Side Effects of Arava (leflunomide)

Arava (leflunomide) is a disease-modifying drug used to treat rheumatoid arthritis. 

Arava reduces inflammation in the joints that is responsible for both the symptoms of rheumatoid arthritis and the destruction of joints. This reduces symptoms as well as the progressive deformities of the joints caused by the arthritis. 

Arava reduces inflammation by suppressing the activity of immune cells responsible for the inflammation. Arava suppresses immune cells by inhibiting dihydroorotate dehydrogenase, an enzyme that is necessary for the production of DNA and RNA. 

Without DNA and RNA the immune cells (and most other types of cells) cannot multiply or function (or exist). Because of its unique and different mechanism of action, Arava is of value when added to other medications used for treating rheumatoid arthritis. 

Common side effects of Arava include

• diarrhea,
• nausea,
• headache,
• rash,
• itching,
• loss or thinning of hair, and
• weight loss.

Serious side effects of Arava include

• high blood pressure,
• chest pain,
• abnormal heartbeats,
• increased risk of infections since Arava suppresses the immune system, and
• fatal liver failure. 

Drug interactions of Arava include cholestyramine and charcoal, because these drugs decrease the concentration of the active form of Arava in the blood probably by preventing absorption. 

Rifampin increases the blood concentration of the active form of Arava by 40% probably by increasing the conversion of Arava to its active form. This may increase the side effects of Arava. 

Increased activity of warfarin by Arava has been reported rarely. 

Arava also may increase the blood concentration of tolbutamide. 

Arava is harmful to the developing fetus and should not be used during pregnancy. 

It is unknown if Arava accumulates in breast milk. Since l Arava could cause harm to the infant, women taking Arava probably should refrain from breastfeeding.

The most frequently reported side effects are:

• diarrhea,
• nausea,
• headache,
• rash,
• itching,
• loss or thinning of hair, and
• weight loss.

Other important side effects of leflunomide include:

• high blood pressure,
• chest pain, and
• abnormal heartbeats.

Since leflunomide suppresses the immune system, it may increase the risk to patients of infections. The most frequently reported infections involve the respiratory tract. Leflunomide may cause fatal liver failure. More often it causes abnormal liver tests in the blood, suggesting damage to the liver. The liver tests usually return to normal with continued treatment.

The dose of leflunomide should be reduced if liver tests are persistently greater than twice the upper limit of normal, and leflunomide should be discontinued if the levels remain above three times the upper limit of normal despite a reduction in dose. Leflunomide should not be administered to individuals with liver problems.

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

• Hepatotoxicity
• Immunosuppression
• Bone marrow suppression
• Stevens-Johnson syndrome and toxic epidermal necrolysis
• Peripheral neuropathy
• Interstitial lung disease

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**

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

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.

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.

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.

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.

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.

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.

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.