflunomide -associated hepatotoxicity and leflunomide associated myelosuppression.

The loading dosage provides steady-state concentrations more rapidly.

For patients who are at low risk for leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression the recommended leflunomide loading dosage is 100 mg once daily for 3 days.

Subsequently administer 20 mg once daily.

For patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide dosage is 20 mg once daily without a loading dose.

The maximum recommended daily dosage is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1).

Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma.

After stopping leflunomide treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide.

Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide. 2.2 Evaluation and Testing Prior to Starting leflunomide tablets Prior to starting leflunomide treatment the following evaluations and tests are recommended: Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts For females of reproductive potential, pregnancy testing Check blood pressure.

Tablets, USP Strength Quantity NDC Number Description 10 mg 30 count bottle 62135-793-30 White, round bi-convex tablet debossed with "HP 43" on one side and plain on the other. 20 mg 30 count bottle 62135-794-30 White, triangular bi-convex tablet debossed with "HP 44" on one side and plain on the other.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from light.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to leflunomide during pregnancy.

Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit a-study/.

Leflunomide is contraindicated for use in pregnant women because of the potential for fetal harm.

In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of and equivalent to the maximum recommended human dose (MRHD) based on AUC, respectively in rats and rabbits, caused teratogenicity (rats and rabbits) and embryo-lethality (rats) .

Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of leflunomide during pregnancy.

The background risk of major birth defects and miscarriage for the indicated populations is unknown.

The background risk in the

U.S. general population of major birth defects is to 4% and of miscarriage is to 20% of clinically recognized pregnancies.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with leflunomide, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) .

Fetal/Neonatal adverse reactions Lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from leflunomide.

The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L. .

In an embryofetal development study, pregnant rats administered leflunomide during organogenesis from gestation days to 19 at a dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microophthalmia and internal hydrocephalus, were observed.

Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses.

In an embryofetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days to 18 at a dose approximately equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed.

Leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in both rats and rabbits).

In a pre.

• and post-natal development study, when female rats were treated leflunomide at a dose that was approximately 1/100 of the MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival.

The safety and effectiveness of leflunomide in pediatric patients have not been established.

The safety and effectiveness of leflunomide in the treatment of polyarticular course juvenile idiopathic arthritis (JIA) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (JIA) as defined by the American College of Rheumatology (ACR).

In this population, leflunomide treatment was found not to be effective.

The safety of leflunomide was studied in 74 patients with polyarticular course JIA ranging in age from to 17 years (47 patients from the active-controlled study and from an open-label safety and pharmacokinetic study).

The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness.

Less common adverse events included anemia, hypertension, and weight loss.

Fourteen pediatric patients experienced

ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between and 8-fold the upper limit of normal.

Of the total number of subjects in controlled clinical trials (Trials 1, 2, and 3) of leflunomide, 234 subjects were 65 years and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment is needed in patients over 65.