Indicated for the treatment of adults with active rheumatoid arthritis (RA).

Severe liver injury, including fatal liver failure, has been reported in patients treated with ARAVA. ARAVA is contraindicated in patients with severe hepatic impairment. Concomitant use of ARAVA with other potentially hepatotoxic drugs may increase the risk of liver injury.

Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2×ULN before initiating treatment, are at increased risk and should not be treated with ARAVA.

Monitor ALT levels at least monthly for six months after starting ARAVA, and thereafter every 6–8 weeks. If leflunomide-induced liver injury is suspected, stop ARAVA treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized.

For patients who are at low risk for ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression the recommended ARAVA loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily.

For patients at high risk for ARAVA-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or ARAVA-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended ARAVA dosage is 20 mg once daily without a loading dose.

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. 

ARAVA is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. If a serious infection occurs, consider interrupting ARAVA therapy and initiating the accelerated drug elimination procedure.

Medications like ARAVA that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving ARAVA, especially Pneumocystis jiroveci pneumonia and aspergillosis.

Prior to initiating ARAVA, all patients should be screened for active and inactive (“latent”) tuberculosis infection as per commonly used diagnostic tests. ARAVA has not been studied in patients with a positive tuberculosis screen, and the safety of ARAVA in individuals with latent tuberculosis infection is unknown.

Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving ARAVA alone–An accelerated elimination procedure should be considered at any time after discontinuation of ARAVA, and in particular, when a patient has experienced a severe adverse reaction (e.g., hepatotoxicity, serious infection, bone marrow suppression, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected hypersensitivity, or has become pregnant. It is recommended that all women of childbearing potential undergo an accelerated elimination procedure after stopping ARAVA treatment.

Cases of peripheral neuropathy have been reported in patients receiving ARAVA and in clinical studies with teriflunomide, the active metabolite of leflunomide. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy.

Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with ARAVA and has been associated with fatal outcomes.

In placebo-controlled studies with the active metabolite of ARAVA, teriflunomide, elevations in blood pressure were observed in some subjects.

The most common adverse reactions in ARAVA-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash.

Prior to starting ARAVA treatment the following evaluations and tests are recommended:

• Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection
• Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts
• For females of reproductive potential, pregnancy testing
• Check blood pressure

ARAVA is contraindicated in:

• Pregnant women. Arava may cause fetal harm. If a woman becomes pregnant while taking this drug, stop ARAVA, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure
• Patients with severe hepatic impairment
• Patients being treated with teriflunomide

If ARAVA and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.

Concomitant use of ARAVA and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%.

In patients taking ARAVA, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased.

Co-administration of ARAVA with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of ARAVA, may decrease peak INR by approximately 25%.

Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel.

In patients taking ARAVA, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced.

In patients taking ARAVA, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased.

Vaccination with live vaccines is not recommended.

For a patient taking ARAVA, 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 ARAVA.

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. Pregnancy must be avoided during ARAVA treatment or prior to the completion of the drug elimination procedure after ARAVA treatment.

Because of the potential for serious adverse reactions in a breastfed infant from ARAVA, advise a nursing woman to discontinue breastfeeding during treatment with ARAVA.

GoToSource

• Sarcoidosis. GoToSource

• Use in patients under the age of 18. GoToSource

• Systemic lupus erythematosus. GoToSource

• Psoriatic arthritis. GoToSource

• Polyomavirus BK-associated nephropathy in renal transplant recipients. GoToSource

• Dosage greater than one 100 mg tablet per day for 3 days as an initial loading dose and greater than 20 mg per day for maintenance therapy for patients who are at low risk for ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression. GoToSource 

• Anti-melanoma therapy. GoToSource

• Primary sjögren’s syndrome. GoToSource

• Takayasu arteritis. GoToSource 

• Inhibitor of cytomegalovirus. GoToSource

• Giant cell arteritis and polymyalgia rheumatica. GoToSource

• Use with oral prednisone for idiopathic membranous nephropathy. GoToSource 

• Medullary thyroid cancer. GoToSource

• Dengue virus infection. GoToSource

• Atopic dermatitis, wegener’s granulomatosis, bullous pemphigoid, dermatomyositis and systemic sclerosis. GoToSource

• Kaposi’s sarcoma. GoToSource

• Idiopathic orbital inflammatory disease. GoToSource

• Crohn’s disease. GoToSource

• Prevention and treatment of corneal graft rejection. GoToSource 

• Acyclovir resistant HSV-2 proctitis. GoToSource 

• Use as agent to overcome chemoresistant CLL cells. GoToSource

Immunosuppression and bone marrow suppression, increased susceptibility to infections including pneumonia, tuberculosis and aspergillosis. GoToSource

Hepatotoxicity (liver damage). GoToSource

Silent liver fibrosis (liver scarring). GoToSource

Interstitial lung disease (scarring or inflammation of the lungs). GoToSource

Drug reaction with eosinophilia and systemic symptoms (potentially life-threatening drug reaction). GoToSource

Birth defects. GoToSource

Multiple keratoacanthomas (skin tumor). GoToSource

Suppressed wound healing. GoToSource

Alopecia areata (hair loss). GoToSource

Pulmonary hypertension (type of high blood pressure affecting arteries in lungs and right side of heart). GoToSource

Tjalma syndrome. GoToSource

Jessner-kanof disease (accumulations of lymph cells in the skin). GoToSource

Polymyositis (muscle weakness). GoToSource

Skin necrosis. GoToSource

Diffuse alveolar hemorrhage. GoToSource

Increased risk of pancreatic cancer. GoToSource

Cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis. GoToSource

Diarrhea and colitis. GoToSource

Lawsuits filed for liver injury and failure, stevens-johnson syndrome, lymphoma and death.