Arava

Embryo-Fetal Toxicity

• Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level.
• Exclude pregnancy before starting treatment with Arava.
• Advise females of reproductive age to use effective contraception during treatment and during an accelerated drug elimination procedure after Arava treatment.
• Stop treatment if pregnancy is confirmed; the patient should be apprised of the potential risk to a fetus. Perform an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide.
• Women receiving Arava treatment who wish to become pregnant must discontinue treatment and undergo an accelerated drug elimination procedure (plasma concentrations of leflunomide, teriflunomide less than 0.02mg/L).
• Human plasma concentrations of teriflunomide of less than 0.02mg/L are expected to have minimal embryo-fetal risk, according to animal studies.

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 ALT >2xULN before initiating treatment: do not treat with Arava.
• Use caution with concomitant hepatotoxic drugs.
• Monitor ALT levels at least every 6 months after starting Arava, then every 6-8 weeks.
• Interrupt therapy if ALT >3xULN; investigate cause.
• If ALT elevation is Arava-induced, perform accelerated drug elimination procedure and monitor liver tests weekly until normalized.
• Resumption of Arava therapy may be considered if livery injury is not connected to Arava.
• Arava + methotrexate: Follow ACR guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.

Procedure for Accelerated Elimination of Arava and Its Active Metabolite

• The active metabolite of leflunomide, teriflunomide, is eliminated slowly from the plasma (median half-life of 18-19 days).
• Consider an accelerated elimination procedure at any time after discontinuation of Arava and when a patient experiences a severe adverse reaction, suspected hypersensitivity, or has become pregnant.
• Women of childbearing potential should undergo an accelerated elimination procedure after stopping treatment.
• Without an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations that are not associated with embryo-fetal toxicity in animals (<.02mg/L).

Elimination can be accelerated by the following procedures:

1. Administer cholestyramine 8g orally 3 times daily for 11 days.

2. Alternatively, administer 50g of activated charcoal powder (made into a suspension) orally every 12 hours for 11 days.

3. May be repeated as needed based on teriflunomide concentrations and clinical status.

Verify plasma teriflunomide concentrations of <0.02mg/L by 2 separate tests at least 14 days apart; repeat procedure if concentrations >0.02mg/L.

Return of disease activity may potentially result from the accelerated drug elimination procedure in patients who responded to Arava treatment.

Immunosuppression, Bone Marrow Suppression, and Risk of Serious Infections

• Severe immunodeficiency, bone marrow dysplasia, severe uncontrolled infections: Arava treatment is not recommended.
• Serious infection: Interrupt treatment and initiate accelerated drug elimination procedure.
• Screen patients for active and inactive tuberculosis infection; if positive, treat by standard medical practice prior to therapy with Arava, monitor for reactivation.
• Pancytopenia, agranulocytosis and thrombocytopenia has been reported in patients receiving Arava.
• Monitor platelets, white blood cell count, hemoglobin or hematocrit at baseline and monthly for 6 months following initiation of therapy and every 6-8 weeks thereafter.
• Concomitant methotrexate or other immunosuppressives: Chronic monitoring should be monthly.
• Bone marrow suppression: Stop Arava, perform accelerated drug elimination procedure.
• Monitor for hematologic toxicity when switching from Arava to another antirheumatic agent with potential for hematologic suppression.

Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS)

• SJS, TEN, and DRESS have been reported with Arava.
• Stop treatment and perform an accelerated drug elimination procedure if these conditions develop.

Malignancy and Lymphoproliferative Disorders

• Immunosuppressive medications increase the risk of malignancy, particularly lymphoproliferative disorders.
• In clinical trials with Arava, there were no apparent increases in malignancies and lymphoproliferative disorders, though longer-term studies would be needed to determine risk.

Peripheral Neuropathy

• Peripheral neuropathy has been reported with Arava treatment.
• Discontinuation of treatment generally led to recovery; however, some patients had persistent symptoms.
• Concomitant neurotoxic drugs, diabetes, >60 years of age: Increased risk for peripheral neuropathy.
• Consider discontinuing if peripheral neuropathy develops; perform accelerated drug elimination procedure.

Interstitial Lung Disease 

• Interstitial lung disease (ILD) and worsening of pre-existing ILD have been reported with Arava.
• Patients with a history of ILD are at greater risk.
• New onset or worsening pulmonary symptoms with or without associated fever may be a reason for discontinuation of treatment, as ILD is potentially fatal.
• If discontinuation is necessary, consider performing an accelerated drug elimination procedure.

Vaccinations

• Vaccination with live vaccines not recommended while on Arava treatment.
• Consider the long half-life of Arava when contemplating administration of live vaccine after stopping treatment.

Blood Pressure Monitoring

• Teriflunomide was associated with elevations in blood pressure in clinical trials.
• Check blood pressure before starting treatment and monitor periodically thereafter.