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1 INDICATIONS AND USAGE Leflunomide Tablets, USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Leflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. ( 1 )

2 DOSAGE AND ADMINISTRATION Loading dosage for patients at low risk for leflunomide -associated hepatotoxicity and leflunomide -associated myelosuppression: 100 mg daily for 3 days. ( 2.1 ) Maintenance dosage: 20 mg daily. ( 2.1 ) Maximum recommended daily dosage: 20 mg once daily. ( 2.1 ) If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily. ( 2.1 ) Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting leflunomide tablets.( 2.2 ) 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 [see Warnings and Precautions ( 5.2 , 5.4 )]. 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 [see Clinical Pharmacology (12.3) ]. After stopping leflunomide treatment, an accelerated drug elimination procedure is recommended…

12.1 Mechanism of Action 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.2) ] Immunosuppression [see Warnings and Precautions (5.4) ] Bone marrow suppression [see Warnings and Precautions (5.4) ] Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.5) ] Peripheral neuropathy [see Warnings and Precautions (5.7) ] Interstitial lung disease [see Warnings and Precautions (5.8) ] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.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 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years. Elevation of Liver Enzymes 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 1 and Trial 2. It was notable…

4 CONTRAINDICATIONS 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 [see Warnings and Precautions ( 5.1 and 5.3 ) and Use in Specific Populations (8.1) ]. Patients with severe hepatic impairment [see Warnings and Precautions (5.2) ]. Patients with known hypersensitivity to leflunomide or any of the other components of leflunomide tablets. Known reactions include anaphylaxis [see Adverse Reactions (6.1) ]. Patients being treated with teriflunomide [see Drug Interactions (7) ]. Pregnancy. ( 4 , 5.1 , 8.1 ) Severe hepatic impairment. ( 4 , 5.2 ) Hypersensitivity to leflunomide tablet or any of its inactive components. ( 4 ) Current teriflunomide treatment. ( 4 )

5 WARNINGS AND PRECAUTIONS After stopping leflunomide, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. ( 5.3 ) Severe infections (including sepsis), pancytopenia, agranulocytosis and thrombocytopenia: Stop leflunomide and use accelerated elimination procedure. Do not start leflunomide in patients with active infection. Monitor CBCs during treatment with leflunomide. ( 5.4 ) Stevens-Johnson syndrome and toxic epidermal necrolysis: Stop leflunomide and use accelerated elimination procedure. ( 5.5 ) Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy evaluate patient and consider discontinuing leflunomide. ( 5.7 ) Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide and initiation of accelerated elimination procedure. ( 5.8 ) Increased blood pressure: Monitor and treat. ( 5.10 ) 5.1 Embryo-Fetal Toxicity Leflunomide may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level [see Use in Specific Populations (8.1) ]. Leflunomide is contraindicated for use in pregnant women [see Contraindications (4) ] . Exclude pregnancy before starting treatment with leflunomide in females of reproductive potential [see Dosage and Administration (2.2) ] . Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated drug elimination procedure after leflunomide treatment [see Use in Specific Populations (8.3) ]. If a woman becomes pregnant while taking leflunomide, stop treatment with leflunomide, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active…

7 DRUG INTERACTIONS Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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. Effect of potent CYP and transporter inducers Leflunomide is metabolized by CYP450 metabolizing enzymes. Concomitant use of leflunomide and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when co-administered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for leflunomide when coadministered with rifampin. Because of the potential for leflunomide concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide and rifampin [see Clinical Pharmacology (12.3) ]. Effect on CYP2C8 substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking leflunomide, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3) ]. Effect on warfarin Coadministration of leflunomide with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of leflunomide, may decrease peak INR by approximately 25%. Effect on oral contraceptives Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with leflunomide [see Clinical Pharmacology (12.3) ] Effect on CYP1A2 substrates Teriflunomide, the active metabolite of…