Leflunomide 10 mg Tablet, 100-count

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)

5.1Embryo-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 metabolite of leflunomide [see Warnings and Precautions (5.3)].

Upon discontinuing leflunomide, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk [see Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.1)] .

5.2Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) of greater than twice the upper limits of normal (>2xULN) before initiating treatment, should not be treated with leflunomide. Use caution when leflunomide is given with other potentially hepatotoxic drugs.

Monitoring of ALT levels is recommended at least monthly for six months after starting leflunomide, and thereafter every 6 to 8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt leflunomide therapy and investigate the cause. If likely leflunomide-induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized [see Warnings and Precautions (5.3)].

If leflunomide-induced liver injury is unlikely because some other cause has been found, resumption of leflunomide therapy may be considered. If leflunomide and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.

5.3 Procedure for Accelerated Elimination of Leflunomi…

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

6.1Clinical 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…

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 leflunomide, may be a weak inducer of CYP1A2 in vivo . In patients taking leflunomide, 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 leflunomide, 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 leflunomide, 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 leflunomide [see Clinical Pharmacology (12.3)] . · 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 terif…