Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 08 May 2018

Indication(s)

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)

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Advisory information

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 and 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)

Adverse reactions

6 ADVERSE REACTIONS 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)] Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.5)] Peripheral neuropathy [see Warnings and Precautions (5.7)] Interstitial lung disease [see Warnings and Precautions (5.8)] The most commonly reported adverse reactions (?10 %) regardless of relation to ARAVA treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, 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 can not 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 3Only 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) 2.0 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 2.0 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 % HypertensionHypertension 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.

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; 6.2 Post Marketing Experience The following additional adverse reactions have been identified during postapproval use of ARAVA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: agranulocytosis, leukopenia, neutropenia, pancytopenia; Infection: opportunistic infections, severe infections including sepsis; Gastrointestinal: acute hepatic necrosis, colitis, including microscopic colitis, 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, pulmonary hypertension; Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis.

Usage information

Dosing and administration

2 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 dosage 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 dosage 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 dosage 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 (5.10)]

Use in special populations

8 USE IN SPECIFIC POPULATIONS Lactation: Discontinue breastfeeding.

(8.2) Safety and effectiveness in pediatric patients <12 years of age has 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 embryofetal 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 microophthalmia 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 embryofetal 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 post-natal 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 when administered during pregnancy.

Advise females of the potential risk to the fetus.

Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see Use in Specific Populations (8.1)].

Women receiving ARAVA treatment who wish to become pregnant should discontinue ARAVA and undergo an accelerated drug elimination procedure to achieve plasma teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

Pregnancy Testing Exclude pregnancy in females of reproductive potential before starting treatment with ARAVA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with ARAVA and while undergoing a drug elimination procedure until verification that the plasma teriflunomide concentration is less than 0.02 mg/L [see Warnings and Precautions (5.3)].

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, five between 3 and 8-fold the upper limit of normal.

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 can not be ruled out.

No dosage adjustment is needed in patients over 65.

8.6 Hepatic Impairment Dedicated studies of the effect of hepatic impairment on leflunomide pharmacokinetics have not been conducted.

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 ARAVA in patients with hepatic impairment is not recommended.

8.7 Renal Impairment Dedicated studies of the effect of renal impairment on leflunomide pharmacokinetics have not been conducted.

Given that the kidney plays an important role in drug elimination, caution should be used when ARAVA is administered to these patients.

Interactions

7 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 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 (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)].

More information

Category Value
Authorisation number NDA020905
Agency product number G162GK9U4W
Orphan designation No
Product NDC 0088-2161,0088-2160,0088-2162
Date Last Revised 29-02-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 213379
Storage and handling Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Protect from light.
Marketing authorisation holder sanofi-aventis U.S. LLC
Warnings

WARNING:

EMBRYO-FETAL TOXICITY and HEPATOTOXICITY WARNING:

EMBRYO-FETAL TOXICITY and HEPATOTOXICITY See full prescribing information for complete boxed warning.

Embryo-Fetal Toxicity Teratogenicity and embryo-lethality occurred in animals administered leflunomide.

(5.1, 8.1) Exclude pregnancy prior to initiating ARAVA therapy.

(5.1, 8.3) Advise use of effective contraception in females of reproductive potential during treatment and during a drug elimination procedure.

(5.1, 5.3, 8.3) Stop ARAVA and use an accelerated drug elimination procedure if the patient becomes pregnant.

(5.1, 5.3, 8.1) Hepatotoxicity Severe liver injury and fatal liver failure have been reported.

(5.2) Avoid ARAVA use in patients with pre-existing liver disease, or those with serum alanine aminotransferase (ALT) >2?ULN. (5.2, 8.6) Use caution when ARAVA is given with other potentially hepatotoxic drugs.

(5.2) Monitor ALT levels.

Interrupt ARAVA treatment if ALT elevation > 3 fold

ULN.

If likely leflunomide-induced, start accelerated drug elimination procedure and monitor liver tests weekly until normalized.

(5.2, 5.3) Embryo-Fetal Toxicity ARAVA is contraindicated for use in pregnant women because of the potential for fetal harm.

Teratogenicity and embryo-lethality occurred in animals administered leflunomide at doses lower than the human exposure level.

Exclude pregnancy before the start of treatment with ARAVA in females of reproductive potential.

Advise females of reproductive potential to use effective contraception during ARAVA treatment and during an accelerated drug elimination procedure after ARAVA treatment.

Stop ARAVA and use an accelerated drug elimination procedure if the patient becomes pregnant.

[see Contraindications (4), Warnings and Precautions (5.1, 5.3), Use in Special Populations (8.1, 8.3)], and Clinical Pharmacology (12.3)] Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in patients treated with ARAVA. ARAVA is contraindicated in patients with severe hepatic impairment.

Concomitant use of ARAVA with other potentially hepatotoxic drugs may increase the risk of liver injury.

Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2?ULN before initiating treatment, are at increased risk and should not be treated with ARAVA. Monitor ALT levels at least monthly for six months after starting ARAVA, and thereafter every 6-8 weeks.

If leflunomide-induced liver injury is suspected, stop ARAVA treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized.

[see Contraindications (4), Warnings and Precautions (5.2, 5.3), Use in Special Populations (8.6)]