Arava

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 ARAVA treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 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 ARAVA 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 ARAVA 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 Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate. Trial 1 Trial 2 Trial 3 ARAVA PL MTX ARAVA PL SSZ ARAVA MTX 20 mg/day (n= 182) (n=118) 7.5–15 mg/wk (n=182) 20 mg/day (n=133) (n=92) 2 g/day (n=133) 20 mg/day (n=501) 7.5–15 mg/wk (n=498) MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal 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 ≤2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0–3 Months 6 1 1 2 1 2 7 27 4–6 Months 1 1 3 - - - 1 34 7–9 Months 1 1 1 - - - - 16 10–12 Months - - - - - - 5 6 In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, ARAVA 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 ARAVA-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 ARAVA treatment group). Table 2: Percentage Of Patients With Adverse Events ≥5% In Any ARAVA 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 Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate. ARAVA 20 mg/day (n=315) PL (n=210) SSZ 2 g/day (n=133) MTX 7.5–15 mg/wk (n=182) ARAVA 20 mg/day (n=501) MTX 7.5–15 mg/wk (n=498) ARAVA (n=1339) Includes all controlled and uncontrolled trials with ARAVA (duration up to 12 months). MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 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 Hypertension as a preexisting condition was overrepresented in all ARAVA treatment groups in phase III trials. 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% Adverse events during a second year of treatment with ARAVA 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 ARAVA 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 ARAVA. 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, skin ulcer

4 CONTRAINDICATIONS ARAVA is contraindicated in: Pregnant women. ARAVA may cause fetal harm. If a woman becomes pregnant while taking this drug, stop ARAVA, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see Warnings and Precautions (5.1 , 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 ARAVA. 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 ARAVA or any of its inactive components. ( 4 ) Current teriflunomide treatment. ( 4 )

11 DESCRIPTION ARAVA (leflunomide) 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: ARAVA is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only). Chemical Structure

2 DOSAGE AND ADMINISTRATION Loading dosage for patients at low risk for ARAVA-associated hepatotoxicity and ARAVA-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 ARAVA. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of ARAVA is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression. The loading dose provides steady-state concentrations more rapidly. For patients who are at low risk for ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression, the recommended ARAVA loading dose is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for ARAVA-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or ARAVA-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended ARAVA dosage is 20 mg once daily without a loading dose [see Warnings and Precautions (5.2 , 5.4) ] . The maximum recommended daily dose 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 ARAVA, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3) ] . After stopping ARAVA 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 ARAVA [see Clinical Pharmacology (12.3) ] . 2.2 Evaluation and Testing Prior to Starting ARAVA Prior to starting ARAVA 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) ]

1 INDICATIONS AND USAGE ARAVA is indicated for the treatment of adults with active rheumatoid arthritis (RA). ARAVA is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. ( 1 )

10 OVERDOSAGE There have been reports of chronic overdose in patients taking ARAVA 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 ARAVA [see Adverse Reactions (6) ] . 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 [see Warnings and Precautions (5.3) ] . Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide, the primary metabolite of leflunomide, is not dialyzable [see Clinical Pharmacology (12.3) ] .

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 ARAVA (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects. Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. ( 7 ) Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. ( 7 ) Warfarin: Monitor INR as teriflunomide may decrease INR. ( 7 ) Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in patients taking ARAVA. ( 7 ) Effect of Potent CYP and Transporter Inducers Leflunomide is metabolized by CYP450 metabolizing enzymes. Concomitant use of ARAVA and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when coadministered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for ARAVA when coadministered with rifampin. Because of the potential for ARAVA concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both ARAVA and rifampin [see Clinical Pharmacology (12.3) ] . Effect on CYP2C8 Substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking ARAVA, 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 ARAVA with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of ARAVA, 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 ARAVA [see Clinical Pharmacology (12.3) ] . Effect on CYP1A2 Substrates Teriflunomide, the active metabolite of ARAVA, may be a weak inducer of CYP1A2 in vivo . In patients taking ARAVA, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3) ] . Effect on Organic Anion Transporter 3 (OAT3) Substrates Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking ARAVA, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3) ] . Effect on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) Substrates Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo . For a patient taking ARAVA, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking ARAVA [see Clinical Pharmacology (12.3) ] .

12 CLINICAL PHARMACOLOGY 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. 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. Chemical Structure Absorption Following oral administration, peak teriflunomide concentrations occurred between 6 to 12 hours after dosing. Due to the very long half-life of teriflunomide (18–19 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. Distribution 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. Elimination Teriflunomide, the active metabolite of leflunomide, has a median half-life of 18 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 [see Warnings and Precautions (5.3) ] . After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h. Metabolism 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. Excretion 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. Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide. Smoking. A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over nonsmokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers. Specific Populations The potential effect of other drugs on ARAVA Potent CYP and transporter inducers: Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when ARAVA was given alone [see Drug Interactions (7) ]. An in vivo interaction study with ARAVA and cimetidine (nonspecific weak CYP inhibitor) has demonstrated a lack of a significant impact on teriflunomide exposure. The potential effect of ARAVA 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 [see Drug Interactions (7) ]. 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 [see Drug Interactions (7) ]. 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) [see Drug Interactions (7) ]. 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 [see Drug Interactions (7) ] . 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). Drug Interaction Studies Drug interaction studies have been conducted with both ARAVA (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

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.

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. Chemical Structure Absorption Following oral administration, peak teriflunomide concentrations occurred between 6 to 12 hours after dosing. Due to the very long half-life of teriflunomide (18–19 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. Distribution 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. Elimination Teriflunomide, the active metabolite of leflunomide, has a median half-life of 18 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 [see Warnings and Precautions (5.3) ] . After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h. Metabolism 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. Excretion 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. Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide. Smoking. A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over nonsmokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers. Specific Populations The potential effect of other drugs on ARAVA Potent CYP and transporter inducers: Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, teriflunomide peak concentrations were increased (~40%) over those seen when ARAVA was given alone [see Drug Interactions (7) ]. An in vivo interaction study with ARAVA and cimetidine (nonspecific weak CYP inhibitor) has demonstrated a lack of a significant impact on teriflunomide exposure. The potential effect of ARAVA 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 [see Drug Interactions (7) ]. 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 [see Drug Interactions (7) ]. 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) [see Drug Interactions (7) ]. 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 [see Drug Interactions (7) ] . 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). Drug Interaction Studies Drug interaction studies have been conducted with both ARAVA (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

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3 DOSAGE FORMS AND STRENGTHS ARAVA Tablets are available in three strengths: Tablets: 10 mg, supplied as white, round film-coated tablet embossed with "ZBN" on one side Tablets: 20 mg, supplied as light-yellow, triangular film-coated tablet embossed with "ZBO" on one side Tablets: 100 mg, supplied as white, round film-coated tablet embossed with "ZBP" on one side Tablets: 10 mg, 20 mg, 100 mg. ( 3 )

Arava leflunomide SILICON DIOXIDE CROSPOVIDONE (120 .MU.M) HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED TALC TITANIUM DIOXIDE STARCH, CORN LEFLUNOMIDE LEFLUNOMIDE ZBN Arava leflunomide SILICON DIOXIDE CROSPOVIDONE (120 .MU.M) HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW STARCH, CORN LEFLUNOMIDE LEFLUNOMIDE ZBO Arava leflunomide SILICON DIOXIDE CROSPOVIDONE (120 .MU.M) HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL, UNSPECIFIED POVIDONE, UNSPECIFIED TALC TITANIUM DIOXIDE STARCH, CORN LEFLUNOMIDE LEFLUNOMIDE ZBP

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human teriflunomide systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human teriflunomide exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human teriflunomide exposure based on AUC). The significance of the findings in mice relative to the clinical use of ARAVA is not known. Leflunomide was not mutagenic in the Ames assay, the unscheduled DNA synthesis assay, or in the HGPRT gene mutation assay. In addition, leflunomide was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames assay and in the HGPRT gene mutation assay, and was clastogenic in the in vitro Chinese hamster cell chromosomal aberration assay. TFMA was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test. Leflunomide had no effect on fertility or reproductive performance in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human teriflunomide exposure based on AUC) [see Use in Specific Populations (8.1 , 8.6) ] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human teriflunomide systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human teriflunomide exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human teriflunomide exposure based on AUC). The significance of the findings in mice relative to the clinical use of ARAVA is not known. Leflunomide was not mutagenic in the Ames assay, the unscheduled DNA synthesis assay, or in the HGPRT gene mutation assay. In addition, leflunomide was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames assay and in the HGPRT gene mutation assay, and was clastogenic in the in vitro Chinese hamster cell chromosomal aberration assay. TFMA was not clastogenic in the in vivo mouse micronucleus assay or in the in vivo Chinese hamster bone marrow cell cytogenic test. Leflunomide had no effect on fertility or reproductive performance in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human teriflunomide exposure based on AUC) [see Use in Specific Populations (8.1 , 8.6) ] .

NDA020905

Arava

leflunomide

0088-2161

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 10 mg Carton NDC 0088-2160-30 Arava ® Tablets leflunomide 10 mg OVERSIZED CONTAINER FOR EASE OF PATIENT USE 30 Tablets sanofi aventis PRINCIPAL DISPLAY PANEL - 10 mg Carton

sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY ©2021 sanofi-aventis U.S. LLC

17 PATIENT COUNSELING INFORMATION Embryo-Fetal Toxicity Advise females of reproductive potential: Of the potential for fetal harm if ARAVA is taken during pregnancy. To notify their healthcare provider immediately if a pregnancy occurs or is suspected. To use effective contraception during treatment with ARAVA and until the active metabolite (teriflunomide) plasma concentration is verified to be less than 0.02 mg/L [see Warnings and Precautions (5.1 , 5.3) , Use in Specific Populations (8.1 , 8.3) , and Clinical Pharmacology (12.3) ] . Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise nursing women to discontinue breastfeeding during treatment with ARAVA [see Use in Specific Populations (8.2) ] . Hypersensitivity or Allergic Reactions Advise patients of the possibility of rare, serious skin reactions. Instruct patients to promptly report if they develop a skin rash or mucous membrane lesions. Investigations Advise patients of the potential hepatotoxic effects of ARAVA and of the need for monitoring liver enzymes. Instruct patients to report if they develop symptoms such as unusual tiredness, abdominal pain or jaundice. Advise patients that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with ARAVA, who have recently discontinued such therapy before starting treatment with ARAVA, or who have had a history of a significant hematologic abnormality. Instruct patients to promptly report if they notice symptoms consistent with pancytopenia, such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness. Inform patients about the early warning signs of interstitial lung disease and ask them to contact their physician promptly if these symptoms appear or worsen during therapy.

14 CLINICAL STUDIES The efficacy of ARAVA in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function. In these trials, efficacy was evaluated by: 1. Reduction of signs and symptoms Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR) 20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An "ACR20 Responder" is a patient who had ≥20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure (Modified Health Assessment Questionnaire [MHAQ]), visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An "ACR20 Responder at Endpoint" is a patient who completed the study and was an ACR20 Responder at the completion of the study. 2. Inhibition of structural damage Inhibition of structural damage compared to control was assessed using the Sharp score, a composite score of x-ray erosions and joint space narrowing in hands/wrists and forefeet. 3. Improvement in physical function Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36). In all ARAVA trials, participants of at least 18 years of age and in ARA functional class of I, II, or III received an initial loading dose of 100 mg leflunomide per day for three days, followed by 20 mg per day thereafter. Exclusion criteria included patients with a history of hypersensitivity to the study medication; women who were pregnant or breastfeeding and men or women of child bearing age and potential who had not received contraceptives for at least 4 weeks before entering the study and to be maintained throughout the study and for at least 6 months after discontinuing treatment; patients with a history of inflammatory disease, impaired renal function or liver impairment, cardiac failure, congenital or acquired immunodeficiency, impaired coagulation, or a history of recent major traumatic injury; and patients taking intra-articular or systemic concomitant medications which could affect the safety and/or efficacy of the study medication. Trial 1 Trial 1, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. The primary analysis was at 52 weeks with blinded treatment to 104 weeks. Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment. Trial 2 Trial 2 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of Trial 2 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine. Of the 168 patients who completed 12 months of treatment, 146 patients (87%) entered a 1-year extension study of double-blind active treatment; (60 leflunomide, 60 sulfasalazine, 26 placebo/sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of Trial 2. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment. Trial 3 Trial 3 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks. Of the 736 patients who completed 52 weeks of treatment in study Trial 3, 612 (83%) entered the double-blind, 1-year extension study (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of Trial 3. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment. Clinical Trial Results Clinical response The ACR20 Responder at Endpoint rates are shown in Figure 1. ARAVA was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study Trial 1 (at the primary 12 months endpoint) and Trial 2 (at 6 month endpoint). ACR20 Responder at Endpoint rates with ARAVA treatment were consistent across the 6 and 12 month studies (41%–49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. ARAVA treatment effect was evident by 1 month, stabilized by 3 to 6 months, and continued throughout the course of treatment as shown in Figure 1. Figure 1: Percentage of ACR20 Responders at Endpoint in Patients with Active RA in Trials 1, 2, and 3 Comparisons 95% Confidence Interval p Value Trial 1 ARAVA vs Placebo (12, 32) <0.0001 Methotrexate vs Placebo (8, 30) <0.0001 ARAVA vs Methotrexate (-4, 16) NS Trial 2 ARAVA vs Placebo (7, 33) 0.0026 Sulfasalazine vs Placebo (4, 29) 0.0121 ARAVA vs Sulfasalazine (-8, 16) NS Trial 3 ARAVA vs Methotrexate (-19, -7) <0.0001 Figure 2: ACR20 Responders over Time in Patients with Active RA in Trial 1* ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 3). Mean change for the individual components of the ACR Responder Index are shown in Table 4. Table 3: Summary of ACR Response Rates in Patients with Active RA in Trials 1, 2, and 3 Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who discontinued early. Study and Treatment Group ACR20 ACR50 ACR70 Placebo-Controlled Studies Trial 1 (12 months) ARAVA (n=178) n is the number of ITT patients for whom adequate data were available to calculate the indicated rates. 52 p<0.001 ARAVA vs placebo 34 20 Placebo (n=118) 26 8 4 Methotrexate (n=180) 46 23 9 Trial 2 (6 months) ARAVA (n=130) 55 33 10 p<0.02 ARAVA vs placebo Placebo (n=91) 29 14 2 Sulfasalazine (n=132) 57 30 8 Non-Placebo Active-Controlled Studies Trial 3 (12 months) ARAVA (n=495) 51 31 10 Methotrexate (n=489) 65 44 16 Table 4 shows the results of the components of the ACR response criteria for Trial 1, Trial 2, and Trial 3. ARAVA was significantly superior to placebo in all components of the ACR Response criteria in study Trial 1 and Trial 2. In addition, ARAVA was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between ARAVA and the active comparators. Table 4: Mean Change in the Components of the ACR Responder Index in Patients with Active RA in Trials 1, 2, and 3 Last Observation Carried Forward; Negative Change Indicates Improvement Components Placebo-Controlled Studies Non–Placebo-Controlled Study Trial 1 (12 months) Trial 2 Non-US (6 months) Trial 3 Non-US (12 months) Leflunomide Methotrexate Placebo Leflunomide Sulfasalazine Placebo Leflunomide Methotrexate Tender joint count Based on 28 joint count -7.7 -6.6 -3.0 -9.7 -8.1 -4.3 -8.3 -9.7 Swollen joint count -5.7 -5.4 -2.9 -7.2 -6.2 -3.4 -6.8 -9.0 Patient global assessment Visual Analog Scale - 0=Best; 10=Worst -2.1 -1.5 0.1 -2.8 -2.6 -0.9 -2.3 -3.0 Physician global assessment -2.8 -2.4 -1.0 -2.7 -2.5 -0.8 -2.3 -3.1 Physical function/disability (MHAQ/HAQ) -0.29 -0.15 0.07 -0.50 -0.29 -0.04 -0.37 -0.44 Pain intensity -2.2 -1.7 -0.5 -2.7 -2.0 -0.9 -2.1 -2.9 Erythrocyte Sedimentation rate -6.26 -6.48 2.56 -7.48 -16.56 3.44 -10.12 -22.18 C-reactive protein -0.62 -0.50 0.47 -2.26 -1.19 0.16 -1.86 -2.45 Not included in the ACR Responder Index Morning Stiffness (min) -101.4 -88.7 14.7 -93.0 -42.4 -6.8 -63.7 -86.6 Figure 1 Figure 2 Maintenance of effect After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years). ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment. Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of ARAVA treatment in all three trials. Radiographic Response The change from baseline to endpoint in progression of structural disease, as measured by the Sharp x-ray score, is displayed in Figure 3. ARAVA was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp score. No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. Figure 3: Change in Sharp Score in Patients with Active RA in Trials 1, 2, and 3 Comparisons 95% Confidence Interval p Value Trial 1 ARAVA vs Placebo (-4.0, -1.1) 0.0007 Methotrexate vs Placebo (-2.6, -0.2) 0.0196 ARAVA vs Methotrexate (-2.3, 0.0) 0.0499 Trial 2 ARAVA vs Placebo (-6.2, -1.8) 0.0004 Sulfasalazine vs Placebo (-6.9, 0.0) 0.0484 ARAVA vs Sulfasalazine (-3.3, 1.2) NS Trial 3 ARAVA vs Methotrexate (-2.2, 7.4) NS Figure 3 Physical Function Response The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12-month placebo and active-controlled trials is shown in Figure 4. ARAVA was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip, and activities) in both placebo controlled studies. The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In Trial 1, at 12 months, ARAVA provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score. Figure 4: Change in Functional Ability Measure in Patients with Active RA in Trials 1, 2, and 3* Comparison 95% Confidence Interval p Value Trial 1 ARAVA vs Placebo (-0.58, -0.29) 0.0001 ARAVA vs Methotrexate (-0.34, -0.07) 0.0026 Trial 2 ARAVA vs Placebo (-0.67, -0.36) <0.0001 ARAVA vs Sulfasalazine (-0.33, -0.03) 0.0163 Trial 3 ARAVA vs Methotrexate (0.01, 0.16) 0.0221 Figure 4 Maintenance of effect The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.

8.5 Geriatric Use Of the total number of subjects in controlled clinical trials (Trials 1, 2, and 3) of ARAVA, 234 subjects were 65 years and over [see Clinical Studies (14) ] . 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.

8.4 Pediatric Use The safety and effectiveness of ARAVA in pediatric patients have not been established. The safety and effectiveness of ARAVA 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, ARAVA treatment was found not to be effective. The safety of ARAVA was studied in 74 patients with polyarticular course JIA ranging in age from 3–17 years (47 patients from the active-controlled study and 27 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, and five between 3 and 8-fold the upper limit of normal.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in-a-study/. Risk Summary ARAVA 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) [see Data ] . Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of ARAVA 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 2%–4% and of miscarriage is 15%–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 ARAVA, 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) [see Warnings and Precautions (5.3) ] . Clinical Considerations 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 ARAVA. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . Data Animal data In an embryo-fetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 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 microphthalmia 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 embryo-fetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 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 postnatal development study, when female rats were treated with 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.

8 USE IN SPECIFIC POPULATIONS Lactation: Discontinue breastfeeding. ( 8.2 ) Safety and effectiveness in pediatric patients <12 years of age have not been established. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in-a-study/. Risk Summary ARAVA 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) [see Data ] . Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of ARAVA 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 2%–4% and of miscarriage is 15%–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 ARAVA, 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) [see Warnings and Precautions (5.3) ] . Clinical Considerations 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 ARAVA. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . Data Animal data In an embryo-fetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 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 microphthalmia 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 embryo-fetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 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 postnatal development study, when female rats were treated with 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. 8.2 Lactation Risk Summary Clinical lactation studies have not been conducted to assess the presence of ARAVA in human milk, the effects of ARAVA on the breastfed child, or the effects of ARAVA on milk production. Because of the potential for serious adverse reactions in a breastfed infant from ARAVA, advise a nursing woman to discontinue breastfeeding during treatment with ARAVA. 8.3 Females and Males of Reproductive Potential ARAVA may cause fetal harm when administered during pregnancy. Advise females of the potential risk to the fetus. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see Use in Specific Populations (8.1) ] . Women receiving ARAVA treatment who wish to become pregnant should discontinue ARAVA and undergo an accelerated drug elimination procedure to achieve plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3) ] . Pregnancy Testing Exclude pregnancy in females of reproductive potential before starting treatment with ARAVA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with ARAVA and while undergoing a drug elimination procedure until verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) ] . 8.4 Pediatric Use The safety and effectiveness of ARAVA in pediatric patients have not been established. The safety and effectiveness of ARAVA 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, ARAVA treatment was found not to be effective. The safety of ARAVA was studied in 74 patients with polyarticular course JIA ranging in age from 3–17 years (47 patients from the active-controlled study and 27 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, and five between 3 and 8-fold the upper limit of normal. 8.5 Geriatric Use Of the total number of subjects in controlled clinical trials (Trials 1, 2, and 3) of ARAVA, 234 subjects were 65 years and over [see Clinical Studies (14) ] . 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. 8.6 Hepatic Impairment Dedicated studies of the effect of hepatic impairment on leflunomide pharmacokinetics have not been conducted. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of ARAVA in patients with hepatic impairment is not recommended. 8.7 Renal Impairment Dedicated studies of the effect of renal impairment on leflunomide pharmacokinetics have not been conducted. Given that the kidney plays an important role in drug elimination, caution should be used when ARAVA is administered to these patients.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ARAVA (leflunomide) Tablets Strength Quantity NDC Number Description 10 mg 30 count bottle 0088-2160-30 White, round film-coated tablet embossed with "ZBN" on one side. 20 mg 30 count bottle 0088-2161-30 Light yellow, triangular film-coated tablet embossed with "ZBO" on one side. 100 mg 3 count blister pack 0088-2162-33 White, round film-coated tablet embossed with "ZBP" on one side. Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.

WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY See full prescribing information for complete boxed warning. Embryo-Fetal Toxicity Teratogenicity and embryo-lethality occurred in animals administered leflunomide. ( 5.1 , 8.1 ) Exclude pregnancy prior to initiating ARAVA therapy. ( 5.1 , 8.3 ) Advise use of effective contraception in females of reproductive potential during treatment and during a drug elimination procedure. ( 5.1 , 5.3 , 8.3 ) Stop ARAVA and use an accelerated drug elimination procedure if the patient becomes pregnant. ( 5.1 , 5.3 , 8.1 ) Hepatotoxicity Severe liver injury and fatal liver failure have been reported. ( 5.2 ) Avoid ARAVA use in patients with pre-existing liver disease, or those with serum alanine aminotransferase (ALT) >2 × ULN. ( 5.2 , 8.6 ) Use caution when ARAVA is given with other potentially hepatotoxic drugs. ( 5.2 ) Monitor ALT levels. Interrupt ARAVA treatment if ALT elevation >3-fold ULN. If likely leflunomide-induced, start accelerated drug elimination procedure and monitor liver tests weekly until normalized. ( 5.2 , 5.3 ) Embryo-Fetal Toxicity ARAVA is contraindicated for use in pregnant women because of the potential for fetal harm. Teratogenicity and embryo-lethality occurred in animals administered leflunomide at doses lower than the human exposure level. Exclude pregnancy before the start of treatment with ARAVA in females of reproductive potential. Advise females of reproductive potential to use effective contraception during ARAVA treatment and during an accelerated drug elimination procedure after ARAVA treatment. Stop ARAVA and use an accelerated drug elimination procedure if the patient becomes pregnant [see Contraindications (4) , Warnings and Precautions (5.1 , 5.3) , Use in Specific Populations (8.1 , 8.3) ], and Clinical Pharmacology (12.3) ] . Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in patients treated with ARAVA. ARAVA is contraindicated in patients with severe hepatic impairment. Concomitant use of ARAVA with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2 × ULN before initiating treatment, are at increased risk and should not be treated with ARAVA. Monitor ALT levels at least monthly for six months after starting ARAVA, and thereafter every 6 to 8 weeks. If leflunomide-induced liver injury is suspected, stop ARAVA treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized [see Contraindications (4) , Warnings and Precautions (5.2 , 5.3) , Use in Specific Populations (8.6) ] .