Teriflunomide 7 mg Tablet, Film Coated, 30-count

5 WARNINGS AND PRECAUTIONS Elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal for 11 days. ( 5.3 ) Teriflunomide may decrease WBC. A recent CBC should be available before starting teriflunomide.

Monitor for signs and symptoms of infection. Consider suspending treatment with teriflunomide in case of serious infection. Do not start teriflunomide in patients with active infections.

( 5.4 ) Stop teriflunomide if patient has anaphylaxis, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms; initiate rapid elimination. ( 5.3 , 5.5 , 5.6 , 5.7 ) If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing teriflunomide. ( 5.8 ) Teriflunomide may increase blood pressure.

Measure blood pressure at treatment initiation and monitor blood pressure during treatment. ( 5.9 )

5.1Hepatotoxicity Clinically significant and potentially life-threatening liver injury, including acute liver failure requiring transplant, has been reported in patients treated with teriflunomide in the postmarketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking teriflunomide. Clinically significant liver injury can occur at any time during treatment with teriflunomide.

Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with teriflunomide. Teriflunomide is contraindicated in patients with severe hepatic impairment [see Contraindications (4) ] . In placebo-controlled trials in adult patients, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving teriflunomide 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period.

These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, teriflunomide was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3) ] .

Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months. One patient in the controlled trials in adult patients developed ALT 32 times the ULN and jaundice 5 months after initiation of teriflunomide 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure.

Teriflunomide-induced liver injury in this patient could not be ruled out. Obtain serum transaminase and bilirubin levels within 6 months before initiation of teriflunomide therapy. Monitor ALT levels at least monthly for six months after starting teriflunomide.

Consider additional monitoring when teriflunomide is given with other potentially hepatotoxic drugs. Consider discontinuing teriflunomide if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on teriflunomide therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.

If liver injury is suspected to be teriflunomide-induced, discontinue teriflunomide and start an accelerated elimination procedure [see Warnings and Precautions (5.3) ] and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide therapy may be considered.

5.2 Embryofetal Tox…

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: Hepatotoxicity [see Contraindications (4) and Warnings and Precautions (5.1) ] Bone Marrow Effects/Immunosuppression Potential/Infections [ see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.5)] Serious Skin Reactions [see Warnings and Precautions (5.6) ] Drug Reaction with Eosinophilia and Systemic Symptoms [ see Warnings and Precautions (5.7) ] Peripheral Neuropathy [see Warnings and Precautions (5.8) ] Increased Blood Pressure [see Warnings and Precautions (5.9) ] Respiratory Effects [see Warnings and Precautions (5.10) ] Pancreatitis in Pediatric Patients [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥10% and ≥2% greater than placebo): headache, diarrhea, nausea, alopecia, increase in ALT.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc., at 1-866-924-6266 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 2047 patients receiving teriflunomide (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo-controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female.

The average age was 37 years. Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for teriflunomide patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea.

The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the teriflunomide 7 mg, teriflunomide 14 mg, and placebo treatment arms, respectively). Table 1: Adverse Reactions in Pooled Placebo-Controlled Studies in Patients with Relapsing Forms of Multiple Sclerosis Adverse Reaction Teriflunomide 7 mg (N=1045) Teriflunomide 14 mg (N=1002) Placebo (N=997) Headache 18% 16% 15% Increase in Alanine aminotransferase 13% 15% 9% Diarrhea 13% 14% 8% Alopecia 10% 13% 5% Nausea 8% 11% 7% Paresthesia 8% 9% 7% Arthralgia 8% 6% 5% Neutropenia 4% 6% 2% Hypertension 3% 4% 2% Cardiovascular Deaths Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to teriflunomide in the premarketing database.

These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between teriflunomide and cardiovascular death has not been established. Acute Renal Failure In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg teriflunomide group and 6/1002 (0.6%) patients in the 14 mg teriflunomide group versus 4/997 (0.4%) patients in the placebo group.

These elevations were transient. Some elevations were accompanied by hyperkalemia. Teriflunomide may cause acute uric acid nephropathy with transient acute renal failure because teriflunomide increases renal uric acid clearance.

Hypophosphatemia In clinical trials, 18% of teriflunomide-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of teriflunomide-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.

6.2 Postmarketing Expe…

7 DRUG INTERACTIONS 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 teriflunomide tablets. ( 7 ) Effect of Teriflunomide on CYP2C8 Substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking teriflunomide, 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 of Teriflunomide on Warfarin Coadministration of teriflunomide with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide may decrease peak INR by approximately 25%. Effect of Teriflunomide 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 teriflunomide [see Clinical Pharmacology (12.3) ] . Effect of Teriflunomide on CYP1A2 Substrates Teriflunomide may be a weak inducer of CYP1A2 in vivo . In patients taking teriflunomide, 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 of Teriflunomide on Organic Anion Transporter 3 (OAT3) Substrates Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking teriflunomide, 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 of Teriflunomide 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 teriflunomide, 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 teriflunomide [see Clinical Pharmacology (12.3) ] .