February 25, 2017
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Side Effects


The following serious adverse reactions are described elsewhere in the labeling:

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.

Table 1: Liver Enzyme Elevations > 3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3**

  Trial 1 Trial 2 Trial 3*
ARAVA 20 mg/day
(n= 182)
MTX 7.5 - 15 mg/wk
ARAVA 20mg/day
SSZ 2.0 g/day
ARAVA 20 mg/day
MTX 7.5 - 15 mg/wk
ALT (SGPT) > 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
  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
MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal
*Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate.

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).

Table 2: Percentage Of Patients With Adverse Events ≥ 5% In Any ARAVA Treated Group in all RA Studies in Patients with RA

  Placebo-Controlled Trials Active-Controlled Trials All RA Studies
Trial 1 and 2 Trial 3 1  
ARAVA 20 mg/day
SSZ 2.0g/day
MTX 7.5 - 15 mg/wk
ARAVA 20 mg/day
MTX 7.5 - 15 mg/wk
Diarrhea 27% 12% 10% 20% 22% 10% 17%
Headache 13% 11% 12% 21% 10% 8% 7%
Nausea 13% 11% 19% 18% 13% 18% 9%
Rash 12% 7% 11% 9% 11% 10% 10%
Abnormal Liver Enzymes 10% 2% 4% 10% 6% 17% 5%
Alopecia 9% 1% 6% 6% 17% 10% 10%
Hypertension3 9% 4% 4% 3% 10% 4% 10%
Asthenia 6% 4% 5% 6% 3% 3% 3%
Back Pain 6% 3% 4% 9% 8% 7% 5%
GI/Abdominal Pain 6% 4% 7% 8% 8% 8% 5%
Abdominal Pain 5% 4% 4% 8% 6% 4% 6%
Allergic Reaction 5% 2% 0% 6% 1% 2% 2%
Bronchitis 5% 2% 4% 7% 8% 7% 7%
Dizziness 5% 3% 6% 5% 7% 6% 4%
Mouth Ulcer 5% 4% 3% 10% 3% 6% 3%
Pruritus 5% 2% 3% 2% 6% 2% 4%
Rhinitis 5% 2% 4% 3% 2% 2% 2%
Vomiting 5% 4% 4% 3% 3% 3% 3%
Tenosynovitis 2% 0% 1% 2% 5% 1% 3%
MTX = methotrexate, PL = placebo, SSZ = sulfasalazine
1 Only 10% of patients in Trial3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate.
2 Includes all controlled and uncontrolled trials with ARAVA (duration up to 12 months).
3Hypertension as a preexisting condition was overrepresented in all ARAVA treatment groups in phase III trials

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.

Blood and Lymphatic System: leukocytosis, thrombocytopenia;

Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein;

Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage;

Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma-GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth;

General Disorders: malaise;

Immune System: anaphylactic reaction;

Infection: abscess, flu syndrome, vaginal moniliasis;

Nervous System: dizziness, headache, somnolence;

Respiratory System: dyspnea;

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.

Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia;

Infection: opportunistic infections, severe infections including sepsis;

Gastrointestinal: acute hepatic necrosis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure

Immune System: angioedema;

Nervous system: peripheral neuropathy;

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

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

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


Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Drug interaction studies have been conducted with both ARAVA (leflunomide) and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.

Effect of Potent CYP and Transporter Inducers

Leflunomide is metabolized by CYP450 metabolizing enzymes. Concomitant use of ARAVA and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when co-administered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for ARAVA when coadministered with rifampin. Because of the potential for ARAVA concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both ARAVA and rifampin [see CLINICAL PHARMACOLOGY].

Effect on CYP2C8 Substrates

Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking ARAVA, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see CLINICAL PHARMACOLOGY].

Effect on Warfarin

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

Effect on oral Contraceptives

Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with ARAVA [see CLINICAL PHARMACOLOGY].

Effect on CYP1A2 Substrates

Teriflunomide, the active metabolite of ARAVA, may be a weak inducer of CYP1A2 in vivo. In patients taking ARAVA, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see CLINICAL PHARMACOLOGY].

Effect on Organic Anion Transporter 3 (OAT3) Substrates

Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking ARAVA, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see CLINICAL PHARMACOLOGY].

Effect on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) Substrates

Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking ARAVA, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking ARAVA [see CLINICAL PHARMACOLOGY].

Read the Arava Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 9/15/2015

Side Effects

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