Leflunomide (Arava) Risks, Warnings, and Complications

RISK DURING PREGNANCY: Leflunomide can cause birth defects and serious harm to the unborn baby if it is taken by a pregnant woman. You will need to take a pregnancy test and must have a negative result before starting treatment with leflunomide. Your doctor will advise you to use an effective method of birth control before starting leflunomide, during treatment, and for 2 years after stopping treatment. If you become pregnant while taking leflunomide, stop treatment immediately and call your doctor. Your doctor will tell you how to perform an accelerated drug elimination procedure to reduce plasma concentrations of teriflunomide, which is the active metabolite of leflunomide.

RISK OF LIVER DAMAGE: There are reports of severe liver damage, including life-threatening and fatal liver failure, in people treated with leflunomide. This medication is contraindicated in people with pre-existing liver disease and those with elevations in serum alanine aminotransferase (ALT), a liver enzyme, if ALT levels are more than twice the normal upper limit. 

Your doctor will monitor liver function and ALT levels during treatment with leflunomide, every month for the first six months and then every 6-8 weeks. If ALT levels rise to more than 3 times the upper limit, you may need to stop taking leflunomide. If you develop leflunomide-induced liver injury, you may need to perform an accelerated drug elimination procedure with weekly monitoring of liver tests. If you are taking leflunomide with other potentially hepatotoxic drugs, such as methotrexate, you may need to undergo laboratory testing for ALT, AST, and serum albumin levels.

PROCEDURE FOR ACCELERATED ELIMINATION OF LEFLUNOMIDE AND ITS ACTIVE METABOLITE: Teriflunomide is the active metabolite of leflunomide and is eliminated slowly from the body. Doctors can perform an accelerated drug elimination procedure that rapidly clears leflunomide and teriflunomide from your plasma. This procedure may be considered after you stop taking leflunomide, in case you have experienced severe adverse reactions like liver damage, serious infections, serious skin reactions, bone marrow suppression, peripheral neuropathy, or interstitial lung disease, or have become pregnant. Women of childbearing age are recommended to undergo an accelerated elimination procedure after stopping leflunomide therap,y even in the absence of any severe drug reactions.

Without an accelerated drug elimination procedure, it can take up to 2 years for the plasma teriflunomide concentrations to reach safe levels of less than 0.02 mg/L or 0.02 mcg/mL.

To perform an accelerated drug elimination procedure, doctors use cholestyramine 8 grams by mouth 3 times daily for 11 days or activated charcoal powder 50 grams made into a suspension by mouth every 12 hours for 11 days.

Your doctor will do a blood test to verify plasma teriflunomide levels and ensure they are below 0.02 mg/L (0.02 mcg/mL) on two separate blood tests done at least 14 days apart. You may need to repeat the elimination procedure if the drug levels remain higher than the safe level. 

Keep in mind that a leflunomide accelerated elimination procedure may result in increased rheumatoid disease activity and return of your symptoms. 

IMMUNOSUPPRESSION AND BONE MARROW PROBLEMS: Leflunomide is an immunosuppressive drug that reduces the body’s immune response. Use of this medication can lead to bone marrow suppression, low blood count, and an increased risk of serious infections, including opportunistic infections such as Pneumocystis jirovecii pneumonia, aspergillosis, and tuberculosis, as well as fatal sepsis.

Leflunomide is contraindicated in patients with bone marrow dysplasia, severe immunodeficiency, or severe uncontrolled infections. Your doctor will screen you for latent tuberculosis before starting leflunomide treatment.

You may need to stop leflunomide treatment if you develop a serious infection. Your doctor may recommend you undergo an accelerated drug elimination procedure (see above). 

The use of other immunosuppressive drugs, such as methotrexate, concomitantly with leflunomide can lead to decreased white blood cells and decreased platelets. Your doctor will check platelet, white blood cell, hemoglobin, and hematocrit levels regularly while you are on leflunomide. If you develop evidence of bone marrow suppression, you will need to stop taking leflunomide and undergo an accelerated drug elimination procedure to rapidly remove the drug from your body. 

SERIOUS SKIN REACTIONS: Rarely, leflunomide can cause serious drug reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Stop taking leflunomide and seek emergency medical care if you develop a serious skin reaction. You will need to undergo an accelerated drug elimination procedure if this happens.

SKIN ULCERS: Patients treated with leflunomide can develop skin ulcers. If the ulcers persist, you may need to stop taking the medicine and undergo an accelerated drug elimination procedure. 

MALIGNANCY AND LYMPHOPROLIFERATIVE DISORDERS: The use of immunosuppressive agents like leflunomide can potentially increase the risk of malignancy (cancer), especially lymphoproliferative disorders (blood cancers affecting white blood cells). Clinical studies have not been done on this risk with higher doses or long-term treatment with leflunomide.

PERIPHERAL NEUROPATHY: There are reports of peripheral neuropathy (nerve damage) after leflunomide use. This is usually a temporary effect and goes away after treatment with leflunomide is discontinued, but can sometimes persist. Risk factors for peripheral neuropathy include older age (60 plus), diabetes, and concomitant use of other neurotoxic medications. Tell your doctor if you develop numbness, tingling, burning, or pain in your hands or feet while on leflunomide. You may need to stop taking the medicine and undergo an accelerated drug elimination procedure to quickly remove the drug from your body if you develop this complication.

INTERSTITIAL LUNG DISEASE: New or worsening interstitial lung disease has been reported in patients receiving leflunomide, including fatal outcomes. These are a group of conditions in which there is progressive pulmonary fibrosis (scarring of lung tissue), leading to symptoms such as dry cough and shortness of breath. Tell your doctor without delay if you develop a new or worsening cough, sore throat, fever, and other symptoms of lung disease or lung infection. If you develop lung problems, you may need to stop leflunomide and undergo accelerated drug elimination.

VACCINATIONS: There is no clinical data on whether it is safe to have vaccinations while on leflunomide. Doctors do not recommend getting live vaccines during treatment with this medication. Keep in mind that leflunomide has a long half-life and can stay in your system for up to 2 years after stopping therapy, so you may need to avoid live vaccines even after stopping treatment.

MONITORING OF BLOOD PRESSURE: Placebo-controlled trials have shown that teriflunomide, the active metabolite of leflunomide, can cause high blood pressure in some people. Your doctor will check your blood pressure before starting treatment and monitor it periodically while you are on this drug.