Leflunomide

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 46708-436

Application: ANDA091369

Effective: 20230130

1 INDICATIONS AND USAGE Leflunomide tablets USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Leflunomide is 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. (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 to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions (5.3)] . Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide [see Clinical Pharmacology (12.3)] . 2.2 Evaluation and Testing Prior to Starting Leflunomide Prior to starting leflunomide treatment the following evaluations and tests are recommended: · Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions (5.4)] · Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions (5.2, 5.4)] · For females of reproductive potential, pregnancy testing [see Warnings and Precautions (5.1)] · Check blood pressure [see Warnings and Precautions (5.10)]

4 CONTRAINDICATIONS Leflunomide is 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. 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 or any of its inactive components. (4) · Current teriflunomide treatment. (4)

Not available.

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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatc 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 that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. Table 1. Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3* Trial 1 Trial 2 Trial 3* Leflunomide 20 mg/day (n=182) PL (n=118) MTX 7.5 to 15 mg/wk(n=182) Leflunomide 20mg/day (n=133) PL (n=92) SSZ 2 g/day (n=133) Leflunomide 20 mg/day(n=501) MTX 7.5 to 15 mg/wk (n=498) ALT (SGPT) >3-fold ULN (n %) Reversed to≤ 2­foldULN: 8(4.4) 8 3(2.5) 3 5(2.7) 5 2(1.5) 2 1(1.1) 1 2(1.5) 2 13(2.6) 12 83 (16.7) 82 Timing of Elevation 0 to 3 Months 6 1 1 2 1 2 7 27 4 to 6 Months 1 1 3 - - - 1 34 7 to 9 Months 1 1 1 - - - - 16 10 to 12 Months - - - - - - 5 6 MTX = methotrexate,PL = placebo,SSZ = sulfasalazine, ULN = Upper limitofnormal *Only10% ofpatients in Trial 3 receivedfolate.All patients in Trial 1 receivedfolate. 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. Most Common Adverse Reactions 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. Percentage Of Patients With Adverse Events ³ 5% In Any Leflunomide Treated Group in all RA Studies in Patients with RA Placebo-Controlled Trials Active-Controlled Trials All RA Studies Trial 1 and 2 Trial 3 1 Leflunomide 20 mg/day(N=315) PL (N=210) SSZ 2 g/day (N=133) MTX 7.5 to 15 mg/wk (N=182) Leflunomide 20 mg/day(N=501) MTX 7 .5 to 15 mg/wk (N=498) Leflunomide (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% AbnormalLiverEnzymes 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/AbdominalPain 6% 4% 7% 8% 8% 8% 5% AbdominalPain 5% 4% 4% 8% 6% 4% 6% AllergicReaction 5% 2% 0% 6% 1% 2% 2% Bronchitis 5% 2% 4% 7% 8% 7% 7% Dizziness 5% 3% 6% 5% 7% 6% 4% MouthUlcer 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% MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 1 Only 10% of patients in Trial3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate. 2 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months). 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. Less Common Adverse Reactions 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. Blood and Lymphatic 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. Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia; Infection: opportunistic infections, severe infections including sepsis; Gastrointestinal: acute hepatic necrosis, colitis, including microscopic 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.