Arava

In clinical trials of over 1339 rheumatoid arthritis patients there were no apparent interactions between ARAVA and concomitantly administered aspirin (acetylsalicylic acid), NSAIDs, and/or low dose corticosteroids. It has been shown that corticosteroid doses may be reduced gradually in patients who respond to ARAVA.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical trials no safety problems were observed when ARAVA and NSAIDs metabolised by CYP2C9 were coadministered.

Based on protein binding measured in vitro using therapeutic concentrations, there was no effect of ibuprofen, or diclofenac on the protein binding of A771726. A771726 lead to a 13% to 50% increase in the unbound fractions of diclofenac and ibuprofen, which would not be expected to be clinically significant.

Aspirin (acetylsalicylic acid), NSAIDs, and/or low dose corticosteroids may be continued during treatment with ARAVA. These combined used of ARAVA with NSAIDs and/or corticosteroids may be associated with hypertension.

ARAVA can be taken during meals or at any time between meals.

In a study in which ARAVA was given concomitantly with a triphasic oral contraceptive pill containing 30 µg ethinyloestradiol to healthy female volunteers, there was no reduction in contraceptive activity and A771726 pharmacokinetic parameters were within predicted ranges.

Interactions with laboratory tests have not been established.

The combined use of ARAVA with antimalarials, intramuscular or oral gold, D penicillamine or azathioprine has not been adequately studied. The risk associated with combination therapy, in particular in long-term treatment, is unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or hematotoxicity), combination with another DMARD is not advisable.

Concomitant administration of ARAVA with cholestyramine or activated charcoal will lead to a rapid and significant decrease in plasma A771726 (the active metabolite of ARAVA) concentration.

Interactions with herbal products have not been established.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. Caution is advised when ARAVA is given together with drugs, other than NSAIDs that are metabolised by CYP2C9 such as tolbutamide.

In vitro, A771726 lead to a 13% to 50% increase in the unbound fractions of tolbutamide, which would not be expected to be clinically significant. Tolbutamide led to an increase in the percent of unbound A771726, which was dependent upon the concentration of tolbutamide but independent of the concentration of A771726.

Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, A771726 levels were increased approximately 40% over those seen when ARAVA was administered 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.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. Caution is advised when ARAVA is given together with drugs, other than NSAIDs that are metabolised by CYP2C9 such as phenytoin.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. Caution is advised when ARAVA is given together with drugs, other than NSAIDs that are metabolised by CYP2C9 such as warfarin.

Based on protein binding measured in vitro using therapeutic concentrations, there was no effect of warfarin on the protein binding of A771726. A771726 had no effect on the binding of warfarin.

There have been case reports of increased prothrombin time when ARAVA and warfarin were coadministered.

Concomitant administration of ARAVA with methotrexate has not been approved in Canada.

In an open label study, 30 patients with active rheumatoid arthritis despite methotrexate therapy (17±4 mg/week (mean±S.D.) for at least six months were administered ARAVA 10-20 mg/day. Twenty-three patients completed one year of treatment. No pharmacokinetic interaction between the methotrexate and ARAVA was noted. 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 ARAVA. A more than 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. Sixteen patients met ACR 20% criteria for clinical response. In the two patients that underwent liver biopsies there was no evidence of significant fibrosis.

Changing from ARAVA to methotrexate without a washout period may raise the possibility of additive risks even for a long time after the switching (i.e. kinetic interaction, organ toxicity) (see Warnings and Precautions, General). 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 (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

No clinical data are available on the efficacy and safety of vaccination during ARAVA treatment. Vaccination with live vaccines is, however, not recommended. A live vaccine should only be given after a period of at least 6 months has elapsed after stopping ARAVA.

Increased side effects may occur when ARAVA is given concomitantly with hepatotoxic, hematotoxic or immunosuppressive substances. This is also to be considered when ARAVA treatment is followed by such drugs without a washout period (see Contraindications and Warnings and Precautions, General, Washout Procedures). Strict vigilance in monitoring of hepatic and hematologic functions is recommended for all patients prescribed ARAVA with other medications associated with increased risk of hepatotoxicity or hematotoxicity.

Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with ARAVA.

In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. In clinical trials no safety problems were observed when ARAVA and NSAIDs metabolised by CYP2C9 were coadministered. Caution is advised when ARAVA is given together with drugs, other than NSAIDs, that are metabolised by CYP2C9 such as phenytoin, warfarin, and tolbutamide (see Drug-Drug Interactions).

When coadministered with cimetidine (nonspecific Cytochrome P450 inhibitor), there were no changes in the pharmacokinetics of A771726 or TFMA, and slight increases in ARAVA concentrations were observed in some subjects.

Due to the long half-life in patients with rheumatoid arthritis and recommended dosing interval (24 hr), a loading dose is needed to yield 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.

Because the kidney plays a role in the elimination of ARAVA, and without sufficient studies of the use of ARAVA in patients with renal insufficiency, caution should be used when considering the administration of ARAVA to patients with mild renal insufficiency (see Contraindications).

Daily dosing of 20 mg is recommended for treatment of patients with rheumatoid arthritis. 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 ARAVA, patients should be carefully observed after dose reduction since it may take several weeks for metabolite levels to decline (see Warnings and Precautions, Monitoring and Laboratory Tests).

ARAVA can be taken with or without food, without regard to meals, at the same time everyday.

A treatment effect may be evident after 4 weeks and may further improve up to 4 to 6 months after start of treatment.

ARAVA tablets should be swallowed whole, with sufficient liquid.

If the patient forgot to take a tablet of ARAVA they should be advised to take it as soon as they remember, unless it is nearly time for their next dose. The patient should be advised not to double-up on the next dose to make up for the missed dose.

No dosage adjustment is needed in patients over 65 years of age.

1% to <3%: menstrual disorder, vaginal moniliasis.

Causal relationship of these events to ARAVA has not been established.

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.

1% to <3%: arthrosis, bursitis, muscle cramps, myalgia, bone necrosis, bone pain, tendon rupture.

1% to <3%: amblyopia, cataract, conjunctivitis, eye disorders.

1% to <3%: diabetes mellitus, hyperthyroidism.

1% to <3%: creatine phosphokinase increased, peripheral edema, hyperglycemia, hyperlipidemia. Less than 1%: hypokalemia, hypophosphatemia.

Uric acid level usually decrease, due to an uricosyric effect.

1% to <3%: angina pectoris, palpitation, tachycardia, vasodilatation, varicose vein.

1% to <3%: asthma, dyspnea, epistaxis, lung disorder. Less than 0.1%: interstitial lung disease (including interstitial pneumonitis and pulmonary fibrosis), sometimes fatal.

1% to <3%: anxiety, asthenia, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweat, vertigo. Less than 0.01%: peripheral neuropathy.

1% to <3%: albuminuria, cystitis, dysuria, hematuria, prostate disorder, urinary frequency.

Less than 0.1%: Severe infections including opportunistic infections and sepsis, which may be fatal.

1% to <3%: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, nail disorder, skin nodule, subcutaneous nodule, maculopapular rash, skin disorder, skin discolour, skin ulcer. Less than 1%: urticaria, anaphylactoid reactions, severe anaphylactic reaction. Less than 0.01%: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, including cutaneous necrotizing vasculitis.

The following adverse events have been reported in 1% to <3%, less than 1%, less than 0.1% or less than 0.01% of the rheumatoid arthritis patients in the ARAVA treatment group in controlled clinical trials or during post-marketing surveillance:

1% to <3%: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain, migraine.

The risk of malignancy, particularly lymphoproliferative disorders, is also known to be increased with use of some immunosuppressive drugs (see Warnings and Precautions, Carcinogenesis and Mutagenesis).

1% to <3%: cholelithiasis. Less than 1%: hepatitis, jaundice/cholestasis, severe disturbances in liver function; increase in alkaline phosphatase and lactate dehydrogenase (LDH). Less than 0.01%: severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal, pancreatitis.

Hypertension, gastrointestinal disturbances, weight loss, headache, dizziness, asthenia, musculoskeletal and skin disorder are considered as some common adverse effects seen with ARAVA.

Leucopenia and hypersensitivity reactions may occur and very rarely, cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported.

Hepatotoxicity has occurred. It is usually mild and reversible but cases of severe, sometimes fatal, liver disease, including acute hepatic necrosis, have been observed. There have been reports of pancreatitis, interstitial lung disease, and infections, including fatal sepsis (see Clinical Trial Adverse Drug Reactions and Less Common Clinical Trial Adverse Drug Reactions/Post-Market Adverse Drug Reactions).

1% to <3%: anemia (including iron deficiency anemia), ecchymosis, leucopenia (leucocytes >2×10⁹/l [2 G/L]). Less than 1%: eosinophilia, leucopenia (leucocytes <2G /L), lymphadenopathy, pancytopenia, thrombocytopenia. Less than 0.01%: agranulocytosis.

1% to <3%: colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder, taste perversion.

The use in patients less than 18 years of age is contraindicated.

No dosage adjustment is needed in patients over 65 years of age.

Each film-coated, white, round tablet, with 'ZBN' code on one side, contains: leflunomide 10 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc and titanium dioxide. HDPE bottles of 30.

Each film-coated, white, round tablet, with 'ZBP' code on one side, contains: leflunomide 100 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc and titanium dioxide. Aluminium/aluminium blister packs of 3.

Each film-coated, light yellow, triangular tablet, with 'ZBO' code on one side, contains: leflunomide 20 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, titanium dioxide and yellow ferric oxide. HDPE bottles of 30.

ARAVA is contraindicated in patients with moderate to severe renal impairment. Because the kidney plays a role in the elimination of ARAVA, and without sufficient studies of the use of ARAVA in patients with renal insufficiency, caution should be used when considering the administration of ARAVA to patients with mild renal insufficiency.

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of ARAVA up to the maximally tolerated dose of 6 mg/kg (approximately 1/40 the maximum human A771726 systemic exposure based on the area under the curve [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 A771726 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 A771726 exposure based on AUC). The significance of the findings in mice relative to the clinical use of ARAVA is not known.

ARAVA was not mutagenic in the Ames Assay, the Unscheduled DNA Synthesis Assay, or in the HGPRT Gene Mutation Assay. In addition, ARAVA 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-trifluoromethylanaline (TFMA), a minor metabolite of ARAVA, 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.

Pregnancy must be avoided if either partner is receiving ARAVA.

One of the following is recommended to achieve a fast decrease in plasma levels after stopping treatment with ARAVA:

1. 8 g cholestyramine 3 times daily for 11 days or

   
   

2. 50 g activated charcoal 4 times daily for 11 days

   
   

The duration may be modified depending on clinical or laboratory variables.

Similarly low A771726 plasma levels may be expected 2 years after stopping ARAVA without one of the above washout methods. Due to individual variation in drug clearance, some patients may decrease to below this plasma level in less time (e.g. 6 months).

For information regarding measurements of A771726, please contact sanofi-aventis Canada Inc.

Rare (<0.1%) spontaneous reports of interstitial lung disease occurring during treatment with ARAVA have been received worldwide (see Adverse Reactions, Respiratory, Thoracic and Mediastinal Disorders). Several of these cases had a fatal outcome. In a Japanese postmarketing surveillance program of 3658 patients with rheumatoid arthritis, the rate of interstitial lung disease was estimated at 0.8%, regardless of causality. Twenty-nine (29) cases of interstitial pneumonitis were reported, 11 with a fatal outcome. Assessment of the causality between ARAVA use and the reported interstitial lung disease is frequently confounded by pre-existing pulmonary disease (e.g. interstitial pneumonitis), and/or previous or concomitant use of other DMARDs known to induce interstitial lung disease (including methotrexate).

In patients with a current or previous history of pulmonary disease or who have been recently treated with drugs known to induce interstitial lung disease, it is recommended that pulmonary status be evaluated prior to initiation of ARAVA therapy and that patients be closely monitored during treatment.

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 needed, the long half-life of the active metabolite of ARAVA may necessitate the initiation of washout procedures (see Warnings and Precautions, General, Washout Procedures).

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.

ARAVA must not be administered to pregnant women or women of child bearing potential. ARAVA must not be administered to male subjects who wish to father a child (see Contraindications and Warnings and Precautions, Sexual Function/Reproduction).

No dosage adjustment is needed in patients over 65 years of age.

The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive 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 malignancies or lymphoproliferative disorders with ARAVA.

ARAVA should have no potential for abuse or dependence.

Monitoring for hematologic toxicity must be adhered to (see Warnings and Precautions, Monitoring and Laboratory Tests).

ARAVA is contraindicated in patients with impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis (see Contraindications). In patients with a lesser degree of pre-existing anemia, leucopenia, and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of hematological disorders is increased. The same effects also occur in patients on concomitant myelosuppressive medications, for example methotrexate, therefore strict vigilance in monitoring is recommended for all patients on ARAVA on concomitant myelosuppressive medication. If such effects occur, a washout procedure to reduce plasma levels of A771726 should be considered.

In case of severe hematological reactions, including pancytopenia, ARAVA and any concomitant myelosuppressive medication must be discontinued and a washout procedure initiated (see Warnings and Precautions, General, Washout Procedures).

ARAVA is not recommended for patients with bone marrow dysplasia, or severe, uncontrolled infections or immunodeficiency due to causes other than rheumatoid arthritis (see Contraindications).

Medications like ARAVA that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections (see Adverse Reactions). Infections may be more severe in nature.

It is known that patients with rheumatoid arthritis have an increased risk of severe infections, which may lead to sepsis and death. Rare cases of severe infection (including P. jiroveci and cytomegalovirus infections) and sepsis (with fatal outcome in isolated cases) were reported in patients treated with ARAVA. Although in most cases a causal relationship to leflunomide has not been established and multiple confounding factors were present, infections developing in patients receiving ARAVA may require early and vigorous treatment.

In the event that a severe or uncontrolled infection occurs, it may be necessary to interrupt ARAVA treatment and administer a washout procedure (see Warnings and Precautions, General, Washout Procedures).

Patients should be questioned about history of tuberculosis or tuberculin reactivity and, if positive, they should be carefully monitored for tuberculosis reactivation.

The active metabolite of ARAVA, A771726, has a long half-life. Serious undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below), even if the treatment with ARAVA has been stopped. For the management of the above-mentioned toxicities a washout procedure should be performed.

If a severe adverse reaction to ARAVA occurs, or if for any other reason A771726 needs to be cleared rapidly from the body, cholestyramine or activated charcoal has to be initiated and continued/repeated as clinically necessary (see Overdosage). For suspected severe immunologic/allergic reactions, more prolonged cholestyramine or activated charcoal administration may be necessary to achieve rapid and sufficient clearance (see below the Washout Procedures).

Similarly, when switching to another DMARD (e.g. methotrexate) after treatment with ARAVA a washout procedure should be performed since there exist a possibility of additive risks of adverse events for a long time after the switching (see Washout Procedures and see also Contraindications and Drug Interactions).

Recent treatment with hepatotoxic DMARDs may result in increased side effects; therefore, the initiation of ARAVA treatment has to be carefully considered regarding these benefit/risk aspects. Caution and careful monitoring of liver and bone marrow function is necessary if these drugs are used concomitantly (see Contraindications and Drug Interactions).

Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: If ALT elevations between 2- and 3-fold the upper limit of normal persist or if ALT elevations of more than 3-fold the upper limit of normal are present, ARAVA should be discontinued. Cholestyramine or activated charcoal should be administered to more rapidly lower A771726 level (see Warnings and Precautions, General, Washout Procedures and Monitoring and Laboratory Tests).

Rare elevations of alkaline phosphatase and bilirubin have been observed. Trial US301 used ACR Methotrexate Liver Biopsy Guidelines for monitoring therapy. One of 182 patients receiving ARAVA and 1 of 182 patients receiving methotrexate underwent liver biopsy at 106 and 50 weeks, respectively. The biopsy for the leflunomide subject was Roegnik Grade IIIA and for the methotrexate subject Roegnik Grade I.

ARAVA should be administered to patients only under careful medical supervision.

AST and ALT must be checked before initiation of the treatment and at monthly or more frequent intervals during the first 6 months, and every 8 weeks thereafter (See Warnings and Precautions, Hepatic/Biliary/Pancreatic).

ALT values are elevated more frequently than AST.

For confirmed ALT elevations between 2- and 3-times the upper limit of normal, dose may be reduced from 20 to 10 mg/day and monitoring should be performed weekly. If ALT elevations of more than 2- times the upper limit of normal persist, or, if confirmed ALT increases to more than 3- times the upper limit of normal, ARAVA must be discontinued and washout procedures initiated.

If a severe undesirable effect of ARAVA occurs, or if for any other reason the active metabolite needs to be cleared rapidly from the body (e.g.: desired or unintended pregnancy, switching to another DMARD such as methotrexate), the washout procedures should be initiated. Cholestyramine or activated charcoal should be administered to more rapidly lower A771726 levels (see Contraindications, Warnings and Precautions, General, Washout Procedures).

A complete blood cell count, including differential white blood cell count and platelets, must be performed before start of ARAVA treatment as well as every 2 weeks for the first 6 months of treatment and every 8 weeks thereafter (see Warnings and Precautions, Hematologic).

In addition to hypertension noted in Clinical Trials, isolated reports of difficulty with blood pressure control including cases of malignant hypertension and hypertensive crisis have been submitted. Although a causal relationship to ARAVA has not been established and confounding factors were present in most cases, it is considered essential that monitoring recommendations are closely followed. Therefore, blood pressure must be checked before the start of ARAVA treatment and periodically thereafter (see Adverse Reactions, Clinical Trial Adverse Drug Reactions).

In patients with a current or previous history of pulmonary disease or who have been recently treated with drugs known to induce interstitial lung disease, it is recommended that pulmonary status be evaluated prior to initiation of ARAVA therapy and that patients be closely monitored during treatment.

Other Laboratory Tests Changes: Due to an uricosuric effect presumably at the brush border of the proximal renal tubule, uric acid levels usually decrease. Phosphaturia and hypokalemia may also occur.

ARAVA must not be used by men who could potentially father a child and are not using reliable contraception during and for a total of 2 years after treatment with ARAVA, if no elimination procedure is used.

There are no specific data on the risk of male-mediated foetal 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 use elimination procedure or wait 2 years after treatment cessation.

For men having received ARAVA treatment and wishing to father a child, plasma levels of the active metabolite (A771726) must be less than 0.02 mg/L (0.02µg/mL) to be verified by two separate tests at an interval of at least 14 days. After the second test confirming that the plasma concentration is below 0.02 mg/L an additional waiting period of 3 months is required. After that period, the risk of male-mediated foetal toxicity is considered very low (see Contraindications and Warnings and Precautions, General, Washout Procedures).

ARAVA had no effect on fertility in either male or female rats at oral doses up to 0.4 mg/kg (approximately 1/30 the human A771726 exposure based on AUC).

The safety and efficacy of ARAVA in the pediatric population have not been fully evaluated, and its use in patients less than 18 years of age is contraindicated.

In case of ulcerative stomatitis, ARAVA administration should be discontinued.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with ARAVA. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, ARAVA and any other possibly associated medication must be discontinued, and a washout procedure initiated immediately. A complete washout is essential in such cases. In such cases re-exposure to ARAVA is contraindicated (see Contraindications and Warnings and Precautions, General, Washout Procedures).

There are no adequate and well-controlled studies evaluating ARAVA in pregnant women. However, based on animal studies, ARAVA may cause fetal death or teratogenic effects when administered to a pregnant woman. 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 counselled on the potential for serious risk to the fetus. 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. Should pregnancy occur, the physician and patient should discuss the risk of continuing the pregnancy (see Information for the Patient). 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.

For women who have received ARAVA treatment and wish to become pregnant, the following procedures is recommended:

• After stopping treatment with ARAVA, cholestyramine 8 g is administered 3 times daily for a period of 11 days.

  
  

• After stopping treatment with ARAVA, 50 g of activated charcoal is administered 4 times daily for a period of 11 days.

  
  

The plasma levels of the active metabolite (A771726) must be less than 0.02 mg/L (0.02 µg/mL). Below this plasma level (to be verified by 2 separate tests at an interval of at least 14 days), the teratogenic risk is considered very low (see Contraindications and Warnings and Precautions, General, Washout Procedures).

Without the drug elimination procedure, it may take up to 2 years to reach A771726 levels <0.02 mg/L. However, also after a such waiting period, verification of A771726 levels less than 0.02 mg/L (0.02 µg/mL) by 2 separate tests at an interval of a least 14 days is required.

If a waiting period of up to approximately 2 years under reliable contraception is considered unpractical, prophylactic institution of a washout procedure may be advisable (see Warnings and Precautions, General, Washout Procedures).

Reliable contraception with oral contraceptive may not be guaranteed during the washout procedure with cholestyramine or activated charcoal. Use of alternative contraceptive methods is recommended.

Animal studies indicate that ARAVA or its metabolites pass into breast milk. Therefore, ARAVA must not be administered to nursing mothers (see Contraindications).

In studies with plasma samples obtained from healthy subjects, A771726 was extensively bound to protein (>99%) (albumin). The unbound fraction of A771726 was 0.62%. Binding of A771726 was linear up to 573 µg/mL. Compared to healthy subjects, the unbound fraction was slightly increased (0.80%) in plasma from patients with rheumatoid arthritis and was approximately doubled in patients with chronic renal insufficiency. The extensive protein binding of A771726 is consistent with its low volume of distribution. After independent intravenous administration of A771726, steady-state volume of distribution averaged 11 L.

The pharmacokinetics of leflunomide, based upon plasma concentrations of the active metabolite, A771726, have been studied in healthy subjects and in patients with rheumatoid arthritis.

After oral administration of a 100 mg dose of ¹⁴C-leflunomide to healthy volunteers, leflunomide was not detectable (<25 ng/mL) in plasma over the plasma sampling period (0.5 hrs to 37 days). Plasma concentrations of total radioactivity and A771726 were superimposable, demonstrating extensive conversion to the active metabolite A771726 during the absorption process. The minor metabolite 4-trifluoromethylaniline (TFMA) has been detected in the plasma of animals and man, but at concentrations (ng/mL) much less than those of A771726 (μg/mL). The slow but nearly complete recovery of radioactivity as metabolites indicated near complete absorption of leflunomide in man.

In a 24-week study in patients with rheumatoid arthritis, steady-state was reached between 7 and 8 weeks. Mean plasma A771726 concentrations 24 hours after a 100 mg loading dose (8.5 µg/mL) were twice those after a 50 mg loading dose (4.0 µg/mL). Pre-dose plasma concentrations after 24 weeks of dosing were linearly related to the maintenance dose (9, 18, and 63 µg/mL after 5, 10 or 25 mg/day, respectively). The pharmacokinetics of A771726 are, therefore, linear over the range of loading and maintenance doses to be used clinically.

After single doses of ARAVA to healthy subjects, peak plasma concentrations of A771726 were approached between 6 and 12 hours. Based on determination of A771726, the bioavailability of leflunomide from a tablet formulation relative to an oral solution was 80%. ARAVA administered with a high fat/high carbohydrate meal was bioequivalent to administration under fasted conditions.

Leflunomide is an isoxazole immunomodulatory agent which inhibits de novo pyrimidine synthesis and has antiproliferative activity. Following oral administration, it is rapidly metabolized to A771726, which is active in vitro and is presumed to be the active drug in vivo. Leflunomide has demonstrated prophylactic and therapeutic effects in animal models of autoimmune disease. In addition, leflunomide has exhibited antiinflammatory and weak analgesic and antipyretic activity. In a model of experimental septicemia, leflunomide did not alter the resistance of mice to bacterial pathogens.

In vitro, after mitogen stimulation, A771726 inhibits T-cell proliferation, DNA synthesis, and expression of certain cell surface and nuclear antigens directly involved in T-cell activation and proliferation. It inhibits antigen-stimulated proliferation of human peripheral blood mononuclear cells (PBMCs) and proliferation in transformed murine and human cell lines, in a dose-dependent fashion. The antiproliferative activity is reversed by the addition of uridine to the cell culture, indicating that A771726 acts at the level of the de novo pyrimidine biosynthesis.

Leflunomide inhibition of GvHD in vivo is also reversed by feeding uridine, further indicating that A771726 acts at the level of the de novo pyrimidine biosynthesis pathway.

It has been demonstrated that A771726 binds to and is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway important for DNA synthesis. In the heterotopic cardiac transplant model, DHODH activity is decreased in lymphocytes infiltrating heart allograft tissue in leflunomide-treated animals. In vitro, incubation of PHA/IL 2 stimulated human peripheral T cells with A771726 triggered cell cycle arrest at the GI phase or, in those cells undergoing DNA synthesis, at S phase. Exogenous uridine reversed this effect, and no increase in apoptotic cell numbers was observed. Increased levels of the tumor suppressor protein p53 with subsequent expression of the cyclin-dependent kinase (CDK) inhibitor p21 appear to mediate this reversible cell cycle arrest.

In vitro incubation of A771726 with rat, mouse, and human DHODH demonstrated inhibition of enzyme activity at concentrations lower than those, which exert antiproliferative effects upon rapidly dividing cells (10-367 mM). Rat and mouse enzymes are more sensitive to the inhibitory effect of A771726 (IC₅₀ 0.14±0.08 and 16±11 µM, respectively) than the human enzyme (IC₅₀ 46±6 µM).

Together, these data suggest that, in vivo at concentrations achievable in patients, leflunomide inhibits de novo pyrimidine synthesis in activated lymphocytes and other rapidly dividing cell populations resulting in reversible cell cycle arrest.

The inhibition of tyrosine kinase activities has also been reported for both in vitro and in vivo situations. These effects are observed at A771726 concentrations much higher than those needed for DHODH inhibition and could be secondary to the effect on DHODH. In addition, leflunomide orally and A771726 in vitro have been demonstrated to modulate the cell adhesion process in rheumatoid arthritis patients.

After oral administration of a 100 mg dose of ¹⁴C-leflunomide to healthy volunteers, urinary and fecal recovery of ¹⁴C-leflunomide over 28 days accounted for 43% and 48% of total radioactivity, respectively. Unchanged leflunomide was not detected in urine or feces. A771726 is cleared by slow excretion in feces, probably by biliary elimination and slow metabolism to the oxanilic acid metabolite excreted in urine.

After independent intravenous administration of A771726, clearance averaged 31 mL/hr and elimination half-life 10 days. A similar clearance estimate (29±17 mL/h) was obtained from population pharmacokinetics analysis of rheumatoid arthritis patients enrolled in pivotal safety and efficacy studies.

After single doses of ARAVA to healthy subjects, plasma concentrations of A771726 declined monoexponentially, with a half-life of approximately 8 days. After 24 weeks, the elimination half-life averaged 14-18 days.

The elimination half-life in patients is approximately 2 weeks. Oral administration of activated charcoal or cholestyramine is effective in enhancing the elimination of A771726. During oral administration of activated charcoal (50 g four times a day) or cholestyramine (8 g three times a day), the half-life of A771726 decreased to approximately 24 hours. Although the mechanism for the enhanced elimination is unknown, it may be related to interruption of enterohepatic recycling and/or dialysis across the gastrointestinal mucosa.

When subjects with end-stage renal disease were administered a single 100 mg dose of leflunomide orally, plasma concentrations of A771726 both prior to and after dialysis (chronic ambulatory peritoneal dialysis [CAPD] or hemodialysis) were comparable to those of healthy volunteers administered the same dose. With hemodialysis, A771726 was cleared somewhat more rapidly and with a shorter half-life. The pharmacokinetic parameters for the CAPD patients were consistent with the values for healthy volunteers.

Following oral administration, leflunomide is rapidly converted to the active metabolite, A771726. Animal studies suggest that conversion takes place during passage through both the gut wall and the liver.

The metabolic biotransformation of A771726 is not controlled by a single enzyme and has been shown to occur in microsomal and cytosolic cellular fractions.

The urinary metabolites were primarily glucuronide conjugates of leflunomide and an oxanilic acid derivative of A771726, while A771726 was the primary metabolite in the feces.