Lefluniclo

For the treatment of adults with active rheumatoid arthritis (RA). For the temporary relief of arthritis pain. 1 INDICATIONS AND USAGE Leflunomide tablets USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Uses

• for the temporary relief of arthritis pain ONLY in the following areas:
• hand, wrist, elbow (upper body areas)
• foot, ankle, knee (lower body areas)
• this product may take up to 7 days to work for arthritis pain; it is not for immediate relief. If no pain relief in 7 days, stop use.

CONTRADICTIONS Do not use if known hypersensitivity to any of the listed ingredients of any of the components included on the kit. 4 CONTRAINDICATIONS Leflunomide tablet is contraindicated in: Pregnant women. Leflunomide tablets may cause fetal harm. If a woman becomes pregnant while taking this drug, stop leflunomide tablets, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see Warnings and Precautions (5.1 and 5.3) and Use in Specific Populations (8.1)].

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

(4) Current teriflunomide treatment. (4)

Warnings For external use only Allergy alert: Diclofenac may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include:

• hives
• asthma (wheezing)
• skin reddening
• blisters
• facial swelling
• shock
• rash If an allergic reaction occurs, stop use and seek medical help right away. Liver warning: This product contains diclofenac. Liver damage may occur if you apply
• more or for a longer time than directed
• when using other drugs containing diclofenac Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is small but higher if you
• are age 60 or older
• have had stomach ulcers or bleeding problems
• take a blood thinning (anticoagulant) or steroid drug
• take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others)
• have 3 or more alcoholic drinks every day while using this product
• apply more or for longer than directed Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed. Do not use
• if you have ever had an allergic reaction to any other pain reliever or to a fever reducer
• for strains, sprains, bruises or sports injuries. This product has not been shown to work for these types of injuries.
• right before or after heart surgery
• on more than 2 body areas at the same time
• in the eyes, nose or mouth Ask a doctor before use if
• you have problems or serious side effects from taking pain relievers or fever reducers
• stomach bleeding warning applies to you
• you have a history of stomach problems, such as heartburn
• you have high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, or had a stroke
• you are taking a diuretic
• you are under age 18 years. It is not known if this drug works or is safe in children under age 18 years. Ask a doctor or pharmacist before use if you are
• under a doctor’s care for any serious condition
• taking any other drug When using this product
• avoid contact with eyes, nose, or mouth
• if eye contact occurs, rinse thoroughly with water Stop use and ask a doctor if
• pain gets worse or lasts more than 21 days
• redness or swelling is present in the painful area
• fever occurs
• skin irritation occurs
• any new symptoms appear. These could be signs of a serious condition.

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 tablets 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 tablets when coadministered with rifampin. Because of the potential for leflunomide tablets concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide tablets and rifampin [see Clinical Pharmacology (12.3)].

Effect on CYP2C8 substrates Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking leflunomide tablets, 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 tablets with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of leflunomide tablets, 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 tablets [see Clinical Pharmacology (12.3)]. Effect on CYP1A2 substrates Teriflunomide, the active metabolite of leflunomide tablets, may be a weak inducer of CYP1A2 in vivo. In patients taking leflunomide tablets, 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 tablets, 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 tablets, 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 tablets [see Clinical Pharmacology (12.3)].

8.1Pregnancy Risk Summary

Leflunomide tablet 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 leflunomide tablets 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 to 4% and of miscarriage is 15 to 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 leflunomide tablets, 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 leflunomide tablets. 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 embryofetal 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 microophthalmia 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 embryofetal 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 post-natal development study, when female rats were treated 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.

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 tablets treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceutical Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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 tablets 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 tablets 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. In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide tablets 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 tablets -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 tablets treatment group).