Arava
leflunomide · Tablet, Film Coated · Oral
Uses
1 INDICATIONS AND USAGE ARAVA is indicated for the treatment of adults with active rheumatoid arthritis (RA). ARAVA is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. ( 1 )
Dosage and administration
Loading dosage for patients at low risk for ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression: 100 mg daily for 3 days. ( 2.1 ) Maintenance dosage: 20 mg daily. ( 2.1 ) Maximum recommended daily dosage: 20 mg once daily. ( 2.1 ) If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily. ( 2.1 ) Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting ARAVA. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of ARAVA is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression. The loading dose provides steady-state concentrations more rapidly. For patients who are at low risk for ARAVA-associated hepatotoxicity and ARAVA-associated myelosuppression, the recommended ARAVA loading dose is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for ARAVA-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or ARAVA-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended ARAVA dosage is 20 mg once daily without a loading dose [see Warnings and Precautions (5.2 , 5.4) ] . The maximum recommended daily dose is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1). Monitor patients carefully after dosage reduction and after stopping therapy with ARAVA, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3) ] . After stopping ARAVA treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions (5.3) ] . Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping ARAVA [see Clinical Pharmacology (12.3) ] . 2.2 Evaluation and Testing Prior to Starting ARAVA Prior to starting ARAVA treatment, the following evaluations and tests are recommended: Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions (5.4) ] Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions (5.2 , 5.4) ] For females of reproductive potential, pregnancy testing [see Warnings and Precautions (5.1) ] Check blood pressure [see Warnings and Precautions (5.11) ]
Dosage forms and strengths
Tablets are available in three strengths: Tablets: 10 mg, supplied as white, round film-coated tablet embossed with "ZBN" on one side Tablets: 20 mg, supplied as light-yellow, triangular film-coated tablet embossed with "ZBO" on one side Tablets: 100 mg, supplied as white, round film-coated tablet embossed with "ZBP" on one side Tablets: 10 mg, 20 mg, 100 mg. ( 3 )
Contraindications
4 CONTRAINDICATIONS ARAVA is contraindicated in: Pregnant women. ARAVA may cause fetal harm. If a woman becomes pregnant while taking this drug, stop ARAVA, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see Warnings and Precautions (5.1 , 5.3) and Use in Specific Populations (8.1) ] . Patients with severe hepatic impairment [see Warnings and Precautions (5.2) ] . Patients with known hypersensitivity to leflunomide or any of the other components of ARAVA. Known reactions include anaphylaxis [see Adverse Reactions (6.1) ] . Patients being treated with teriflunomide [see Drug Interactions (7) ] . Pregnancy. ( 4 , 5.1 , 8.1 ) Severe hepatic impairment. ( 4 , 5.2 ) Hypersensitivity to ARAVA or any of its inactive components. ( 4 ) Current teriflunomide treatment. ( 4 )
Warnings and precautions
After stopping ARAVA, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. ( 5.3 ) Severe infections (including sepsis), pancytopenia, agranulocytosis, and thrombocytopenia: Stop ARAVA and use accelerated elimination procedure. Do not start ARAVA in patients with active infection. Monitor CBCs during treatment with ARAVA. ( 5.4 ) Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS): Stop ARAVA and use accelerated elimination procedure. ( 5.5 ) Skin ulcers: If skin ulcer is suspected, discontinue leflunomide treatment and consider an accelerated drug elimination procedure. ( 5.6 ) Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing ARAVA. ( 5.8 ) Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of ARAVA and initiation of accelerated elimination procedure. ( 5.9 ) Increased blood pressure: Monitor and treat. ( 5.11 ) 5.1 Embryo-Fetal Toxicity ARAVA may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level [see Use in Specific Populations (8.1) ] . ARAVA is contraindicated for use in pregnant women [see Contraindications (4) ] . Exclude pregnancy before starting treatment with ARAVA in females of reproductive potential [see Dosage and Administration (2.2) ] . Advise females of reproductive potential to use effective contraception during ARAVA treatment and during an accelerated drug elimination procedure after ARAVA treatment [see Use in Specific Populations (8.3) ] . If a woman becomes pregnant while taking ARAVA, stop treatment with ARAVA, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve nondetectable plasma concentrations of teriflunomide, the active metabolite of leflunomide [see Warnings and Precautions (5.3) ] . Upon discontinuing ARAVA, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving ARAVA treatment who wish to become pregnant must discontinue ARAVA and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk [see Contraindications (4) , Warnings and Precautions (5.3) , and Use in Specific Populations (8.1) ] . 5.2 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) of greater than twice the upper limits of normal (>2 × ULN) before initiating treatment, should not be treated with ARAVA. Use caution when ARAVA is given with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended at least monthly for six months after starting ARAVA, and thereafter every 6 to 8 weeks. If ALT elevation >3-fold ULN occurs, interrupt ARAVA therapy and investigate the cause. If likely ARAVA-induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized [see Warnings and Precautions (5.3) ] . If ARAVA-induced liver injury is unlikely because some other cause has been found, resumption of ARAVA therapy may be considered. If ARAVA and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing. 5.3 Procedure for Accelerated Elimination of ARAVA and its Active Metabolite The active metabolite of leflunomide, teriflunomide, is eliminated slowly from the plasma [see Clinical Pharmacology (12.3) ] . Use of an accelerated drug elimination procedure will rapidly reduce plasma concentrations of leflunomide and its active metabolite, teriflunomide. Therefore, an accelerated elimination procedure should be considered at any time after discontinuation of ARAVA, and in particular, when a patient has experienced a severe adverse reaction (e.g., hepatotoxicity, serious infection, bone marrow suppression, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral neuropathy, interstitial lung disease), suspected hypersensitivity, or has become pregnant. It is recommended that all women of childbearing potential undergo an accelerated elimination procedure after stopping ARAVA treatment. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, the plasma concentration not associated with embryo-fetal toxicity in animals. Elimination can be accelerated by the following procedures: Administer cholestyramine 8 grams orally 3 times daily for 11 days. Alternatively, administer 50 grams of activated charcoal powder (made into a suspension) orally every 12 hours for 11 days. Verify plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 µg/mL) by two separate tests at least 14 days apart. If plasma teriflunomide concentrations are higher than 0.02 mg/L, repeat cholestyramine and/or activated charcoal treatment. The duration of accelerated drug elimination treatment may be modified based on the clinical status and tolerability of the elimination procedure. The procedure may be repeated as needed, based on teriflunomide concentrations and clinical status.
Side effects
The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.2) ] Immunosuppression [see Warnings and Precautions (5.4) ] Bone marrow suppression [see Warnings and Precautions (5.4) ] Serious infections [see Warnings and Precautions (5.4) ] Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms [see Warnings and Precautions (5.5) ] Skin ulcers [see Warnings and Precautions (5.6) ] Peripheral neuropathy [see Warnings and Precautions (5.8) ] Interstitial lung disease [see Warnings and Precautions (5.9) ] The most commonly reported adverse reactions (≥10%) regardless of relation to ARAVA treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with ARAVA administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years. Elevation of Liver Enzymes Treatment with ARAVA was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. Table 1: Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3 Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate. Trial 1 Trial 2 Trial 3 ARAVA PL MTX ARAVA PL SSZ ARAVA MTX 20 mg/day (n=182) (n=118) 7.5–15 mg/wk (n=182) 20 mg/day (n=133) (n=92) 2 g/day (n=133) 20 mg/day (n=501) 7.5–15 mg/wk (n=498) MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal 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 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 Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate. ARAVA 20 mg/day (n=315) PL (n=210) SSZ 2 g/day (n=133) MTX 7.5–15 mg/wk (n=182) ARAVA 20 mg/day (n=501) MTX 7.5–15 mg/wk (n=498) ARAVA (n=1339) Includes all controlled and uncontrolled trials with ARAVA (duration up to 12 months). MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 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% Hypertension Hypertension as a preexisting condition was overrepresented in all ARAVA treatment groups in phase III trials. 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% 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.
Drug interactions
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. Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. ( 7 ) Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs. ( 7 ) Warfarin: Monitor INR as teriflunomide may decrease INR. ( 7 ) Drugs metabolized by BCRP and OATP1B1/B3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs. ( 7 ) Rosuvastatin: The dose of rosuvastatin should not exceed 10 mg once daily in patients taking ARAVA. ( 7 ) 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 coadministered 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 (12.3) ] . 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 (12.3) ] . 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 (12.3) ] . 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 (12.3) ] . 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 (12.3) ] . 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 (12.3) ] .
Use in specific populations
Lactation: Discontinue breastfeeding. ( 8.2 ) Females and Males of Reproductive Potential: See FPI for information regarding contraception. ( 8.3 ) Safety and effectiveness in pediatric patients <12 years of age have not been established. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in-a-study/. Risk Summary ARAVA is contraindicated for use in pregnant women because of the potential for fetal harm. In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of, and equivalent to, the maximum recommended human dose (MRHD) based on AUC, respectively, in rats and rabbits, caused teratogenicity (rats and rabbits), and embryo-lethality (rats) [see Data ] . Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of ARAVA during pregnancy. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The background risk in the U.S. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with ARAVA, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3) ] . Clinical Considerations Fetal/Neonatal adverse reactions Lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from ARAVA. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . Data Animal data In an embryo-fetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microphthalmia and internal hydrocephalus, were observed. 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 an embryo-fetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. Leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in both rats and rabbits). In a pre and postnatal development study, when female rats were treated with leflunomide at a dose that was approximately 1/100 of the MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival. 8.2 Lactation Risk Summary Clinical lactation studies have not been conducted to assess the presence of ARAVA in human milk, the effects of ARAVA on the breastfed child, or the effects of ARAVA on milk production. Because of the potential for serious adverse reactions in a breastfed infant from ARAVA, advise a nursing woman to discontinue breastfeeding during treatment with ARAVA. 8.3 Females and Males of Reproductive Potential ARAVA may cause fetal harm if administered during pregnancy [see Use in Specific Populations (8.1) ] . Pregnancy Testing Exclude pregnancy prior to initiation of treatment with ARAVA in females of reproductive potential. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see Warnings and Precautions (5.1 , 5.3) and Use in Specific Populations (8.1) ] . Contraception Females Females of reproductive potential should use effective contraception while taking ARAVA. If ARAVA is discontinued, use of contraception should be continued until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL, the level expected to have minimal fetal risk, based on animal data). Females of reproductive potential who wish to become pregnant should discontinue ARAVA and undergo an accelerated elimination procedure. Effective contraception should be used until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.1 , 5.3) and Use in Specific Populations (8.1) ]. Males Teriflunomide, the active metabolite of ARAVA, is detected in human semen. Animal studies to specifically evaluate the risk of male mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception. Men wishing to father a child should discontinue use of ARAVA and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3) ]. 8.4 Pediatric Use The safety and effectiveness of ARAVA in pediatric patients have not been established.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in-a-study/. Risk Summary ARAVA is contraindicated for use in pregnant women because of the potential for fetal harm. In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of, and equivalent to, the maximum recommended human dose (MRHD) based on AUC, respectively, in rats and rabbits, caused teratogenicity (rats and rabbits), and embryo-lethality (rats) [see Data ] . Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of ARAVA during pregnancy. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The background risk in the U.S. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with ARAVA, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3) ] . Clinical Considerations Fetal/Neonatal adverse reactions Lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from ARAVA. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . Data Animal data In an embryo-fetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microphthalmia and internal hydrocephalus, were observed. 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 an embryo-fetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. Leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in both rats and rabbits). In a pre and postnatal development study, when female rats were treated with leflunomide at a dose that was approximately 1/100 of the MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of ARAVA in pediatric patients have not been established. The safety and effectiveness of ARAVA in the treatment of polyarticular course juvenile idiopathic arthritis (JIA) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (JIA) as defined by the American College of Rheumatology (ACR). In this population, ARAVA treatment was found not to be effective. The safety of ARAVA was studied in 74 patients with polyarticular course JIA 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, and five between 3 and 8-fold the upper limit of normal.
Geriatric use
8.5 Geriatric Use Of the total number of subjects in controlled clinical trials (Trials 1, 2, and 3) of ARAVA, 234 subjects were 65 years and over [see Clinical Studies (14) ] . 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.
Overdosage
There have been reports of chronic overdose in patients taking ARAVA at daily dose up to five times the recommended daily dose and reports of acute overdose in adults and children. Adverse events were consistent with the safety profile for ARAVA [see Adverse Reactions (6) ] . The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia, and elevated liver function tests. In the event of a significant overdose or toxicity, perform an accelerated drug elimination procedure to accelerate elimination [see Warnings and Precautions (5.3) ] . Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide, the primary metabolite of leflunomide, is not dialyzable [see Clinical Pharmacology (12.3) ] .
Description
(leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C 12 H 9 F 3 N 2 O 2 , a molecular weight of 270.2 and the following structural formula: ARAVA is available for oral administration as tablets containing 10, 20, or 100 mg of active drug. Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide, and yellow ferric oxide (20 mg tablet only). Chemical Structure
Mechanism of action
12.1 Mechanism of Action Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial 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.
How supplied
How Supplied 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°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.
Patient information
Embryo-Fetal Toxicity Advise females of reproductive potential: Of the potential for fetal harm if ARAVA is taken during pregnancy. To notify their healthcare provider immediately if a pregnancy occurs or is suspected. To use effective contraception during treatment with ARAVA and until the active metabolite (teriflunomide) plasma concentration is verified to be less than 0.02 mg/L [see Warnings and Precautions (5.1 , 5.3) , Use in Specific Populations (8.1 , 8.3) , and Clinical Pharmacology (12.3) ] . Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARAVA during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise nursing women to discontinue breastfeeding during treatment with ARAVA [see Use in Specific Populations (8.2) ] . Serious Skin Reactions Advise patients of the possibility of rare, serious skin reactions. Instruct patients to promptly seek medical attention if they develop a skin rash, mucous membrane lesions, or skin ulcers. Investigations Advise patients of the potential hepatotoxic effects of ARAVA and of the need for monitoring liver enzymes. Instruct patients to report if they develop symptoms such as unusual tiredness, abdominal pain or jaundice. Advise patients 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. Instruct patients to promptly report if they notice symptoms consistent with pancytopenia, such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness. Inform patients about the early warning signs of interstitial lung disease and ask them to contact their physician promptly if these symptoms appear or worsen during therapy.
Label text from the FDA structured product label by sanofi-aventis U.S. LLC (revised Jun 4, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Leflunomide in 3 products
Arava NDC products (3)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0088-2160 | Leflunomide 10 mg/1 Tablet, Film Coated | sanofi-aventis U.S. LLC | NDA |
| 0088-2161 | Leflunomide 20 mg/1 Tablet, Film Coated | sanofi-aventis U.S. LLC | NDA |
| 0088-2162 | Leflunomide 100 mg/1 Tablet, Film Coated | sanofi-aventis U.S. LLC | NDA |
Frequently asked questions
What is Arava used for?
1 INDICATIONS AND USAGE ARAVA is indicated for the treatment of adults with active rheumatoid arthritis (RA). ARAVA is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. ( 1 )
What are the side effects of Arava?
The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.2) ] Immunosuppression [see Warnings and Precautions (5.4) ] Bone marrow suppression [see Warnings and Precautions (5.4) ] Serious infections [see Warnings and Precautions (5.4) ] Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia… See the full label for the complete list.
Who makes Arava?
Arava is listed by 1 labeler in the FDA NDC directory, including sanofi-aventis U.S. LLC.