Arava (Leflunomide)
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Arava (Leflunomide)

ARAVA®
(leflunomide) 10 mg, 20 mg, 100 mg Tablets

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.)

DRUG DESCRIPTION

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® (leflunomide) Structural Formula Illustration

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).

What are the possible side effects of leflunomide (Arava)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using leflunomide and call your doctor at once if you have any of these serious side effects:

  • fever, chills, body aches, flu symptoms;
  • white patches or sores inside your mouth or on your lips;
  • chest pain;
  • chest pain, dry cough, wheezing, feeling short of breath (you may also have a fever);
  • pain or burning when you urinate;
  • pale skin, easy bruising or bleeding, unusual...

Read All Potential Side Effects and See Pictures of Arava »

What are the precautions when taking leflunomide (Arava)?

Before taking leflunomide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: immune system disorder (e.g., HIV infection), current/recent infection (e.g., tuberculosis), cancer, bone marrow/blood disorder, kidney disease, liver disease (e.g., hepatitis B or C), alcohol abuse, heart disease (e.g., congestive heart failure), lung disease.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities...

Read All Potential Precautions of Arava »

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

ARAVA is indicated in adults for the treatment of active rheumatoid arthritis (RA):

  1. to reduce signs and symptoms
  2. to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing
  3. to improve physical function. (see Clinical Studies)

Aspirin, nonsteroidal anti-inflammatory agents and/or low dose corticosteroids may be continued during treatment with ARAVA (see PRECAUTIONS: DRUG INTERACTIONSNSAIDs). The combined use of ARAVA with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied. (See WARNINGS -Immunosuppression Potential/Bone Marrow Suppression.)

DOSAGE AND ADMINISTRATION

Loading Dose

Due to the long half-life in patients with RA and recommended dosing interval (24 hours), a loading dose is needed to provide steady-state concentrations more rapidly. It is recommended that ARAVA therapy be initiated with a loading dose of one 100 mg tablet per day for 3 days.

Elimination of the loading dose regimen may decrease the risk of adverse events. This could be especially important for patients at increased risk of hematologic or hepatic toxicity, such as those receiving concomitant treatment with methotrexate or other immunosuppressive agents or on such medications in the recent past. (See WARNINGS - Hepatotoxicity).

Maintenance Therapy

Daily dosing of 20 mg is recommended for treatment of patients with RA. A small cohort of patients (n=104), treated with 25 mg/day, experienced a greater incidence of side effects; alopecia, weight loss, liver enzyme elevations. Doses higher than 20 mg/day are not recommended. If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily. Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction, since it may take several weeks for metabolite levels to decline.

Monitoring

Hematology parameters and liver enzymes should be monitored (see PRECAUTIONSLaboratory Tests; WARNINGSHepatotoxicity; WARNINGSImmunosuppression Potential/Bone Marrow Suppression).

HOW SUPPLIED

ARAVA Tablets in 10 and 20 mg strengths are packaged in bottles. ARAVA Tablets 100 mg strength are packaged in blister packs.

ARAVA® (leflunomide) Tablets

Strength Quantity NDC Number Description
10 mg 30 count bottle 0088-2160-30 White, round film-coated tablet embossed with “ZBN” on one side.
20 mg 30 count bottle 0088-2161-30 Light yellow, triangular film-coated tablet embossed with “ZBO” on one side.
100 mg 3 count blister pack 0088-2162-33 White, round film-coated tablet embossed with “ZBP” on one side.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light.

Revised: November 2012. sanofi-aventis U.S. LLC Bridgewater, NJ 08807

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See Table 9.)

Table 9: Percentage Of Patients With Adverse Events ≥ 3% In Any Leflunomide Treated Group

  All RA Studies Placebo-Controlled Trials Active-Controlled Trials
MN 301 and US 301 MN 302*
LEF (N=1339)1 LEF (N=315) PBO (N=210) SSZ (N=133) MTX (N=182) LEF (N=501) MTX (N=498)
BODY AS A WHOLE
Allergic Reaction 2% 5% 2% 0% 6% 1% 2%
Asthenia 3% 6% 4% 5% 6% 3% 3%
Flu Syndrome 2% 4% 2% 0% 7% 0% 0%
Infection, upper respiratory 4% 0% 0% 0% 0% 0% 0%
Injury Accident 5% 7% 5% 3% 11% 6% 7%
Pain Abdominal 2% 4% 2% 2% 5% 1% < 1%
Pain Back 6% 5% 4% 4% 8% 6% 4%
Pain 5% 6% 3% 4% 9% 8% 7%
CARDIOVASCULAR
Hypertension2 10% 9% 4% 4% 3% 10% 4%
- New onset of hypertension 1% < 1% 0% 2% 2% < 1%
Chest Pain 2% 4% 2% 2% 4% 1% 2%
GASTROINTESTINAL
Anorexia 3% 3% 2% 5% 2% 3% 3%
Diarrhea 17% 27% 12% 10% 20% 22% 10%
Dyspepsia 5% 10% 10% 9% 13% 6% 7%
Gastroenteritis 3% 1% 1% 0% 6% 3% 3%
Abnormal Liver Enzymes 5% 10% 2% 4% 10% 6% 17%
Nausea 9% 13% 11% 19% 18% 13% 18%
GI/Abdominal Pain 5% 6% 4% 7% 8% 8% 8%
Mouth Ulcer 3% 5% 4% 3% 10% 3% 6%
Vomiting 3% 5% 4% 4% 3% 3% 3%
METABOLIC AND NUTRITIONAL
Hypokalemia 1% 3% 1% 1% 1% 1% < 1%
Weight Loss3 4% 2% 1% 2% 0% 2% 2%
MUSCULO-SKELETAL SYSTEM
Arthralgia 1% 4% 3% 0% 9% < 1% 1%
Leg Cramps 1% 4% 2% 2% 6% 0% 0%
Joint Disorder 4% 2% 2% 2% 2% 8% 6%
Synovitis 2% < 1% 1% 0% 2% 4% 2%
Tenosynovitis 3% 2% 0% 1% 2% 5% 1%
NERVOUS SYSTEM
Dizziness 4% 5% 3% 6% 5% 7% 6%
Headache 7% 13% 11% 12% 21% 10% 8%
Paresthesia 2% 3% 1% 1% 2% 4% 3%
RESPIRATORY SYSTEM
Bronchitis 7% 5% 2% 4% 7% 8% 7%
Increased Cough 3% 4% 5% 3% 6% 5% 7%
Respiratory 15% 21% 21% 20% 32% 27% 25%
Infection 3% 2% 1% 2% 1% 3% 3%
Pharyngitis 2% 3% 0% 0% 1% 2% 2%
Pneumonia 2% 5% 2% 4% 3% 2% 2%
Rhinitis Sinusitis 2% 5% 5% 0% 10% 1% 1%
SKIN AND APPENDAGES
Alopecia 10% 9% 1% 6% 6% 17% 10%
Eczema 2% 1% 1% 1% 1% 3% 2%
Pruritus 4% 5% 2% 3% 2% 6% 2%
Rash 10% 12% 7% 11% 9% 11% 10%
Dry Skin 2% 3% 2% 2% 0% 3% 1%
UROGENITAL SYSTEM
Urinary Tract Infection 5% 5% 7% 4% 2% 5% 6%
* Only 10% of patients in MN302 received folate. All patients in US301 received folate; none in MN301 received folate.
1 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months).
2 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials
3 In a meta-analysis of all phase II and III studies, during the first 6 months in patients receiving leflunomide, 10% lost 10-19 lbs (24 cases per 100 patient years) and 2% lost at least 20 lbs (4 cases/100 patient years). Of patients receiving leflunomide, 4% lost 10% of their baseline weight during the first 6 months of treatment.

Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.

In addition, the following adverse events have been reported in 1% to < 3% of the RA patients in the leflunomide treatment group in controlled clinical trials.

Body as a Whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain;

Cardiovascular: angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation;

Gastrointestinal: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder;

Endocrine: diabetes mellitus, hyperthyroidism;

Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis;

Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema;

Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture;

Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo;

Respiratory System: asthma, dyspnea, epistaxis, lung disorder;

Skin and Appendages: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin;

Special Senses: blurred vision, cataract, conjunctivitis, eye disorder, taste perversion;

Urogenital System: albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis.

Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia < 2000 WBC/mm3 (rare).

Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.

In post-marketing experience, the following have been reported:

Body as a whole: opportunistic infections, severe infections including sepsis that may be fatal;

Gastrointestinal: pancreatitis;

Hematologic: agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia;

Hypersensitivity: angioedema;

Hepatic: hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal;

Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;

Nervous system: peripheral neuropathy;

Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.

Adverse Reactions (Pediatric Patients)

The safety of ARAVA was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3-17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between 3 and 8-fold the upper limit of normal.

Drug Abuse And Dependence

ARAVA has no known potential for abuse or dependence.

Read the Arava (leflunomide) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Cholestyramine and Charcoal

Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration (see PRECAUTIONSGeneralNeed for Drug Elimination).

Hepatotoxic Drugs

Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small (n=30) combination study of ARAVA with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A > 3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. Three patients met “ACR criteria” for liver biopsy (1: Roegnik Grade I, 2: Roegnik Grade IIIa). No pharmacokinetic interaction was identified (see CLINICAL PHARMACOLOGY).

NSAIDs

In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however, there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed.

Tolbutamide

In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of tolbutamide at concentrations in the clinical range. The clinical significance of this finding is unknown.

Rifampin

Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both ARAVA and rifampin.

Warfarin

Increased INR (International Normalized Ratio) when ARAVA and warfarin were coadministered has been rarely reported.

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

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 (see PRECAUTIONS - General - Need for Drug Elimination). If leflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of ARAVA therapy may be considered.

In addition, if ARAVA and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly.

In clinical trials, ARAVA treatment as monotherapy or in combination with methotrexate 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 ( ≤ 2fold ULN) and usually resolved while continuing treatment. Marked elevations ( > 3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 8 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.

Table 8: Liver Enzyme Elevations > 3-fold Upper Limits of Normal (ULN)

  US301 MN301 MN302*
LEF PL MTX LEF PL SSZ LEF MTX
ALT (SGPT)
> 3-fold ULN 8 3 5 2 1 2 13 83
(n %) (4.4) (2.5) (2.7) (1.5) (1.1) (1.5) (2.6) (16.7)
Reversed to ≤ 2-fold ULN: 8 3 5 2 1 2 12 82
Timing of Elevation
  0-3 Months 6 1 1 2 1 2 7 27
  4-6 Months 1 1 3 - - - 1 34
  7-9 Months 1 1 1 - - - - 16
  10-12 Months - - - - - - 5 6
*Only 10% of patients in MN302 received folate. All patients in US301 received folate.

In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was added 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 added.

Immunosuppression Potential/Bone Marrow Suppression

ARAVA is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with ARAVA and administer cholestyramine or charcoal (see PRECAUTIONSGeneralNeed for Drug Elimination). Medications like leflunomide 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. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection.

There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia 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, treatment with ARAVA should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite (see PRECAUTIONSGeneralNeed for Drug Elimination).

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. ARAVA washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to ARAVA treatment.

Skin Reactions

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving ARAVA. If a patient taking ARAVA develops any of these conditions, ARAVA therapy should be stopped, and a drug elimination procedure is recommended. (See PRECAUTIONS - General - Need for Drug Elimination.)

Malignancy

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 and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with ARAVA.

Use in Women of Childbearing Potential

There are no adequate and well-controlled studies evaluating ARAVA in pregnant women. However, based on animal studies, leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman (see CONTRAINDICATIONS). Women of childbearing potential must not be started on ARAVA until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with ARAVA, patients must be fully counseled on the potential for serious risk to the fetus.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from ARAVA.

Upon discontinuing ARAVA, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving ARAVA treatment who wish to become pregnant must discontinue ARAVA and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 μg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 μg/mL) are expected to have minimal risk based on available animal data.

Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving ARAVA. Most patients recovered after discontinuation of ARAVA, 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 the drug elimination procedure. (See WARNINGSDrug Elimination Procedure.).

Drug Elimination Procedure

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:

  1. 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.)
  2. 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.

PRECAUTIONS

General

Need for Drug Elimination

The active metabolite of leflunomide is eliminated slowly from the plasma. In instances of any serious toxicity from ARAVA, including hypersensitivity, use of a drug elimination procedure as described in this section is highly recommended to reduce the drug concentration more rapidly after stopping ARAVA therapy. If hypersensitivity is the suspected clinical mechanism, more prolonged cholestyramine or charcoal administration may be necessary to achieve rapid and sufficient clearance. The duration may be modified based on the clinical status of the patient.

Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of M1 by approximately 40% in 24 hours and by 49 to 65% in 48 hours.

Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite, M1, by 37% in 24 hours and by 48% in 48 hours.

These drug elimination procedures may be repeated if clinically necessary.

Respiratory

Interstitial lung disease has been reported during treatment with leflunomide and has been associated with fatal outcomes (see ADVERSE REACTIONS). The risk of its occurrence is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, which 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 the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, initiation of wash-out procedures should be considered. (See WARNINGSDrug Elimination Procedure.)

Tuberculosis Reactivation

Prior to initiating immunomodulatory therapies, including Arava, patients should be screened for latent tuberculosis infection with a tuberculin skin test. 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.

Renal Insufficiency

Single dose studies in dialysis patients show a doubling of the free fraction of M1 in plasma. There is no clinical experience in the use of ARAVA in patients with renal impairment. Caution should be used when administering this drug in this population.

Vaccinations

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 ARAVA should be considered when contemplating administration of a live vaccine after stopping ARAVA.

Blood Pressure Monitoring

Blood pressure should be checked before start of leflunomide treatment and periodically thereafter.

Laboratory Tests

Hematologic Monitoring

At minimum, 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.

Bone Marrow Suppression Monitoring

If used concomitantly with immunosuppressants such as methotrexate, chronic monitoring should be monthly. (See WARNINGS - Immunosuppression Potential/Bone Marrow Suppression.)

Liver Enzyme Monitoring

At minimum, ALT (SGPT) must be performed at baseline and at least monthly for six months after starting ARAVA, and thereafter every 6-8 weeks. In addition, if ARAVA and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month. (See WARNINGSHepatotoxicity.)

Due to a specific effect on the brush border of the renal proximal tubule, ARAVA has a uricosuric effect. A separate effect of hypophosphaturia is seen in some patients. These effects have not been seen together, nor have there been alterations in renal function.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of leflunomide up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human M1 systemic exposure based on AUC). However, male mice in a 2-year bioassay exhibited an increased incidence in lymphoma at an oral dose of 15 mg/kg, the highest dose studied (1.7 times the human M1 exposure based on AUC). Female mice, in the same study, exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas combined beginning at 1.5 mg/kg (approximately 1/10 the human M1 exposure based on AUC).

The significance of the findings in mice relative to the clinical use of ARAVA is not known. Leflunomide was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, leflunomide was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames Assay and in the HGPRT Gene Mutation Assay, and was clastogenic in the in vitro Assay for Chromosome Aberrations in the Chinese Hamster Cells. TFMA was not clastogenic in the in vivo Mouse Micronucleus Assay nor in the in vivo Cytogenetic Test in Chinese Hamster Bone Marrow Cells. Leflunomide had no effect on fertility in either male or female rats at oral doses up to 4.0 mg/kg (approximately 1/30 the human M1 exposure based on AUC).

Pregnancy

Pregnancy Category X (see CONTRAINDICATIONS section).

Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to leflunomide, health care providers are encouraged to register such patients by calling 1-877-311-8972.

Nursing Mothers

ARAVA should not be used by nursing mothers. It is not known whether ARAVA is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from ARAVA. Therefore, a decision should be made whether to proceed with nursing or to initiate treatment with ARAVA, taking into account the importance of the drug to the mother.

Use in Males

Available information does not suggest that ARAVA would be associated with an increased risk of male-mediated fetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. 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.

Pediatric Use

The safety and effectiveness of ARAVA in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA) have not been fully evaluated. (See Clinical Studies and ADVERSE REACTIONS.)

Geriatric Use

Of the total number of subjects in controlled clinical (Phase III) studies of ARAVA, 234 subjects were 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in patients over 65.

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

In mouse and rat acute toxicology studies, the minimally toxic dose for oral leflunomide was 200 - 500 mg/kg and 100 mg/kg, respectively (approximately > 350 times the maximum recommended human dose, respectively).

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 or children. There were no adverse events reported in the majority of case reports of overdose. Adverse events were consistent with the safety profile for ARAVA (see ADVERSE REACTIONS). 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, cholestyramine or charcoal administration is recommended to accelerate elimination (see PRECAUTIONSGeneralNeed for Drug Elimination).

Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1, the primary metabolite of leflunomide, is not dialyzable. (See CLINICAL PHARMACOLOGYElimination.)

CONTRAINDICATIONS

ARAVA is contraindicated in patients with known hypersensitivity to leflunomide or any of the other components of ARAVA.

ARAVA can cause fetal harm when administered to a pregnant woman. Leflunomide, when administered orally to rats during organogenesis at a dose of 15 mg/kg, was teratogenic (most notably anophthalmia or microophthalmia and internal hydrocephalus). The systemic exposure of rats at this dose was approximately 1/10 the human exposure level based on AUC. Under these exposure conditions, leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In rabbits, oral treatment with 10 mg/kg of leflunomide during organogenesis resulted in fused, dysplastic sternebrae. The exposure level at this dose was essentially equivalent to the maximum human exposure level based on AUC. At a 1 mg/kg dose, leflunomide was not teratogenic in rats and rabbits.

When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately 1/100 the human exposure level based on AUC.

ARAVA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.

Pharmacokinetics

Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. Plasma levels of leflunomide are occasionally seen, at very low levels. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of this active metabolite.

ARAVA® (leflunomide) Structural Formula Illustration

Absorption

Following oral administration, peak levels of the active metabolite, M1, occurred between 6 - 12 hours after dosing. Due to the very long half-life of M1 (~2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of M1. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that M1 plasma levels are dose proportional.

Table 1: Pharmacokinetic Parameters for M1 after Administration of Leflunomide at Doses of 5, 10, and 25 mg/day for 24 Weeks to Patients (n=54) with Rheumatoid Arthritis (Mean ± SD) (Study YU204)

Maintenance (Loading) Dose
Parameter 5 mg (50 mg) 10 mg (100 mg) 25 mg (100 mg)
C24 (Day 1) (μg/mL)1 4.0 ± 0.6 8.4 ± 2.1 8.5 ± 2.2
C24 (ss) (μg/mL)2 8.8 ± 2.9 18 ± 9.6 63 ± 36
t½(DAYS) 15 ± 3 14 ± 5 18 ± 9
1 Concentration at 24 hours after loading dose
2 Concentration at 24 hours after maintenance doses at steady state

Relative to an oral solution, ARAVA tablets are 80% bioavailable. Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on M1 plasma levels.

Distribution

M1 has a low volume of distribution (Vss = 0.13 L/kg) and is extensively bound ( > 99.3%) to albumin in healthy subjects. Protein binding has been shown to be linear at therapeutic concentrations. The free fraction of M1 is slightly higher in patients with rheumatoid arthritis and approximately doubled in patients with chronic renal failure; the mechanism and significance of these increases are unknown.

Metabolism

Leflunomide is metabolized to one primary (M1) and many minor metabolites. Of these minor metabolites, only 4-trifluoromethylaniline (TFMA) is quantifiable, occurring at low levels in the plasma of some patients. The parent compound is rarely detectable in plasma. At the present time the specific site of leflunomide metabolism is unknown. In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. No specific enzyme has been identified as the primary route of metabolism for leflunomide; however, hepatic cytosolic and microsomal cellular fractions have been identified as sites of drug metabolism.

Elimination

The active metabolite M1 is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. Subsequent analysis of the samples revealed the primary urinary metabolites to be leflunomide glucuronides and an oxanilic acid derivative of M1. The primary fecal metabolite was M1. Of these two routes of elimination, renal elimination is more significant over the first 96 hours after which fecal elimination begins to predominate. In a study involving the intravenous administration of M1, the clearance was estimated to be 31 mL/hr.

In small studies using activated charcoal (n=1) or cholestyramine (n=3) to facilitate drug elimination, the in vivo plasma half-life of M1 was reduced from > 1 week to approximately 1 day. (See PRECAUTIONS - General - Need for Drug Elimination.)Similar reductions in plasma half-life were observed for a series of volunteers (n=96) enrolled in pharmacokinetic trials who were given cholestyramine. This suggests that biliary recycling is a major contributor to the long elimination half-life of M1. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that M1 is not dialyzable.

Special Populations

Gender: Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of M1.

Age: Age has been shown to cause a change in the in vivo pharmacokinetics of M1 (see CLINICAL PHARMACOLOGYSpecial Populations -Pediatrics).

Smoking: A population based pharmacokinetic analysis of the phase III data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.

Chronic Renal Insufficiency: In single dose studies in patients (n=6) with chronic renal insufficiency requiring either chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, neither had a significant impact on circulating levels of M1. The free fraction of M1 was almost doubled, but the mechanism of this increase is not known. In light of the fact that the kidney plays a role in drug elimination and without adequate studies of leflunomide use in subjects with renal insufficiency, caution should be used when ARAVA is administered to these patients.

Hepatic Insufficiency: Studies of the effect of hepatic insufficiency on M1 pharmacokinetics have not been done. Given the need to metabolize leflunomide into the active species, the role of the liver in drug elimination/recycling, and the possible risk of increased hepatic toxicity, the use of leflunomide in patients with hepatic insufficiency is not recommended.

Pediatrics

The pharmacokinetics of M1 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ≤ 40 kg have a reduced clearance of M1 (see Table 2) relative to adult rheumatoid arthritis patients.

Table 2: Population Pharmacokinetic Estimate of M1 Clearance Following Oral Administration of Leflunomide in Pediatric Patients with Polyarticular Course JRA Mean ±SD [Range]

N Body Weight (kg) CL (mL/h)
10 < 20 18 ± 9.8 [6.8-37]
30 20-40 18± 9.5 [4.2-43]
33 > 40 26 ± 16 [9.7-93.6]

Drug Interactions

In vivo drug interaction studies have demonstrated a lack of a significant drug interaction between leflunomide and tri-phasic oral contraceptives, and cimetidine.

In vitro studies of protein binding indicated that warfarin did not affect M1 protein binding. At the same time M1 was shown to cause increases ranging from 13 - 50% in the free fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical range. In vitro studies of drug metabolism indicate that M1 inhibits CYP 450 2C9, which is responsible for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. M1 has been shown to inhibit the formation of 4´-hydroxydiclofenac from diclofenac in vitro. The clinical significance of these findings with regard to phenytoin and tolbutamide is unknown; however, there was extensive concomitant use of NSAIDs in the clinical studies and no differential effect was observed. (See PRECAUTIONS: DRUG INTERACTIONS.).

Methotrexate: Coadministration, in 30 patients, of ARAVA (100 mg/day x 2 days followed by 10 - 20 mg/day) with methotrexate (10 - 25 mg/week, with folate) demonstrated no pharmacokinetic interaction between the two drugs. However, co-administration increased risk of hepatotoxicity (see PRECAUTIONS: DRUG INTERACTIONSHepatotoxic Drugs).

Rifampin: Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA levels to continue to increase with multiple dosing, caution should be used if patients are to receive both ARAVA and rifampin.

Clinical Studies

Adults

The efficacy of ARAVA in the treatment of rheumatoid arthritis (RA) was demonstrated in three controlled trials showing reduction in signs and symptoms, and inhibition of structural damage. In two placebo controlled trials, efficacy was demonstrated for improvement in physical function.

Reduction of signs and symptoms

Relief of signs and symptoms was assessed using the American College of Rheumatology (ACR)20 Responder Index, a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. An “ACR20 Responder” is a patient who had ≥ 20% improvement in both tender and swollen joint counts and in 3 of the following 5 criteria: physician global assessment, patient global assessment, functional ability measure [Modified Health Assessment Questionnaire (MHAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. An “ACR20 Responder at Endpoint” is a patient who completed the study and was an ACR20 Responder at the completion of the study.

Inhibition of structural damage

Inhibition of structural damage compared to control was assessed using the Sharp Score (Sharp, JT. Scoring Radiographic Abnormalities in Rheumatoid Arthritis, Radiologic Clinics of North America, 1996; vol. 34, pp. 233-241), a composite score of X-ray erosions and joint space narrowing in hands/wrists and forefeet.

Improvement in physical function

Improvement in physical function was assessed using the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Survey Short Form (SF-36).

In all Arava monotherapy studies, an initial loading dose of 100 mg per day for three days only was used followed by 20 mg per day thereafter.

US301 Clinical Trial in Adults

Study US301, a 2 year study, randomized 482 patients with active RA of at least 6 months duration to leflunomide 20 mg/day (n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients received folate 1 mg BID. Primary analysis was at 52 weeks with blinded treatment to 104 weeks.

Overall, 235 of the 508 randomized treated patients (482 in primary data analysis and an additional 26 patients), continued into a second 12 months of double-blind treatment (98 leflunomide, 101 methotrexate, 36 placebo). Leflunomide dose continued at 20 mg/day and the methotrexate dose could be increased to a maximum of 20 mg/week. In total, 190 patients (83 leflunomide, 80 methotrexate, 27 placebo) completed 2 years of double-blind treatment.

The rate and reason for withdrawal is summarized in Table 3.

Table 3: Withdrawals in US301

  n(%) patients
Leflunomide 190 Placebo 128 Methotrexate190
Withdrawals in Year-1
  Lack of efficacy 33 (17.4) 70 (54.7) 50 (26.3)
  Safety 44 (23.2) 12 (9.4) 22 (11.6)
  Other1 15 (7.9) 10 (7.8) 17 (9.0)
  Total 92 (48.4) 92 (71.9) 89 (46.8)
  Patients entering Year 2 98 36 101
Withdrawals in Year-2
  Lack of efficacy 4 (4.1) 1 (2.8) 4 (4.0)
  Safety 8 (8.2) 0 (0.0) 10 (9.9)
  Other1 3 (3.1) 8 (22.2) 7 (6.9)
  Total 15 (15.3) 9 (25.0) 21 (20.8)
1Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

MN301/303/305 Clinical Trial in Adults

Study MN301 randomized 358 patients with active RA to leflunomide 20 mg/day (n=133), sulfasalazine 2.0 g/day (n=133), or placebo (n=92). Treatment duration was 24 weeks. An extension of the study was an optional 6-month blinded continuation of MN301 without the placebo arm, resulting in a 12-month comparison of leflunomide and sulfasalazine (study MN303).

Of the 168 patients who completed 12 months of treatment in MN301 and MN303, 146 patients (87%) entered a 1-year extension study of double blind active treatment (MN305; 60 leflunomide, 60 sulfasalazine, 26 placebo/ sulfasalazine). Patients continued on the same daily dosage of leflunomide or sulfasalazine that they had been taking at the completion of MN301/303. A total of 121 patients (53 leflunomide, 47 sulfasalazine, 21 placebo/sulfasalazine) completed the 2 years of double-blind treatment.

Patient withdrawal data in MN301/303/305 is summarized in Table 4.

Table 4: Withdrawals in study MN301/303/305

  n (%) patients
Leflunomide 133 Placebo 92 Sulfasalazine 133
Withdrawals in MN301 (Mo 0-6)
Lack of efficacy 10 (7.5) 29 (31.5) 14 (10.5)
Safety 19 (14.3) 6 (6.5) 25 (18.8)
Other1 8 (6.0) 6 (6.5) 11 (8.3)
Total 37 (27.8) 41 (44.6) 50 (37.6)
Patients entering MN303 80   76
Withdrawals in MN303 (Mo 7-12)
  Lack of efficacy 4 (5.0)   2 (2.6)
  Safety 2 (2.5)   5 (6.6)
  Other1 3 (3.8)   1 (1.3)
  Total 9 (11.3)   8 (10.5)
  Patients entering MN305 60   60
Withdrawals in MN305 (Mo 13-24)
  Lack of efficacy 0 (0.0)   3 (5.0)
  Safety 6 (10.0)   8 (13.3)
  Other1 1 (1.7)   2 (3.3)
  Total 7 (11.7)   13 (21.7)
1Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion.

MN302/304 Clinical Trial in Adults

Study MN302 randomized 999 patients with active RA to leflunomide 20 mg/day (n=501) or methotrexate at 7.5 mg/week increasing to 15 mg/week (n=498). Folate supplementation was used in 10% of patients. Treatment duration was 52 weeks.

Of the 736 patients who completed 52 weeks of treatment in study MN302, 612 (83%) entered the double-blind, 1-year extension study MN304 (292 leflunomide, 320 methotrexate). Patients continued on the same daily dosage of leflunomide or methotrexate that they had been taking at the completion of MN302. There were 533 patients (256 leflunomide, 277 methotrexate) who completed 2 years of double-blind treatment.

Patient withdrawal data in MN302/304 is summarized in Table 5.

Table 5: Withdrawals in MN302/304

n(%) patients Leflunomide 501 Methotrexate 498
Withdrawals in MN302 (Year-1)
  Lack of efficacy 37 (7.4) 15 (3.0)
  Safety 98 (19.6) 79 (15.9)
  Other1 17 (3.4) 17 (3.4)
  Total 152 (30.3) 111 (22.3)
  Patients entering MN304 292 320
Withdrawals in MN304 (Year-2)
  Lack of efficacy 13 (4.5) 9 (2.8)
  Safety 11 (3.8) 22 (6.9)
  Other1 12 (4.1) 12 (3.8)
  Total 36 (12.3) 43 (13.4)
1Includes: lost to follow up, protocol violation, noncompliance, voluntary withdrawal, investigator discretion

Clinical Trial Data

Signs and symptoms Rheumatoid Arthritis

The ACR20 Responder at Endpoint rates are shown in Figure 1. ARAVA was statistically significantly superior to placebo in reducing the signs and symptoms of RA by the primary efficacy analysis, ACR20 Responder at Endpoint, in study US301 (at the primary 12 months endpoint) and MN301 (at 6 month endpoint). ACR20 Responder at Endpoint rates with ARAVA treatment were consistent across the 6 and 12 month studies (41 - 49%). No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine. ARAVA treatment effect was evident by 1 month, stabilized by 3 - 6 months, and continued throughout the course of treatment as shown in Figure 2.

Figure 1 : % ACR 20 Responder at Endpoint

% ACR 20 Responder at Endpoint - illustration

  Comparisons 95%Confidence Interval p Value
US301 Leflunomide vs. Placebo (12, 32) <0.0001
  Methotrexate vs. Placebo (8, 30) <0.0001
  Leflunomide vs. Methotrexate (-4, 16) NS
MN301 Leflunomide vs. Placebo (7, 33) 0.0026
  Sulfasalazine vs. Placebo (4, 29) 0.0121
  Leflunomide vs. Sulfasalazine (-8, 16) NS
MN302 Leflunomide vs. Methotrexate (-19, -7) <0.0001

Figure 2

US 301 ACR Responders Over Time - Illustration

ACR50 and ACR70 Responders are defined in an analogous manner to the ACR 20 Responder, but use improvements of 50% or 70%, respectively (Table 6). Mean change for the individual components of the ACR Responder Index are shown in Table 7.

Table 6: Summary of ACR Response Rates*

Study and Treatment Group ACR20 ACR50 ACR70
Placebo-Controlled Studies      
US301 (12 months)      
  Leflunomide (n=178)† 52.2‡ 34.3‡ 20.2‡
  Placebo (n=118) † 26.3 7.6 4.2
  Methotrexate (n=180)† 45.6 22.8 9.4
MN301(6 months)      
  Leflunomide (n=130)† 54.6‡ 33.1‡ 10.0§
  Placebo (n=91)† 28.6 14.3 2.2
  Sulfasalazine (n=132)† 56.8 30.3 7.6
Non-Placebo Active-Controlled Studies      
MN302 (12 months)      
  Leflunomide (n=495)† 51.1 31.1 9.9
  Methotrexate (n=489)† 65.2 43.8 16.4
* Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who discontinued early.
† N is the number of ITT patients for whom adequate data were available to calculate the indicated rates.
‡ p < 0.001 leflunomide vs placebo
§ p < 0.02 leflunomide vs placebo

Table 7 shows the results of the components of the ACR response criteria for US301, MN301, and MN302. ARAVA was significantly superior to placebo in all components of the ACR Response criteria in study US301 and MN301. In addition, Arava was significantly superior to placebo in improving morning stiffness, a measure of RA disease activity, not included in the ACR Response criteria. No consistent differences were demonstrated between ARAVA and the active comparators.

Table 7: Mean Change in the Components of the ACR Responder Index*

Components Placebo-Controlled Studies Non-placebo Controlled Study
US301 (12 months) MN301 Non-US (6 months) MN302 Non-US (12 months)
Leflu-nomide Metho- trexate Placebo Leflu-nomide Sulfasalazine Placebo Leflu-nomide Metho- trexate
Tender joint count1 -7.7 -6.6 -3 -9.7 -8.1 -4.3 -8.3 -9.7
Swollen joint count1 -5.7 -5.4 -2.9 -7.2 -6.2 -3.4 -6.8 -9
Patient global assessment2 -2.1 -1.5 0.1 -2.8 -2.6 -0.9 -2.3 -3
Physician global assessment2 -2.8 -2.4 -1 -2.7 -2.5 -0.8 -2.3 -3.1
Physical function/disability (MHAQ/HAQ) -0.29 -0.15 0.07 -0.5 -0.29 -0.04 -0.37 -0.44
Pain intensity2 -2.2 -1.7 -0.5 -2.7 -2 -0.9 -2.1 -2.9
Erythrocyte Sedimentation rate -6.26 -6.48 2.56 -7.48 -16.56 3.44 -10.12 -22.18
C-reactive protein -0.62 -0.5 0.47 -2.26 -1.19 0.16 -1.86 -2.45
Not included in the ACR Responder Index
Morning Stiffness (min) -101.4 -88.7 14.7 -93 -42.4 -6.8 -63.7 -86.6
* Last Observation Carried Forward; Negative Change Indicates Improvement
1 Based on 28 joint count
2 Visual Analog Scale - 0=Best; 10=Worst

Maintenance of effect

After completing 12 months of treatment, patients continuing on study treatment were evaluated for an additional 12 months of double-blind treatment (total treatment period of 2 years) in studies US301, MN305, and MN304. ACR Responder rates at 12 months were maintained over 2 years in most patients continuing a second year of treatment.

Improvement from baseline in the individual components of the ACR responder criteria was also sustained in most patients during the second year of Arava treatment in all three trials.

Inhibition of structural damage

The change from baseline to endpoint in progression of structural disease, as measured by the Sharp X-ray score, is displayed in Figure 3. ARAVA was statistically significantly superior to placebo in inhibiting the progression of disease by the Sharp Score. No consistent differences were demonstrated between leflunomide and methotrexate or between leflunomide and sulfasalazine.

Figure 3

Change in Sharp X-ray score - Illustration

  Comparisons 95% Confidence Interval p Value
US301 Leflunomide vs. Placebo (-4.0, -1.1) 0.0007
  Methotrexate vs. Placebo (-2.6, -0.2) 0.0196
  Leflunomide vs. Methotrexate (-2.3, 0.0) 0.0499
MN301 Leflunomide vs. Placebo (-6.2, -1.8) 0.0004
  Sulfasalazine vs. Placebo (-6.9, 0.0) 0.0484
  Leflunomide vs. Sulfasalazine (-3.3, 1.2) NS
MN302 Leflunomide vs. Methotrexate (-2.2, 7.4) NS

Improvement in physical function

The Health Assessment Questionnaire (HAQ) assesses a patient's physical function and degree of disability. The mean change from baseline in functional ability as measured by the HAQ Disability Index (HAQ DI) in the 6 and 12 month placebo and active controlled trials is shown in Figure 4. ARAVA was statistically significantly superior to placebo in improving physical function. Superiority to placebo was demonstrated consistently across all eight HAQ DI subscales (dressing, arising, eating, walking, hygiene, reach, grip and activities) in both placebo controlled studies.

The Medical Outcomes Survey Short Form 36 (SF-36), a generic health-related quality of life questionnaire, further addresses physical function. In US301, at 12 months, ARAVA provided statistically significant improvements compared to placebo in the Physical Component Summary (PCS) Score.

Figure 4

Change in HAQ Disability Index - Illustration

  Comparison 95% Confidence Interval p Value
US301 Leflunomide vs. Placebo (-0.58, -0.29) 0.0001
  Leflunomide vs. Methotrexate (-0.34, -0.07) 0.0026
MN301 Leflunomide vs. Placebo (-0.67, -0.36) < 0.0001
  Leflunomide vs. Sulfasalazine (-0.33, -0.03) 0.0163
MN302 Leflunomide vs. Methotrexate (0.01, 0.16) 0.0221

Maintenance of effect

The improvement in physical function demonstrated at 6 and 12 months was maintained over two years. In those patients continuing therapy for a second year, this improvement in physical function as measured by HAQ and SF-36 (PCS) was maintained.

Pediatrics

Clinical Trials in Pediatrics

ARAVA was studied in a single multicenter, double-blind, active-controlled trial in 94 patients (1:1 randomization) with polyarticular course juvenile rheumatoid arthritis (JRA) as defined by the American College of Rheumatology (ACR). Approximately 68% of pediatric patients receiving ARAVA, versus 89% of pediatric patients receiving the active comparator, improved by Week 16 (end-of-study) employing the JRA Definition of Improvement (DOI) ≥ 30 % responder endpoint. In this trial, the loading dose and maintenance dose of ARAVA was based on three weight categories: < 20 kg, 20-40kg, and > 40 kg. The response rate to ARAVA in pediatric patients ≤ 40 kg was less robust than in pediatric patients > 40 kg suggesting suboptimal dosing in smaller weight pediatric patients, as studied, resulting in less than efficacious plasma concentrations, despite reduced clearance of M1. (See Pharmacokinetics -Pediatrics.)

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

  • The potential for increased risk of birth defects should be discussed with female patients of childbearing potential. It is recommended that physicians advise women that they may be at increased risk of having a child with birth defects if they are pregnant when taking ARAVA, become pregnant while taking ARAVA, or do not wait to become pregnant until they have stopped taking ARAVA and followed the drug elimination procedure (as described in WARNINGS – Use In Women of Childbearing Potential – Drug Elimination Procedure).
  • Patients should be advised of the possibility of rare, serious skin reactions. Patients should be instructed to inform their physicians promptly if they develop a skin rash or mucous membrane lesions.
  • Patients should be advised of the potential hepatotoxic effects of ARAVA and of the need for monitoring liver enzymes. Patients should be instructed to notify their physicians if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.
  • Patients should be advised that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with ARAVA, who have recently discontinued such therapy before starting treatment with ARAVA, or who have had a history of a significant hematologic abnormality. Patients should be instructed to notify their physicians promptly if they notice symptoms of pancytopenia (such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness).
  • Patients should be informed about the early warning signs of interstitial lung disease and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy.

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

  • The potential for increased risk of birth defects should be discussed with female patients of childbearing potential. It is recommended that physicians advise women that they may be at increased risk of having a child with birth defects if they are pregnant when taking ARAVA, become pregnant while taking ARAVA, or do not wait to become pregnant until they have stopped taking ARAVA and followed the drug elimination procedure (as described in WARNINGS – Use In Women of Childbearing Potential – Drug Elimination Procedure).
  • Patients should be advised of the possibility of rare, serious skin reactions. Patients should be instructed to inform their physicians promptly if they develop a skin rash or mucous membrane lesions.
  • Patients should be advised of the potential hepatotoxic effects of ARAVA and of the need for monitoring liver enzymes. Patients should be instructed to notify their physicians if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.
  • Patients should be advised that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with ARAVA, who have recently discontinued such therapy before starting treatment with ARAVA, or who have had a history of a significant hematologic abnormality. Patients should be instructed to notify their physicians promptly if they notice symptoms of pancytopenia (such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness).
  • Patients should be informed about the early warning signs of interstitial lung disease and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy.

Last reviewed on RxList: 11/30/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Arava Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

LEFLUNOMIDE - ORAL

(leh-FLEW-no-mide)

COMMON BRAND NAME(S): Arava

WARNING: Leflunomide must not be used during pregnancy because it may cause serious harm (possibly death) to an unborn baby. Women of childbearing age must have a negative pregnancy test before starting this medication. They must also use 2 forms of reliable birth control before starting leflunomide, while taking it, and after stopping it until they have finished taking another drug that helps leflunomide leave the body and confirmed through 2 blood tests that the leflunomide levels are very low (see How to Use section). If you become pregnant or think you may be pregnant, inform your doctor immediately (see Precautions section).

This drug may rarely cause serious (possibly fatal) liver disease. Most cases occur within 6 months of taking this drug. If you already have liver disease (such as hepatitis B or C), leflunomide should not be used. Liver function (blood) tests must be performed periodically while taking leflunomide. Tell your doctor immediately if you notice dark urine, persistent nausea/vomiting, light-colored stools, stomach/abdominal pain, yellowing eyes/skin. See Drug Interactions section.

USES: This medication is used to treat rheumatoid arthritis, a condition in which the body's defense system (immune system) fails to recognize the body as itself and attacks the healthy tissues around the joints. Leflunomide helps to reduce the joint damage/pain/swelling and helps you to move better. It works by weakening your immune system and decreasing swelling (inflammation).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to prevent rejection of organ transplant.

HOW TO USE: Take this medication by mouth with or without food, usually once daily or as directed by your doctor. Take this medication exactly as prescribed. You may be instructed to take a higher dose for the first 3 days of treatment.

Dosage is based on your medical condition and response to therapy.

Take this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time each day.

After treatment is stopped, a different drug (cholestyramine) may be given as directed to help remove leflunomide from your body. This procedure is used if you need a rapid removal of the drug from your system (e.g., a female/male planning to have children, a person suffering from severe side effects). Without the procedure, the drug may stay in your body for up to 2 years. Consult your doctor or pharmacist for more details.

Inform your doctor if your symptoms persist or worsen.

Disclaimer

Arava Consumer (continued)

SIDE EFFECTS: Diarrhea, nausea, and dizziness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: cough, numbness/tingling of hands/feet, hair loss, chest pain, fast/pounding heartbeat, increased thirst/urination, muscle cramp/pain, mental/mood changes, vision changes.

Tell your doctor immediately if any of these rare but very serious side effects occur: easy bruising/bleeding, unusual growths/lumps, swollen glands (lymph nodes), unexplained weight loss, unusual tiredness.

This medication can lower the body's ability to fight an infection. Tell your doctor immediately if you develop any signs of an infection such as fever, chills, or persistent sore throat.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

Leflunomide can commonly cause a mild rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Therefore, seek immediate medical attention if you develop any rash.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Arava (leflunomide) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking leflunomide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: immune system disorder (e.g., HIV infection), current/recent infection (e.g., tuberculosis), cancer, bone marrow/blood disorder, kidney disease, liver disease (e.g., hepatitis B or C), alcohol abuse, heart disease (e.g., congestive heart failure), lung disease.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages since they can make you dizzy and also cause liver disease.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

Since this medication can increase your risk of developing serious infections, wash your hands well to prevent the spread of infections. Avoid contact with people who have illnesses that may spread to others (e.g., flu, chickenpox).

This medication must not be used during pregnancy. It may harm an unborn baby. Before starting this medication, women of childbearing age must have a negative pregnancy test before starting this medication. Men and women must use two effective forms of birth control (e.g., condoms and birth control pills) while taking this medication. Consult your doctor for more details and to discuss reliable forms of birth control. (See also Warning section.)

It is not known whether this medication affects the sperm. To minimize any possible risk, the manufacturer recommends that men wishing to father a child should consider stopping the medication and using another drug (cholestyramine) as directed to help this drug leave the body before attempting to father a child. (See How to Use section.) Consult your doctor for more details.

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

Disclaimer

Arava Consumer (continued)

DRUG INTERACTIONS: See also How to Use Section.

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: warfarin, rifamycins (e.g., rifampin), drugs affecting the liver (e.g., methotrexate), cholestyramine, other drugs that weaken the immune system (e.g., tacrolimus, cyclosporine).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center.

NOTES: Do not share this medication with others.

A skin test to check for tuberculosis should be performed before you start this medication. While taking this medication, laboratory and/or medical tests (e.g., liver function, blood counts, blood pressure) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2010. Copyright(c) 2010 First Databank, Inc.

Arava Patient Information Including Side Effects

Brand Names: Arava

Generic Name: leflunomide (Pronunciation: le FLOO noe mide)

What is leflunomide (Arava)?

Leflunomide affects the immune system and reduces swelling and inflammation in the body.

Leflunomide is used to treat the symptoms of rheumatoid arthritis. Leflunomide also helps reduce joint damage and improves physical functioning.

Leflunomide may also be used for other purposes not listed in this medication guide.

Arava 20 mg

triangular, yellow, imprinted with ZBO

Leflunomide 10 mg-APO

round, white, imprinted with APO, LE 10

Leflunomide 10 mg-BAR

round, white, imprinted with 10, b 351

Leflunomide 10 mg-TEV

round, white, imprinted with 173, 93

Leflunomide 20 mg-APO

triangular, white, imprinted with APO, LE 20

Leflunomide 20 mg-BAR

round, yellow, imprinted with 20, B352

Leflunomide 20 mg-TEV

round, yellow, imprinted with 174, 93

What are the possible side effects of leflunomide (Arava)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using leflunomide and call your doctor at once if you have any of these serious side effects:

  • fever, chills, body aches, flu symptoms;
  • white patches or sores inside your mouth or on your lips;
  • chest pain;
  • chest pain, dry cough, wheezing, feeling short of breath (you may also have a fever);
  • pain or burning when you urinate;
  • pale skin, easy bruising or bleeding, unusual weakness;
  • nausea, stomach pain, loss of appetite, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
  • fever, sore throat, and headache with a severe blistering, peeling, and red skin rash.

Less serious side effects may include:

  • mild stomach pain, diarrhea, loss of appetite;
  • weight loss;
  • headache, dizziness;
  • back pain;
  • numbness or tingling;
  • runny or stuffy nose, cold symptoms; or
  • mild itching or skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Arava (leflunomide) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about leflunomide (Arava)?

Stop taking leflunomide and tell your doctor right away if you become pregnant during treatment. You will need to receive medications to help your body eliminate the drug quickly and reduce the risk of harm to your unborn baby.

Use effective birth control while you are taking leflunomide, whether you are a man or a woman. After your treatment ends, continue using birth control until you have received the drug elimination medications.

Before taking leflunomide, tell your doctor if you have a history of liver disease or hepatitis, kidney disease, any type of infection, a history of tuberculosis, a blood cell disorder such as anemia or low platelets, a bone marrow disorder, or if you are using any drugs that weaken your immune system (such as cancer medicine or steroids).

Leflunomide can make it easier for you to get sick. Avoid being near people who have colds, the flu, or other contagious illnesses. Contact your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while you are being treated with leflunomide, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

After you stop taking leflunomide, you may need to be treated with other medications to help your body eliminate leflunomide quickly. Without receiving this drug elimination procedure, leflunomide could stay in your body for up to 2 years. Follow your doctor's instructions.

Side Effects Centers

Arava Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking leflunomide (Arava)?

You should not use this medication if you are allergic to leflunomide, if you have liver disease, or if you are pregnant or may become pregnant.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely take this medication:

  • a history of liver disease or hepatitis;
  • kidney disease;
  • any type of infection;
  • a history of tuberculosis;
  • a blood cell disorder (such as anemia, easy bruising or bleeding);
  • a weak immune system or bone marrow disorder; or
  • if you are using any drugs that weaken your immune system (such as cancer medicine or steroids).

FDA pregnancy category X. This medication can cause birth defects. Do not use leflunomide if you are pregnant. Your doctor may want you to have a pregnancy test to make sure you are not pregnant before you start taking leflunomide.

Stop taking leflunomide if you miss a period, and tell your doctor right away if you become pregnant during treatment. If you become pregnant while taking leflunomide, you will need to receive medications to help your body eliminate the drug quickly. This will reduce the risk of harm to your unborn baby. You will also need to go through this drug elimination procedure if you plan to become pregnant after you stop taking leflunomide.

Use effective birth control while you are taking leflunomide. After your treatment ends, continue using birth control until you have received the drug elimination medications.

If a man fathers a child during or after leflunomide treatment, the baby may have birth defects. Use a condom to prevent pregnancy while you are taking leflunomide. After your treatment ends, continue using condoms until you have received the medications to help your body eliminate leflunomide.

It is not known whether leflunomide passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take leflunomide (Arava)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Before you start taking leflunomide, you may need a skin test to make sure you do not have tuberculosis.

Your doctor may occasionally change your dose to make sure you get the best results.

Leflunomide can lower blood cells that help your body fight infections. This can make it easier for you to get sick from being around others who are ill. To be sure your blood cells do not get too low, your blood will need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.

After you stop taking leflunomide, you may need to be treated with other medications to help your body eliminate leflunomide quickly. Without receiving this drug elimination procedure, leflunomide could stay in your body for up to 2 years. Follow your doctor's instructions.

Rheumatoid arthritis is often treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Store at room temperature away from moisture, heat, and light.

Side Effects Centers

Arava Patient Information including If I Miss a Dose

What happens if I miss a dose (Arava)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Arava)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include diarrhea, stomach pain, easy bruising or bleeding, dark urine, or jaundice (yellowing of the skin or eyes).

What should I avoid while taking leflunomide (Arava)?

Avoid being near people who have colds, the flu, or other contagious illnesses. Contact your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using leflunomide, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), oral polio, typhoid, chickenpox (varicella), BCG (Bacillus Calmette and Guérin), and nasal flu vaccine.

What other drugs will affect leflunomide (Arava)?

Before taking leflunomide, tell your doctor if you are taking cholestyramine (Questran, Prevalite, LoCHOLEST) or rifampin (Rifadin, Rimactane).

Also tell your doctor if you are using medications that can weaken your immune system, such as:

  • methotrexate (Rheumatrex, Trexall);
  • cancer medications;
  • cyclosporine (Neoral, Sandimmune, Gengraf);
  • sirolimus (Rapamune), tacrolimus (Prograf);
  • basiliximab (Simulect), muromonab-CD3 (Orthoclone);
  • mycophenolate mofetil (CellCept); or
  • azathioprine (Imuran), etanercept (Enbrel).

Leflunomide can harm your liver. This effect is increased when you also use other medicines harmful to the liver, such as:

  • acetaminophen (Tylenol);
  • tuberculosis medications;
  • birth control pills or hormone replacement therapy;
  • other arthritis medications such as auranofin (Ridaura) or aurothioglucose (Solganol);
  • an ACE inhibitor such as benazepril (Lotensin), enalapril (Vasotec), lisinopril (Prinivil, Zestril), quinapril (Accupril), ramipril (Altace), and others;
  • an antibiotic such as dapsone or erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole);
  • an antifungal medication such as fluconazole (Diflucan), itraconazole (Sporanox), or ketoconazole (Nizoral);
  • cholesterol medications such as niacin (Advicor, Niaspan, Niacor, Slo-Niacin, and others), atorvastatin (Lipitor, Caduet), simvastatin (Zocor, Simcor, Vytorin), and others;
  • HIV/AIDS medications such as abacavir/lamivudine/zidovudine (Trizivir), lamivudine (Combivir, Epivir), nevirapine (Viramune), tenofovir (Viread), or zidovudine (Retrovir);
  • an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others; or
  • seizure medications such as carbamazepine (Carbatrol, Tegretol), phenytoin (Dilantin), felbamate (Felbatol), valproic acid (Depakene).

This list is not complete and other drugs may interact with leflunomide. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about leflunomide.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 7.01. Revision date: 8/12/2011.

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