IMPORTANT SAFETY INFORMATION:

Pregnancy contraindication: Pregnancy must be excluded before the start of treatment with ARAVA® (leflunomide). ARAVA® is contraindicated in pregnant women, or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during ARAVA® treatment or prior to the completion of the drug elimination procedure after ARAVA® treatment.

• Based on animal studies, Arava® may increase the risk of fetal death or teratogenic effects

Females of childbearing potential

• Do not start Arava® until the following steps are completed:
• Pregnancy is excluded
• Confirm that reliable contraception is being used
• Fully counsel patients on the potential for serious risk to the fetus
• If the patient becomes pregnant while taking this drug, the physician and patient must discuss the risk to the pregnancy
• Upon discontinuation of Arava®, it is recommended that all females of childbearing potential undergo the drug elimination procedure Females on Arava® who wish to become pregnant

Females on Arava® who wish to become pregnant

• Must discontinue Arava® and undergo the drug elimination procedure
• Human plasma levels of the active metabolite less than 0.02 mg/L (0.02 µg/mL) are expected to have minimal risk based on available animal data

Drug elimination procedure for females

• Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.)
• Verify plasma levels less than 0.02 mg/L (0.02 µg/mL) by 2 separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered.

Without the drug elimination procedure, it may take up to 2 years to reach plasma metabolite levels less than 0.02 mg/L due to individual variation in drug clearance.

Information for males

Available information does not suggest that Arava® would be associated with an increased risk of male-mediated fetal toxicity. To minimize any possible risk, men wishing to father a child should consider discontinuing use of Arava® and taking cholestyramine 8 grams 3 times daily for 11 days.

Important hepatic information

• RARE CASES OF SEVERE LIVER INJURY, INCLUDING CASES WITH FATAL OUTCOME, HAVE BEEN REPORTED DURING TREATMENT WITH LEFLUNOMIDE. MOST CASES OF SEVERE LIVER INJURY OCCUR WITHIN 6 MONTHS OF THERAPY AND IN A SETTING OF MULTIPLE RISK FACTORS FOR HEPATOTOXICITY (liver disease, other hepatotoxins)
• Arava® is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses given the risk of increased hepatotoxicity
• In clinical trials, Arava® was associated with generally reversible elevations of liver enzymes, primarily ALT and AST, in a significant number of patients. Marked elevation (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment

Additional safety information

• Arava® is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. Rarely, severe infections including sepsis, which may be fatal, have been reported. Rarely, interstitial lung disease, which may be fatal, has been reported
• Rare cases of pancytopenia, agranulocytosis, thrombocytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in post marketing experience. In these or any other serious toxicities, Arava® should be stopped and a drug elimination procedure (eg, cholestyramine 8 g TID x 1 day or more) should be used to reduce the drug concentration more rapidly
• It would be prudent to monitor for hematologic toxicity when switching from Arava® to another antirheumatic agent with a known potential for hematologic suppression
• Adverse reactions associated with the use of Arava® in clinical trials at 1 year (n=1339) included diarrhea (17%), elevated liver enzymes (ALT and AST) (5%), alopecia (10%), and rash (10%)

Laboratory tests

• At minimum, ALT (SGPT) must be performed at baseline and monitored initially at monthly intervals during the first 6 months, then, if stable, every 6 to 8 weeks thereafter
• For confirmed ALT elevations between 2- and 3-fold ULN, dose reduction to 10 mg/day may allow continued administration of Arava® under close monitoring. If elevations between 2- and 3-fold ULN persist despite dose reduction or if ALT elevations of >3-fold ULN are present, Arava® should be discontinued and cholestyramine should be administered
• If used concomitantly with methotrexate, chronic monitoring with additional AST and albumin should be done monthly
• At minimum, patients taking Arava® should have platelet, white blood cell count, and hemoglobin or hematocrit monitored at baseline and monthly for 6 months following initiation of therapy and every 6 to 8 weeks thereafter
• If used concomitantly with immunosuppressants such as methotrexate, chronic monitoring should be monthly

Please see additional important information including box warning.