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 )

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)] • Serious infections [see Warnings and Precautions (5.4)] • Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms [see Warnings and Precautions (5.5)] • Skin ulcers [see Warnings and Precautions (5.6)] • Peripheral neuropathy [see Warnings and Precautions (5.8)] • Interstitial lung disease [see Warnings and Precautions (5.9)] · The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 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 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 %) 8(4.4) 3(2.5) 5(2.7) 2(1.5) 1(1.1) 2(1.5) 13(2.6) 83(16.7) Reversed to ≤2­foldULN: 8 3 5 2 1 2 12 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 limit of normal *Only 10% ofpatients in Trial 3 receivedfolate.

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.

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 Ev ent s ≥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* 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) † 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 ‡ 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 *Only 10% of patients in Trial 3 received folate.

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

† Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months).

‡ 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 Postmarketing 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, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis