ARAVA

Tablets, USP is a pyrimidine synthesis inhibitor.

The chemical name for leflunomide is

N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide.

It has an empirical formula

C 12 H 9 F 3 N 2 O 2, 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.

Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and talc. "Image Description".

The drug is used to treat rheumatoid arthritis.

Pre-infestation, hepatic disease, leukemia, anemia, arrhythmia, and arrhythmia.

The use of immune system, such as cancer drugs, is a risk of anaemic infection.

Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial 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. 12.3 Pharmacokinetics Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity.

Plasma concentrations of the parent drug, leflunomide, have been occasionally seen at very low concentrations.

Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of the active metabolite, teriflunomide.

Following oral administration, peak teriflunomide concentrations occurred between to 12 hours after dosing.

Due to the very long half-life of teriflunomide (18 to 19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations.

Without a loading dose, it is estimated that attainment of steady.

• state plasma concentrations would require about two months of dosing.

The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional.

Co-administration of leflunomide with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.

Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma.

The volume of distribution is 11 L after a single intravenous (IV) administration.

Teriflunomide, the active metabolite of leflunomide, has a median half-life of to 19 days in healthy volunteers.

The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal.

Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, due to individual variation in drug clearance.

After a single

IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h.

In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in leflunomide metabolism.

In vivo, leflunomide is metabolized to one primary (teriflunomide) and many minor metabolites.

In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes.

The parent compound is rarely detectable in plasma.

Teriflunomide, the active metabolite of leflunomide, is eliminated by direct biliary excretion of unchanged drug as well as renal excretion of metabolites.

Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%).

After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).

Studies with both hemodialysis and

CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialyzable.

Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide.

A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.

Drug interaction studies have been conducted with both leflunomide and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

The Potential Effect of Other Drugs on leflunomide Potent CYP and transporter inducers: Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when leflunomide was given alone.

• An in vivo interaction study with leflunomide and cimetidine (non-specific weak CYP inhibitor) has demonstrated a lack of a significant impact on teriflunomide exposure.

The Potential Effect of leflunomide on Other Drugs.

• CYP2C8 Substrates There was an increase in mean repaglinide C max and AUC (1.7-and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo.

The magnitude of interaction could be higher at the recommended repaglinide dose.

• CYP1A2 Substrates Repeated doses of teriflunomide decreased mean C max and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.

• OAT3 Substrates There was an increase in mean cefaclor C max and AUC (1.43-and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo.

• BCRP and OATP1B1/1B3 Substrates There was an increase in mean rosuvastatin C max and AUC (2.65-and 2.51-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) .

• Oral Contraceptives There was an increase in mean ethinylestradiol C max and AUC 0-24 (1.58-and 1.54-fold, respectively) and levonorgestrel C max and AUC 0-24 (1.33-and 1.41-fold, respectively) following repeated doses of teriflunomide.

• Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate). "Image Description".

AVD is used to treat the anti-Romantic infection with a dose of continuous arthritis after using a dose of 100 mg for 3 days, where a single disc is taken, once a day.

The feeling of the full effect of the drug may take four to six months.

The effects of the

ARAVA pills include the following: the rise of liver enzymes, the skin rash.

The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity Immunosuppression Bone marrow suppression Stevens-Johnson syndrome and toxic epidermal necrolysis Peripheral neuropathy Interstitial lung disease The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia.

To report SUSPECTED ADVERSE

REACTIONS, contact Chartwell RX, LLC.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with leflunomide administered as either monotherapy or in combination with methotrexate or sulfasalazine.

Patients ranged in age from to 85 years, with an overall median age of 58 years.

The mean duration of

RA was 6 years ranging from to 45 years.

Treatment with leflunomide was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible.

Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment.

Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment.

Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial and Trial 2.

It was notable that the absence of folate use in Trial was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.

Table 1.

Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3* Trial 1 Trial 2 Trial 3 LEF 20 mg/day (n=182) PL (n=118) MTX 7.5-15 mg/wk (n=182) LEF 20mg/day (n=133) PL (n=92) SSZ 2.0 g/day LEF 20 mg/day (n=501) MTX 7.5-15 mg/wk (n=498) ALT(SGPT)>3-fold ULN (n%) 8 3 5 2 1 2 13 83 Reversed to ≤ 2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0.

• 3 Months 4.

• 6 Months 7.

• 9 Months 10.

• 12 Months 6 1 1.

• 5 27 34 16 6 LEF = leflunomide, MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal *Only 10% of patients in Trial 3 received folate.

All patients in

Trial 1 received folate.

In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed.

An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo.

The most common adverse reactions in leflunomide-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash.

Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year (≥5% in any leflunomide treatment group).

Table 2.

Events ≥ 5% In Any Leflunomide Treated Group in all RA Studies in Patients with RA Placebo-Controlled Trials Active-Controlled Trials All RA Studies Trial and 2 Trial 3 1 LEF 20 mg/day (N=315) PL (N=210) SSZ 2.0g/day (N=133) MTX 7.5-15 mg/wk (N=182) LEF 20 mg/day (N=501) MTX 7.5–15 mg/wk (N=498) LEF (N=1339) 2 Diarrhea 27% 12% 10% 20% 22% 10% 17% Headache 13% 11% 12% 21% 10% 8% 7% Nausea 13% 11% 19% 18% 13% 18% 9% Rash 12% 7% 11% 9% 11% 10% 10% Abnormal Liver Enzymes 10% 2% 4% 10% 6% 17% 5% Alopecia 9% 1% 6% 6% 17% 10% 10% Hypertension 3 9% 4% 4% 3% 10% 4% 10% Asthenia 6% 4% 5% 6% 3% 3% 3% Back Pain 6% 3% 4% 9% 8% 7% 5% GI/Abdominal Pain 6% 4% 7% 8% 8% 8% 5% Abdominal Pain 5% 4% 4% 8% 6% 4% 6% Allergic Reaction 5% 2% 0% 6% 1% 2% 2% Bronchitis 5% 2% 4% 7% 8% 7% 7% Dizziness 5% 3% 6% 5% 7% 6% 4% Mouth Ulcer 5% 4% 3% 10% 3% 6% 3% Pruritus 5% 2% 3% 2% 6% 2% 4% Rhinitis 5% 2% 4% 3% 2% 2% 2% Vomiting 5% 4% 4% 3% 3% 3% 3% Tenosynovitis 2% 0% 1% 2% 5% 1% 3% LEF = leflunomide, MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 1 Only 10% of patients in Trial3 received folate.

Trial 1 received folate; none in Trial 2 received folate.

Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 3 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials.

Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.

In addition, in controlled clinical trials, the following adverse events in the leflunomide treatment group occurred at a higher incidence than in the placebo group.

These adverse events were deemed possibly related to the study drug.

System: leukocytosis, thrombocytopenia; Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein; Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage; Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma.

• GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth; General.

Disorders: malaise; Immune System: anaphylactic reaction; Infection: abscess, flu syndrome, vaginal moniliasis; Nervous System: dizziness, headache, somnolence; Respiratory System: dyspnea; 6.2 Post Marketing Experience The following additional adverse reactions have been identified during postapproval use of leflunomide.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

System: agranulocytosis, leukopenia, neutropenia, pancytopenia; Infection: opportunistic infections, severe infections including sepsis; Gastrointestinal: acute hepatic necrosis, colitis, including microscpic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure Immune System: angioedema; Nervous system: peripheral neuropathy; Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; pulmonary hypertension; Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.

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.