Arava & Pregnancy

Counseling guidelines for women of childbearing potential

Arava® (leflunomide) Drug Elimination Process

Instructions for the physician:

Discuss drug elimination process with the patient and choose an ending date for the elimination of the drug from the patient's system (consider the date by which the patient would like to complete the elimination procedure and the patient’s ability to tolerate the procedure).  

SEE IMPORTANT PREGNANCY RISK INFORMATION

 
  1. Contact NMS Labs (nmslabs.com) at 800-522-6671 or your local Labcorp representative for assay testing procedures.

  2. The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 µg/mL) after stopping treatment with ARAVA:
    • 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 two 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 M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance.

Important Safety Information

CONTRAINDICATIONS AND WARNINGS

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

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

Monitoring of ALT levels is recommended at least monthly for six months after starting ARAVA, and thereafter every 6-8 weeks. If ALT elevation > 3 fold ULN occurs, interrupt ARAVA therapy while investigating the probable cause of the ALT elevation by close observation and additional tests. If likely leflunomide-induced, start cholestyramine washout and monitor liver tests weekly until normalized. If leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of ARAVA therapy may be considered. (SEE WARNINGS – HEPATOTOXICITY).

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

  • 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 for the active metabolite of leflunomide to reach plasma 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.

Additional safety information

  • ARAVA is contraindicated in patients with known hypersensitivity to leflunomide, teriflunomide, or any of the other components of ARAVA.
  • Arava® is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. Severe infections including sepsis, which may be fatal, have been reported. Rarely, interstitial lung disease, which may be fatal, has been reported
  • Rare reports of pancytopenia, agranulocytosis, thrombocytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis, and peripheral neuropathy 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 11 days) 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%), respiratory infection (15%), alopecia (10%), hypertension (10%), rash (10%), and elevated liver enzymes (ALT and AST) (5%)

Laboratory tests

  • At minimum, ALT (SGPT) must be performed at baseline and at least monthly for six months after starting ARAVA, and thereafter every 6 to 8 weeks.
  • 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 Full Prescribing Information, including boxed WARNING, for additional important information.

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US.LEF.14.10.001 Last Update: October 2014