|Labeler Name||sanofi-aventis U.S. LLC|
|Dosage & Substance||tablet, film coated leflunomide|
|Date First Marketed||September 10, 1998|
ARAVA is indicated for the treatment of adults with active rheumatoid arthritis (RA).
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 with known hypersensitivity to leflunomide or any of the other components of ARAVA. Known reactions include anaphylaxis
- Patients being treated with teriflunomide
The following serious adverse reactions are described elsewhere in the labeling:
- Bone marrow suppression
- Stevens-Johnson syndrome and toxic epidermal necrolysis
- Peripheral neuropathy
- Interstitial lung disease
6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with ARAVA administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years.
Elevation of Liver Enzymes
Treatment with ARAVA was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.
|Trial 1||Trial 2||Trial 3*|
|20 mg/day |
|(n=118)||7.5 – 15 mg/wk |
|20 mg/day |
|(n=92)||2.0 g/day |
|20 mg/day |
|7.5 – 15 mg/wk |
|MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal|
|>3-fold ULN (n %)||8(4.4)||3(2.5)||5(2.7)||2(1.5)||1(1.1)||2(1.5)||13(2.6)||83 (16.7)|
|Reversed to ≤ 2-fold ULN:||8||3||5||2||1||2||12||82|
|Timing of Elevation|
In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, ARAVA was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo.
Most Common Adverse Reactions
The most common adverse reactions in ARAVA-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year (≥ 5% in any ARAVA treatment group).
|Placebo-Controlled Trials||Active-Controlled Trials||All RA Studies|
|Trial 1 and 2||Trial 3 *|
7.5 – 15 mg/wk
7.5 – 15 mg/wk
|MTX = methotrexate, PL = placebo, SSZ = sulfasalazine|
|Abnormal Liver Enzymes||10%||2%||4%||10%||6%||17%||5%|
Adverse events during a second year of treatment with ARAVA in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.
Less Common Adverse Reactions
In addition, in controlled clinical trials, the following adverse events in the ARAVA treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug.
chest pain, palpitation, thrombophlebitis of the leg, varicose vein;
blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage;
alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth;
abscess, flu syndrome, vaginal moniliasis;
dizziness, headache, somnolence;
6.2 Post Marketing Experience
The following additional adverse reactions have been identified during postapproval use of ARAVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
agranulocytosis, leukopenia, neutropenia, pancytopenia;
opportunistic infections, severe infections including sepsis;
acute hepatic necrosis, colitis, including microscopic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure
interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal, pulmonary hypertension;
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.
5.1 Embryo-Fetal Toxicity
ARAVA may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level
ARAVA is contraindicated for use in pregnant women. Exclude pregnancy before starting treatment with ARAVA in females of reproductive potential. Advise females of reproductive potential to use effective contraception during ARAVA treatment and during an accelerated drug elimination procedure after ARAVA treatment. If a woman becomes pregnant while taking ARAVA, stop treatment with ARAVA, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve non-detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide
Upon discontinuing ARAVA, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving ARAVA treatment who wish to become pregnant must discontinue ARAVA and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk.
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) of greater than twice the upper limits of normal (>2×ULN) 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 and investigate the cause. If likely ARAVA-induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized If ARAVA-induced liver injury is unlikely because some other cause has been found, resumption of ARAVA therapy may be considered.
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.
5.3 Procedure for Accelerated Elimination of ARAVA and its Active Metabolite
The active metabolite of leflunomide, teriflunomide, is eliminated slowly from the plasma.
Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. Therefore, 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.
Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, the plasma concentration not associated with embryo-fetal toxicity in animals.
Elimination can be accelerated by the following procedures:
- Administer cholestyramine 8 grams orally 3 times daily for 11 days.
- Alternatively, administer 50 grams of activated charcoal powder (made into a suspension) orally every 12 hours for 11 days.
Verify plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 µg/mL) by two separate tests at least 14 days apart. If plasma teriflunomide concentrations are higher than 0.02 mg/L, repeat cholestyramine and/or activated charcoal treatment.
The duration of accelerated drug elimination treatment may be modified based on the clinical status and tolerability of the elimination procedure. The procedure may be repeated as needed, based on teriflunomide concentrations and clinical status.
Use of the accelerated drug elimination procedure may potentially result in return of disease activity if the patient had been responding to ARAVA treatment.
5.4 Immunosuppression, Bone Marrow Suppression, and Risk of Serious Infections
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 pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. Severe infections including sepsis, which may be fatal, have been reported in patients receiving ARAVA, especially pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid arthritis, may predispose patients to infection.
Cases of tuberculosis were observed in clinical studies with teriflunomide, the metabolite of ARAVA. 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. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ARAVA and monitored carefully during ARAVA treatment for possible reactivation of the infection.
Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving ARAVA alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality.
Patients taking ARAVA should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking ARAVA, stop treatment with ARAVA, and perform an accelerated drug elimination procedure to reduce the plasma concentration of the ARAVA active metabolite, teriflunomide].
In any situation in which the decision is made to switch from ARAVA to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds.
5.5 Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reactions with Eosinophilia and Systemic Symptoms
Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving ARAVA. If a patient taking ARAVA develops any of these conditions, stop ARAVA treatment and perform an accelerated drug elimination procedure].
5.6 Malignancy and Lymphoproliferative Disorders
The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with ARAVA. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of ARAVA, but larger dosages and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with ARAVA.
5.7 Peripheral Neuropathy
Cases of peripheral neuropathy have been reported in patients receiving ARAVA and in clinical studies with teriflunomide, the active metabolite of leflunomide. Most patients recovered after discontinuation of treatment, but some patients had persistent symptoms. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking ARAVA develops a peripheral neuropathy, consider discontinuing ARAVA therapy and performing an accelerated drug elimination proceduresee].
5.8 Interstitial Lung Disease
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]. The risk of ARAVA-associated interstitial lung disease is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder that may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of ARAVA therapy and for further investigation as appropriate. If discontinuation of ARAVA is necessary, consider performing an accelerated drug elimination procedure].
No clinical data are available on the efficacy and safety of vaccinations during ARAVA treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of the active metabolite of ARAVA should be considered when contemplating administration of a live vaccine after stopping ARAVA.
5.10 Blood Pressure Monitoring
In placebo-controlled studies with the active metabolite of ARAVA, teriflunomide, elevations in blood pressure were observed in some subjects. Blood pressure should be checked before starting treatment with ARAVA and monitored periodically thereafter [See Adverse Reactions (6.1)].
There have been reports of chronic overdose in patients taking ARAVA at daily dose up to five times the recommended daily dose and reports of acute overdose in adults and children. Adverse events were consistent with the safety profile for ARAVA [See]. The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.
In the event of a significant overdose or toxicity, perform an accelerated drug elimination procedure to accelerate elimination [see.
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide, the primary metabolite of leflunomide, is not dialyzable [See].
ARAVA (leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C12H9F3N2O2, a molecular weight of 270.2 and the following structural formula:
ARAVA is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only).