Total Cost
Free shipping on all orders

Powered by GeniusRx

leflunomide 10 mg tablet generic arava

Out of Stock Manufacturer WINTHROP US 00955173530
Out of Stock

Uses

Leflunomide is used for the management of the signs and symptoms of rheumatoid arthritis to improve physical function, and to retard structural damage associated with the disease in adults with moderate to severe active rheumatoid arthritis.

Leflunomide is being evaluated to determine whether the drug may have a possible role in patients undergoing transplantation, and leflunomide is designated an orphan drug by the US Food and Drug Administration (FDA) for prevention of acute and chronic rejection in solid organ transplant recipients.

Rheumatoid Arthritis in Adults

Leflunomide is used for the management of the signs and symptoms of rheumatoid arthritis in adults to improve physical function and to retard structural damage associated with the disease. Current data suggest that leflunomide is as effective as methotrexate or sulfasalazine for the management of rheumatoid arthritis in adults and may be a suitable alternative for these disease-modifying antirheumatic drugs (DMARDs); however, long-term experience with leflunomide is limited and the exact role of the drug in the management of rheumatoid arthritis remains to be determined. Leflunomide generally is well tolerated; however, serious hepatic reactions have occurred rarely in patients receiving the drug.(See Cautions: Hepatic Effects.) Leflunomide has been used concomitantly with methotrexate in a limited number of adults with rheumatoid arthritis.

Pharmacologic therapy for rheumatoid arthritis usually consists of combinations of nonsteroidal anti-inflammatory agents (NSAIAs), DMARDs, and/or corticosteroids. The ultimate goal in managing rheumatoid arthritis is to prevent or control joint damage, prevent loss of function, and decrease pain. Although NSAIAs may be useful for initial symptomatic treatment of rheumatoid arthritis, these drugs do not alter the course of the disease or prevent joint destruction. DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health-care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. DMARDs commonly used in the treatment of rheumatoid arthritis include etanercept, hydroxychloroquine, infliximab, leflunomide, methotrexate, and sulfasalazine. Less frequently used DMARDs include azathioprine, cyclosporine, minocycline, penicillamine, and/or oral or injectable gold compounds. The role of anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, in the management of rheumatoid arthritis remains to be established.

While many factors influence the choice of a DMARD, methotrexate has substantially greater long-term efficacy than other DMARDs and is used as the initial or anchor DMARD in many patients with rheumatoid arthritis. Because residual inflammation generally persists in patients receiving maximum dosages of a single DMARD, many rheumatoid arthritis patients are candidates for combination therapy to achieve optimum control. Although the most effective combination regimen of DMARDs has not been determined, regimens that have been found efficacious in clinical studies include combinations of methotrexate and cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, or infliximab.

Low-dose oral corticosteroids and local injection of corticosteroids are effective in relieving symptoms in patients with active rheumatoid arthritis. In addition, limited evidence indicates that low-dose corticosteroids slow the rate of joint damage.

Clinical Experience

Clinical evaluations of leflunomide have shown that usual dosages of the drug are more effective than placebo and as effective as methotrexate or sulfasalazine in the management of rheumatoid arthritis in adults. Response to leflunomide generally occurs 1 month after initiation of therapy and maximum improvement is achieved within 3-6 months. Durable responses have been maintained for up to 24 months in patients receiving leflunomide. Therapy with leflunomide reduces the number of swollen joints, pain, and duration of morning stiffness, improves the quality of life, and reduces disease activity as assessed by laboratory measures (i.e., ESR, CRP). In addition, leflunomide was more effective than placebo and as effective as methotrexate or sulfasalazine in retarding radiographic evidence of disease progression.

Therapy with a Single Disease-modifying Antirheumatic Drug

Leflunomide has been evaluated for the management of rheumatoid arthritis in adults with active disease (American Rheumatism Association criteria for rheumatoid arthritis with American College of Rheumatology [ACR] functional class I, II, III or IV) in a placebo-controlled phase 2 study and in 3 double-blind, placebo- and active-controlled phase 3 studies (studies US301, MN301, and MN302). Most adults included in these studies had received prior therapy with a DMARD; however, patients were required to discontinue DMARD therapy 28-30 days prior to study enrollment. Patients receiving stable dosages of NSAIAs and/or prednisone (10 mg daily or less) at study enrollment could continue such agents during these studies.

ACR criteria for a 20% improvement (ACR 20 response) in measures of disease activity was used as the principal measure of clinical response in studies evaluating the efficacy of leflunomide. An ACR 20 response is achieved if the patient experiences a 20% improvement in tender and swollen joint count, and a 20% or greater improvement in a least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory measures of disease activity (i.e., ESR or CRP level). ACR 50 and ACR 70 responses are defined using the same criteria with a level of improvement of 50 and 70%, respectively. The Sharp Score, a composite score of erosions and joint space narrowing in hands, wrists, and forefeet, was used as the principal measure of structural damage.

In study US301, 482 adults with rheumatoid arthritis (mean age: 54 years, mean disease duration: 6.7 years, mean number of DMARDs that failed: 0.8) were randomized to receive leflunomide (100 mg once daily for 3 days, then 20 mg once daily), methotrexate (7.5-20 mg once weekly), or placebo. All patients received folic acid 1 mg twice daily (to decrease methotrexate toxicity). At 12 months, an ACR 20 (intent-to-treat analysis) was achieved in 52% of patients receiving leflunomide, and an ACR 50 or 70 was achieved in 34 or 20%, respectively. An ACR 20 was observed at month 12 in 46 or 26% of patients receiving methotrexate or placebo, respectively; an ACR 50 was observed in 23 or 8%, respectively, and an ACR 70 was observed in 9 or 4% of patients, respectively. Evaluation at 12 months indicated that leflunomide therapy was associated with greater decreases in the number of tender joints (from 15.5 at baseline to 7.8), number of swollen joints (from 13.7 at baseline to 7), pain (from 5.9 at baseline to 3.7), HAQ disability index (from 1.3 at baseline to 0.85), ESR (from 38.4 mm/hour at baseline to 32.1), CRP (from 2.08 mg/dL at baseline to 1.46 mg/dL), and greater improvement in physician and patient assessments than placebo; improvement in these parameters in patients receiving leflunomide was essentially the same as that in patients receiving methotrexate. Radiographic analysis at month 12 indicated that leflunomide or methotrexate therapy was associated with less disease progression than placebo. Data from an extension of study US301 indicate that clinical and radiographic improvement observed in patients receiving leflunomide or methotrexate at 12 months was maintained at 24 months.

In study MN302, 999 adults with rheumatoid arthritis (mean age: 58 years, mean disease duration: 3.75 years, mean number of DMARDs that failed: 1.1) were randomized to receive leflunomide (100 mg daily for 3 days, then 20 mg daily) or methotrexate (7.5-15 mg weekly). Analysis at month 12 indicated that more patients receiving methotrexate achieved an ACR 20 than patients receiving leflunomide; the ACR 20 response rate in patients receiving leflunomide in this study was similar to the response rate reported in study US301. Improvements in the number of tender or swollen joints, pain, ESR, CRP, and physician and patient assessments observed in leflunomide-treated patients in study MN302 were similar to those observed in study US301. At month 12, disease progression as assessed by radiographic analysis in patients receiving leflunomide was similar to that in patients receiving methotrexate.

In study MN301, 358 adults with rheumatoid arthritis (mean age: 58.3-58.9 years, mean disease duration: 5.7-7.6 years, 40-53% had not received prior therapy with a DMARD) were randomized to receive leflunomide (100 mg daily for 3 days, then 20 mg daily), sulfasalazine (dose increased to 2 g daily over 1-4 weeks), or placebo. At 24 weeks, an ACR 20 or ACR 50 was achieved in 48 or 30%, respectively, of patients receiving leflunomide. An ACR 20 was observed at 24 weeks in 44 or 29% of patients receiving sulfasalazine or placebo, respectively; an ACR 50 was observed in 30 or 14%, respectively. Radiographic analysis at week 24 indicated that leflunomide or sulfasalazine therapy was associated with less disease progression than placebo.

Physical functioning and disability were assessed using the Health Assessment Questionnaire (HAQ) and the general health-related quality-of-life questionnaire SF-36. Leflunomide therapy was associated with greater improvement from baseline in all 8 HAQ Disability Index subscales (dressing, arising, eating, walking, hygiene, reach, grip, activities) and the SF-36 physical component summary score compared with placebo; in addition, leflunomide was at least as effective as methotrexate as measured by the HAQ Disability Index. Improvements in HAQ and SF-36 were maintained over 2 years.

Combination Therapy with Methotrexate

Leflunomide has been used concomitantly with methotrexate in a limited number of adults with rheumatoid arthritis, and there is some evidence from clinical studies that addition of leflunomide may be useful in patients who have a suboptimal response to methotrexate. However, additional study is needed to clarify the role of leflunomide in combination with methotrexate versus other therapies (e.g., changing from methotrexate to another DMARD, adding a DMARD other than leflunomide) in patients who have not responded adequately to methotrexate. Although some data from patients with rheumatoid arthritis who received leflunomide in combination with methotrexate indicate that the adverse effect profile in patients receiving concomitant therapy with the drugs is similar to that in patients receiving either leflunomide or methotrexate, increased serum concentrations of liver enzymes are frequently observed in such patients. In addition, serious hepatic reactions have occurred in patients receiving leflunomide in combination with methotrexate. The manufacturer of leflunomide states that concomitant use with methotrexate has not been adequately studied in controlled settings.(See Cautions: Precautions and Contraindications and see Drug Interactions: Methotrexate.)

Solid Organ Transplantation

Results of studies in animal models of transplantation indicate that leflunomide may provide some benefits when used in conjunction with other drugs for prevention of allograft rejection. There also is evidence from in vitro studies using human fibroblasts and endothelial cells infected with cytomegalovirus (CMV) that leflunomide's active metabolite (A77 1726; commercially available as teriflunomide) has antiviral activity against CMV. Leflunomide has been evaluated in a limited number of renal or hepatic transplant recipients. Experience with leflunomide in these patients indicates that the drug possesses substantial immunosuppressive potency. Although safety and efficacy of leflunomide in transplant recipients have not been established, the drug is designated an orphan drug by FDA for the prevention of acute and chronic rejection in recipients of solid organ transplants.

Dosage and Administration

Administration

Leflunomide is administered orally as a single daily dose. The drug may be taken without regard to meals.

When leflunomide is used for the management of rheumatoid arthritis, the manufacturer recommends that therapy be initiated with a loading dosage given for 3 days followed by the usual daily dosage. Eliminating the loading dose regimen may decrease the risk of adverse effects; this could be important for patients at increased risk of hematologic or hepatic toxicity (e.g., those currently receiving or who have recently received methotrexate or other immunosuppressive agents). If this initial loading dosage is not used, steady-state plasma concentrations may not be attained for 2 months or longer.

Aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), and low-dose corticosteroids may be continued in adults receiving leflunomide for the management of rheumatoid arthritis. Leflunomide has been used concomitantly with methotrexate in a limited number of patients with rheumatoid arthritis. The manufacturer states that concomitant administration of leflunomide with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold has not been adequately studied.

Dosage

Rheumatoid Arthritis in Adults

For the management of rheumatoid arthritis in adults 18 years of age or older, the recommended initial loading dosage of leflunomide is 100 mg once daily for 3 days. Dosage of leflunomide should then be decreased to 20 mg once daily. If this dosage is not tolerated, dosage may be decreased to 10 mg once daily. Because the incidence of some adverse effects is increased in patients receiving a higher dosage (25 mg once daily), dosages exceeding 20 mg daily are not recommended. Discontinuance of leflunomide may be necessary in patients who develop evidence of hepatotoxicity during therapy with the drug.(See Hepatic Precautions under Cautions: Precautions and Contraindications.)

Solid Organ Transplantation

In renal or hepatic transplant recipients, leflunomide has been given at an initial loading dosage of 1.2-1.4 g (administered in divided doses over 5-7 days), followed by maintenance dosages of 10-120 mg daily.

Dosage in Renal and Hepatic Impairment

Because of the possible role of the liver in the metabolism, elimination, and recirculation of leflunomide and because adverse hepatic effects have been reported with the drug, leflunomide is not recommended in patients with preexisting acute or chronic liver disease, including those who are seropositive for hepatitis B or C, or those with baseline serum ALT concentrations exceeding twice the upper limit of normal (ULN).

The manufacturer makes no specific recommendation for dosage adjustment in patients with renal impairment; however, caution is advised if leflunomide is used in such patients.

Drug Elimination Procedures

Because it can take up to 2 years for plasma concentrations of the active metabolite of leflunomide (A77 1726; commercially available as teriflunomide) to decrease to undetectable levels (less than 0.02 mcg/mL) following discontinuance of leflunomide, the manufacturer recommends use of a drug elimination procedure whenever more rapid elimination of A77 1726 is indicated or desirable. A drug elimination procedure should be used whenever leflunomide is discontinued in women of childbearing potential. A drug elimination procedure also is recommended in men who wish to father a child after discontinuance of leflunomide or when the drug is discontinued because of potentially serious adverse effects (e.g., persistently increased liver enzymes, severe dermatologic or sensitivity reactions, bone marrow suppression, pancytopenia, serious infection). A drug elimination procedure also may be appropriate in patients who are discontinuing leflunomide therapy and will receive subsequent therapy with a drug with a known potential for hematologic suppression.

An 11-day oral cholestyramine drug elimination procedure is recommended whenever leflunomide is discontinued in women of childbearing potential or in men who wish to father a child after discontinuing leflunomide since this regimen reduces plasma concentrations of A77 1726 to undetectable levels, thereby minimizing the risk of fetotoxicity. For this regimen, the manufacturer recommends that 8 g of oral cholestyramine be administered 3 times daily for 11 days (the 11 days do not need to be consecutive unless plasma concentrations need to be reduced rapidly). Following completion of the cholestyramine regimen, plasma concentrations of A77 1726 should be determined twice (at least 14 days apart) to verify that plasma concentrations are undetectable. If plasma concentrations of A77 1726 exceed 0.02 mcg/mL, additional cholestyramine should be administered.

A shorter regimen of cholestyramine or activated charcoal (1 or more days) can be used to hasten elimination of A77 1726 in other patients likely to benefit from a drug elimination procedure. In patients who discontinued leflunomide because of a hypersensitivity reaction, a more prolonged regimen may be necessary to achieve rapid and sufficient clearance of A77 1726. Oral cholestyramine (8 g 3 times daily) given for 24 hours has been shown to reduce plasma concentrations of A77 1726 by approximately 40% in 24 hours and 49-65% in 48 hours. Alternatively, administration of a suspension of activated charcoal (50 g every 6 hours) for 24 hours either orally or via a nasogastric tube has been shown to reduce plasma concentrations of A77 1726 by approximately 37% in 24 hours and 48% in 48 hours. These drug elimination procedures may be repeated if clinically necessary.

Cautions

Information on the safety of leflunomide has been obtained principally from uncontrolled studies and from placebo- and active-controlled clinical studies in adults with rheumatoid arthritis who received the drug for up to 12 months. At the usual dosage (10-20 mg once daily), leflunomide is well tolerated. Some of the most common adverse effects associated with leflunomide therapy in adults with rheumatoid arthritis include diarrhea, increased serum concentrations of liver enzymes, alopecia, and rash. In adult dose-ranging studies, the incidence of some adverse effects (i.e., alopecia, weight loss, increased serum concentrations of liver enzymes) was greater in patients receiving higher dosages of leflunomide (25 mg daily) than in those receiving lower dosages of the drug. About 15% of patients receiving leflunomide in clinical studies discontinued the drug because of adverse effects.

Hepatic Effects

Leflunomide therapy has been associated with reversible increases in serum concentrations of liver enzymes (principally increases in serum ALT [SGPT] and AST [SGOT]) in a substantial number of patients in clinical studies. Most increases in serum ALT and/or AST concentrations in patients receiving leflunomide were mild (no more than twice the upper limit of normal [ULN]) and resolved despite continued administration of leflunomide. Substantial increases in serum ALT (exceeding 3 times the ULN) occurred in 1.5-4.4% of patients receiving leflunomide in clinical studies (US301, MN301, MN302); these increases usually returned to concentrations no more than twice the ULN with continued therapy at a lower dosage or following discontinuance of leflunomide. Increases in serum concentrations of liver enzymes also have been observed in patients receiving leflunomide in conjunction with methotrexate. In a 6-month study that evaluated addition of leflunomide or placebo in patients (with normal liver function test values at study entry) with persistent active rheumatoid arthritis despite ongoing methotrexate therapy, substantial increases in serum ALT (3 times the ULN or greater) occurred in 3.8 or 0.8% of patients receiving leflunomide and methotrexate or methotrexate and placebo, respectively.(See Hepatic Precautions under Cautions: Precautions and Contraindications.)

Rare cases of severe liver injury, including cases with fatal outcome, have been reported to the US Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products. Hepatic reactions generally occurred within 6-12 months of initiation of leflunomide therapy; reactions included hepatitis, jaundice/cholestasis, and rarely, severe liver injury (e.g., liver failure, acute hepatic necrosis).

Of 296 reports to the European Agency as of March 12, 2001, 129 were considered serious and 9 were fatal. Confounding factors were present in many of these incidents; 78% of patients who experienced a serious reaction were receiving concomitant therapy with another hepatotoxic agent, and 58% of patients with increases in serum concentrations of liver enzymes were receiving concomitant therapy with methotrexate and/or nonsteroidal anti-inflammatory agents (NSAIAs). Other risk factors noted in 27% of those experiencing a serious reaction were history of alcohol abuse, liver function abnormality, acute heart failure, severe pulmonary disease, or pancreatic cancer. Preliminary analysis of these case reports by the European Agency suggests that clinicians did not fully adhere to the recommended liver function monitoring and/or drug elimination procedures.

In a subsequent safety review, FDA identified 49 cases of severe liver injury, reported between August 2002 and May 2009, in patients receiving leflunomide. Of the 49 patients, 36 required hospitalization; 14 patients died and an additional 5 patients required liver transplantation. Approximately 94% of the leflunomide-treated patients with severe liver injury also had received other potentially hepatotoxic drugs, and about 29% of the patients had preexisting liver disease and/or a history of alcohol abuse. FDA concluded that patients at greatest risk of leflunomide-associated liver injury are those receiving concomitant therapy with other potentially hepatotoxic agents and those with preexisting liver disease.

Increases in alkaline phosphatase have been reported rarely in patients receiving leflunomide. In study US301, criteria used to monitor liver toxicity associated with methotrexate led to liver biopsy in one patient receiving leflunomide; the biopsy was interpreted as Roenigk IIIA (mild fibrosis). Early cirrhosis was reported in one patient who received combination therapy with leflunomide and methotrexate in a clinical study; the patient, who had received methotrexate for about 4 years prior to the study, received methotrexate for a total of 7.5 years (total cumulative dose of about 4.5 g) and leflunomide for 3.5 years (total cumulative dose of 12.9 g). Increases in serum aminotransferase concentrations occurred intermittently during the first 18 months following initiation of combination therapy. In addition, decreases in the platelet count occurred after 9 months of combination therapy; low platelet counts (92,000-133,000/mm) persisted for the duration of the study (3.5 years). Liver biopsy at study end showed diffuse marked fibrous septal formation with architectural distortions consistent with early micronodular cirrhosis and mild steatosis, and nuclear variation without periseptal or lobular inflammation; the biopsy was interpreted as Roenigk IV.

Infectious Complications

Opportunistic infections and serious infection, including sepsis and death, have been reported rarely in patients receiving leflunomide and include Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia, tuberculosis (including extrapulmonary disease), and aspergillosis. Most serious infections reported in patients receiving leflunomide occurred in those receiving concomitant therapy with immunosuppressive agents and/or those with comorbid illness that, in addition to rheumatoid arthritis, could have predisposed them to infections.

Hematologic Effects

Adverse hematologic effects reported in less than 3% of patients receiving leflunomide include anemia (including iron deficiency anemia) and ecchymosis. Eosinophilia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, or pancytopenia has occurred rarely. Most cases of pancytopenia, agranulocytosis, and thrombocytopenia have occurred when leflunomide was given with or immediately after methotrexate or another immunosuppressive agent. In some cases, patients had a history of a clinically important hematologic abnormality.

GI and Biliary Effects

Diarrhea, nausea, GI/abdominal pain, or dyspepsia has occurred in 17, 9, 5-6, or 5%, respectively, of patients receiving leflunomide in clinical studies. Adverse GI effects reported in 3% of patients receiving leflunomide in clinical studies include anorexia, gastroenteritis, mouth ulcer, and vomiting. Cholelithiasis, colitis, constipation,esophagitis, flatulence, gastritis, gingivitis, melena, oral candidiasis, salivary gland enlargement, stomatitis including aphthous stomatitis, dry mouth, taste perversion, or tooth disorder has been reported in less than 3% of patients receiving leflunomide. Pancreatitis has been reported rarely.

Dermatologic and Sensitivity Reactions

Reversible alopecia has been reported in 10% of patients receiving leflunomide in clinical studies. Rash has been reported in 10% and pruritus in approximately 4% of leflunomide-treated patients. Acne, contact dermatitis, eczema, dry skin, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin nodule, subcutaneous nodule, skin disorder, skin discoloration, skin ulcer, sweat, or urticaria has been reported in less than 3% of leflunomide-treated patients.

During postmarketing surveillance, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and vasculitis (including cutaneous necrotizing vasculitis) have been reported rarely in patients receiving leflunomide.

Allergic reaction has occurred in 2% of patients receiving leflunomide in clinical studies. Drug rechallenge resulted in an anaphylactic reaction in at least one patient who had experienced rash while receiving leflunomide in a phase 2 study. Angioedema has been reported rarely.

Nervous System Effects

Headache, dizziness, or asthenia has occurred in 7, 4, or 3%, respectively, of patients receiving leflunomide in clinical studies. Other adverse nervous system effects reported in less than 3% of patients include anxiety, depression, malaise, insomnia, migraine, neuralgia, pain, neuritis, paresthesia, sleep disorder, and vertigo. Peripheral neuropathy has occurred rarely.

Respiratory Effects

Respiratory infection or bronchitis has occurred in 15 or 7%, respectively, of patients receiving leflunomide in clinical studies; however, respiratory infections have not been directly attributed to the drug. Increased cough and pharyngitis have each been reported in 3% of leflunomide-treated patients. Asthma, dyspnea, epistaxis, lung disorder, pneumonia, rhinitis, or sinusitis has occurred in less than 3% of patients receiving leflunomide. Interstitial lung disease, including pneumonitis and pulmonary fibrosis, has been reported rarely and sometimes has resulted in death.

Cardiovascular Effects

Hypertension was reported in 10% of patients receiving leflunomide in clinical studies. While patients randomized to receive leflunomide in clinical studies had a higher incidence of hypertension at baseline than patients randomized to other treatment, analysis of new-onset hypertension did not reveal any differences between patients receiving leflunomide and those receiving other therapy (i.e., placebo, sulfasalazine, methotrexate). Of 137 leflunomide-treated patients with hypertension, 135 received antihypertensive therapy; at follow-up, 76 had achieved antihypertensive treatment goals, one had achieved antihypertensive treatment goal with sequelae, and 60 were continuing antihypertensive therapy without achieving treatment goals (these patients did not have indications that their blood pressure was more difficult to control than expected).

Adverse cardiovascular effects reported in less than 3% of leflunomide-treated patients include angina pectoris, chest pain, palpitation, tachycardia, vasculitis, vasodilation, and varicose veins.

Musculoskeletal Effects

Back pain, joint disorder, or tenosynovitis has been reported in approximately 5, 4, or 3%, respectively, of patients receiving leflunomide. Arthralgia, arthrosis, bursitis, muscle cramps, myalgia, bone necrosis, bone pain, leg cramps, neck pain, and tendon rupture have occurred in less than 3% of patients receiving leflunomide.

Genitourinary Effects

Urinary tract infection has been reported in 5% of leflunomide-treated patients. Effects reported in less than 3% of leflunomide-treated patients include albuminuria, cystitis, dysuria, hematuria, menstrual disorder, vaginal candidiasis, pelvic pain, prostate disorder, and urinary frequency.

Ocular Effects

Blurred vision, cataract, conjunctivitis, or ocular disorder has occurred in less than 3% of leflunomide-treated patients.

Other Adverse Effects

Accidental injury, weight loss, or infection has occurred in 5, 4, or 4%, respectively, of patients receiving leflunomide. Abscess, cyst, diabetes mellitus, fever, flu-like syndrome, hernia, hyperglycemia,hyperlipidemia, hyperthyroidism, increased creatine kinase (CK, creatine phosphokinase, CPK) concentration, or peripheral edema has been reported in less than 3% of leflunomide-treated patients.

Precautions and Contraindications

Prolonged Leflunomide Exposure following Discontinuance

Because it can take up to 2 years for plasma concentrations of the active metabolite of leflunomide (A77 1726; commercially available as teriflunomide) to decrease to undetectable concentrations (less than 0.02 mcg/mL) following discontinuance of leflunomide, the possibility that adverse effects or drug interactions associated with the drug could continue to occur even though the patient is no longer receiving leflunomide should be considered. When more rapid elimination of A77 1726 is indicated or desirable, including following discontinuance of leflunomide in women of childbearing potential (see Pregnancy under Pregnancy, Fertility, and Lactation) or in patients with potentially serious drug-related adverse effects (e.g., persistently increased liver function test results, severe dermatologic or sensitivity reactions, bone marrow suppression, pancytopenia), the manufacturer recommends use of a drug elimination procedure. A drug elimination procedure also may be appropriate in patients who are discontinuing leflunomide therapy and will receive subsequent therapy with a drug with a known potential for hematologic suppression. For information on procedures to hasten elimination of leflunomide following discontinuance of the drug, see Dosage and Administration: Drug Elimination Procedures.

Hepatic Precautions

Leflunomide therapy has been associated with increased serum concentrations of liver enzymes in a substantial number of patients in clinical studies, and patients receiving leflunomide should be closely monitored for hepatotoxicity. Serum ALT concentrations should be determined prior to initiation of leflunomide and repeated periodically throughout therapy. During the initial 6 months of therapy, ALT should be determined at least once monthly; if ALT concentrations remain stable during the initial phase, ALT should be determined every 6-8 weeks thereafter. If leflunomide is used concomitantly with methotrexate, the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity also must be followed.

Guidance for discontinuance of leflunomide therapy based on the severity of ALT elevation has been provided by the manufacturer. If ALT concentrations exceed 3 times the ULN, leflunomide should be interrupted while the cause of the ALT elevation is investigated (e.g., by close observation and additional testing). If leflunomide is considered the likely cause of the ALT elevation, cholestyramine should be administered to hasten elimination of the active metabolite of leflunomide (see Dosage and Administration: Drug Elimination Procedures) and liver function tests should be evaluated weekly until values return to normal. If leflunomide is considered unlikely to have caused the ALT elevation because another probable cause of liver injury is identified, then resumption of leflunomide therapy may be considered.

Because of the liver's role in the metabolism, elimination, and recirculation of the drug, leflunomide therapy is not recommended in patients with preexisting acute or chronic liver disease or baseline serum ALT concentrations exceeding twice the upper limit of normal. In addition, leflunomide therapy is not recommended in patients who are seropositive for hepatitis B or C. Caution is advised when the drug is administered concurrently with other potentially hepatotoxic drugs.(See Drug Interactions: Hepatotoxic Agents.)

Other Precautions and Contraindications

Drugs with an immunosuppressive potential, including leflunomide, may increase susceptibility to infections, including opportunistic infections. Leflunomide therapy should be interrupted and cholestyramine or charcoal administered to hasten elimination of the active metabolite of leflunomide in any patient who develops a serious infection.(See Dosage and Administration: Drug Elimination Procedures.)

Leflunomide therapy has been associated with bone marrow suppression and patients receiving the drug should have their platelet count, leukocyte count, and hemoglobin concentration or hematocrit determined prior to initiation of leflunomide therapy and periodically throughout therapy. Platelet count, leukocyte count, and hemoglobin concentration or hematocrit should be determined once monthly during the first 6 months of therapy and every 6-8 weeks thereafter. Patients receiving leflunomide in conjunction with methotrexate or another immunosuppressive agent should have platelet count, leukocyte count, and hemoglobin concentration or hematocrit determined once monthly throughout therapy. If evidence of bone marrow suppression occurs during leflunomide therapy, the drug should be discontinued and use of a drug elimination procedure is recommended. Monitoring for hematologic toxicity should be considered in patients who discontinue leflunomide and receive subsequent therapy with a drug with a known potential for hematologic suppression.

Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely in patients receiving leflunomide, and patients should be advised of the possibility of these rare, serious skin reactions and instructed to inform their clinician promptly if they develop a skin rash or mucous membrane lesion. If such severe skin reactions occur, leflunomide should be discontinued immediately and use of a drug elimination procedure is recommended.

Interstitial lung disease, sometimes fatal, has been reported in patients receiving leflunomide. Interstitial lung disease may occur at any time during therapy, and patients should be advised to inform their clinician of new or worsening pulmonary symptoms (e.g., cough, dyspnea) occurring with or without fever. In patients experiencing pulmonary symptoms, discontinuance of leflunomide therapy and further evaluation, as clinically appropriate, should be considered.(See Dosage and Administration: Drug Elimination Procedures.) If discontinuance of leflunomide is warranted, use of a drug elimination procedure should also be considered.

Leflunomide should be used with caution in patients with renal impairment since the drug has not been evaluated clinically in this population and the kidneys play a role in elimination of the drug.

The risk of malignancy, particularly lymphoproliferative disorders, is increased in patients receiving some immunosuppressant drugs. The possibly exists that leflunomide may increase the risk of malignancy since the drug has the potential for immunosuppression. While an increased incidence of malignancies or lymphoproliferative disorders has not been observed in clinical studies to date, long-term experience is needed to determine any effect of leflunomide on the incidence of these disorders. Although not specifically studied in these groups, leflunomide therapy is not recommended in patients with severe immunodeficiency, bone marrow dysplasia, or severe uncontrolled infection since the drug has the potential for immunosuppression.

All patients should be evaluated for latent tuberculosis prior to initiation of leflunomide therapy. Leflunomide has not been evaluated in patients with latent tuberculosis infection, and safety of therapy with the drug in such individuals is unknown. When indicated, an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection should be initiated prior to leflunomide therapy.

Blood pressure should be measured before leflunomide therapy is initiated and monitored periodically during treatment.

Leflunomide is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Because of the embryotoxic and teratogenic effects of the drug, leflunomide should not be initiated in pregnant women or in women of childbearing potential unless the possibility of pregnancy has been excluded and an effective method of contraception has been started.(See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Pediatric Precautions

Safety and efficacy of leflunomide in pediatric patients with juvenile rheumatoid arthritis have not been fully evaluated. In a double-blind study, 94 children and adolescents 3-17 years of age with active polyarticular course juvenile rheumatoid arthritis (as defined by American College of Rheumatology [ACR] criteria) who had not previously received leflunomide or methotrexate therapy were randomized to receive either leflunomide or methotrexate for 16 weeks. Leflunomide dosage was based on the child's weight, with children weighing less than 20 kg receiving an initial dose of 100 mg (day 1 only) followed by a maintenance dosage of 10 mg every other day, those weighing 20-40 kg receiving an initial dosage of 100 mg daily for 2 days followed by a maintenance dosage of 10 mg daily, and those weighing more than 40 kg receiving an initial dosage of 100 mg daily for 3 days followed by a maintenance dosage of 20 mg daily; methotrexate was administered at a dosage of 0.5 mg/kg (maximum of 25 mg) weekly. At 16 weeks, an ACR Pediatric 30% (ACR Pedi 30) response (i.e., 30% or greater improvement in at least 3 of 6 and 30% or greater deterioration in no more than 1 of 6 core set criteria that include physician and patient/parent global assessments, active joint count, limitation of motion, functional assessment, and erythrocyte sedimentation rate [ESR]) was observed in 68% of children or adolescents receiving leflunomide compared with 89% of those receiving methotrexate. Leflunomide-treated patients who weighed more than 40 kg had a higher response rate than did those who weighed 40 kg or less. It has been suggested that leflunomide dosage was inadequate in children who weighed 40 kg or less, and pharmacokinetic analysis confirmed that concentrations of leflunomide's active A77 1726 metabolite (commercially available as teriflunomide) in these patients were lower than A77 1726 concentrations associated with clinical responses in adults with rheumatoid arthritis. The safety and efficacy of alternative dosage regimens (i.e., regimens predicted to provide A77 1726 concentrations comparable to those achieved in adults) remain to be established in clinical trials.

Adverse effects reported in pediatric patients receiving leflunomide generally are similar to those reported in adults; the most common adverse effects observed in children include abdominal pain, nausea, vomiting, diarrhea, oral ulcers, upper respiratory tract infections, headache, dizziness, alopecia, rash, and AST and/or ALT elevations.

Geriatric Precautions

When the total number of patients studied in clinical trials of leflunomide is considered, 234 patients were 65 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger adults, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Studies have not revealed differences in the pharmacokinetics of leflunomide based on adult age, and the manufacturer states that routine dosage adjustment is not necessary in geriatric patients older than 65 years of age.

Mutagenicity and Carcinogenicity

Leflunomide was not mutagenic in the Ames test, the unscheduled DNA synthesis assay, or the HGPRT gene mutation assay. In addition, leflunomide was not clastogenic in the in vivo mouse micronucleus assay or the cytogenetic test in Chinese hamster bone marrow cells. However, 4-trifluoromethylaniline (TFMA), a minor metabolite of leflunomide, was mutagenic in the Ames test and in the HGPRT gene mutation assay and was clastogenic in the in vitro assay for chromosome aberrations in Chinese hamster cells. TFMA was not clastogenic in the in vivo mouse micronucleus assay or the cytogenetic test in Chinese hamster bone marrow cells.

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral leflunomide dosages up to the maximally tolerated dose of 6 mg/kg daily (approximately 2.5% of the maximum human systemic exposure to A77 1726 based on the area under the plasma concentration-time curve [AUC]). However, in a 2-year bioassay, male mice exhibited an increased incidence in lymphoma at an oral dosage of 15 mg/kg daily, the highest dosage studied (1.7 times the human exposure to A77 1726 based on AUC). Female mice in the same study exhibited a dose-related increased incidence of bronchoalveolar adenomas and carcinomas beginning at 1.5 mg/kg daily (approximately 10% of the human exposure to A77 1726 based on AUC). The relevance of the findings in mice to the clinical use of leflunomide is not known.

Pregnancy, Fertility, and Lactation

Pregnancy

Leflunomide can cause fetal toxicity when administered to pregnant women. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. Leflunomide therapy should not be initiated in a woman of childbearing potential until pregnancy is excluded and it has been confirmed that the woman is using a reliable form of contraception.

Although there are no adequate and controlled studies to date in humans, leflunomide has been shown to increase the risk of fetal death or teratogenic effects in animals. Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, leflunomide is contraindicated in such women. The potential for increased risk of birth defects should be discussed with female patients of childbearing potential, and clinicians should advise women that they may be at increased risk of having a child with birth defects if they are pregnant, become pregnant while receiving leflunomide, or do not wait to become pregnant until they have followed a drug elimination procedure following discontinuance of leflunomide.

If leflunomide is administered inadvertently during pregnancy or if the patient becomes pregnant while receiving the drug, leflunomide should be discontinued and the patient informed of the potential hazard to the fetus. Women of childbearing potential should be advised to notify their clinician immediately if they experience a delay in menses or believe they may be pregnant so that pregnancy testing can be done. Use of a drug elimination procedure to rapidly lower plasma concentrations of A77 1726 to undetectable concentrations early in a pregnancy (i.e., at the first delay in menses) may decrease the risk to the fetus. To monitor fetal outcomes of pregnant women exposed to leflunomide, clinicians are encouraged to register such patients by calling 877-311-8972.

The manufacturer recommends that all women of childbearing potential receive an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable concentrations (less than 0.02 mcg/mL) following discontinuance of leflunomide therapy since these concentrations are presumed to be associated with minimal risk based on animal data. Following completion of the cholestyramine regimen, plasma concentrations of A77 1726 should be determined to verify that concentrations are undetectable. This is especially important in women who wish to become pregnant after discontinuing the drug.

Although available information does not indicate that leflunomide therapy is associated with an increased risk of male-mediated fetal toxicity, animal studies to evaluate this specific risk have not been conducted. To minimize risk, men wishing to father a child should consider discontinuing leflunomide therapy and undergoing an 11-day cholestyramine drug elimination procedure to decrease plasma concentrations of A77 1726 to undetectable levels.

Reproduction studies in rats and rabbits using leflunomide oral doses of 1 mg/kg have not revealed evidence of harm to the fetus. However, reproduction studies in rats using oral leflunomide dosages of 15 mg/kg daily during organogenesis (systemic exposure approximately 10% of the human exposure level to A77 1726 based on AUC) have shown teratogenic effects (most notably anophthalmia or microphthalmia and internal hydrocephalus). Under these exposure conditions, leflunomide also caused a decrease in maternal body weight, an increase in embryolethality, and a decrease in fetal body weight for surviving fetuses. Reproduction studies in rabbits using oral leflunomide dosages of 10 mg/kg daily during organogenesis (exposure equivalent to the maximum human exposure to A77 1726 based on AUC) resulted in fused, dysplastic sternebrae in offspring. In reproduction studies in female rats using leflunomide dosages of 1.25 mg/kg daily (systemic exposure approximately 1% of the human exposure level to A77 1726 based on AUC) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (exceeding 90%) decreases in postnatal survival.

Fertility

Reproduction studies in male or female rats using oral leflunomide dosages up to 4 mg/kg (exposure approximately 3.3% of the human exposure level to A77 1726 based on AUC) have not revealed evidence of impaired fertility.

Lactation

A77 1726 distributes into milk in rats. It is not known whether A77 1726 is distributed into human milk. Because of the potential for serious adverse reactions to leflunomide in nursing infants if it were distributed, a decision should be made whether to proceed with nursing or initiate therapy with leflunomide, taking into account the importance of the drug to the woman.

Drug Interactions

Although specific drug interaction studies are not available, leflunomide has been administered concomitantly with aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), or low dosages of oral corticosteroids (e.g., prednisone 10 mg daily) in clinical studies in patients with rheumatoid arthritis, and the manufacturer states that these drugs may be continued in patients receiving leflunomide. Leflunomide has been used concomitantly with methotrexate in a limited number of patients with rheumatoid arthritis, but the manufacturer states that concomitant administration of leflunomide with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold has not been adequately studied.(See Drug Interactions: Methotrexate and also see Nonsteroidal Anti-inflammatory Agents.)

Because it can take up to 2 years for plasma concentrations of the active metabolite of leflunomide (A77 1726; commercially available as teriflunomide) to decrease to undetectable concentrations following discontinuance of the drug, the possibility exists that drug interactions could occur in patients who are no longer receiving leflunomide therapy. The risk of such drug interactions can be reduced by use of a drug elimination procedure to hasten elimination of A77 1726 after discontinuance of leflunomide therapy.(See Dosage and Administration: Drug Elimination Procedures.) A drug elimination procedure may be appropriate in patients who are discontinuing leflunomide therapy and will receive subsequent therapy with a drug having a known potential for hematologic suppression. However, it is possible that such a strategy may worsen rheumatoid arthritis symptoms in patients who had been responding to leflunomide.

Drugs Affecting Hepatic Microsomal Enzymes

A77 1726 inhibits the cytochrome P-450 (CYP) isoenzyme 2C9, and the possibility exists that leflunomide therapy may alter the pharmacokinetics of drugs, including many nonsteroidal anti-inflammatory agents (NSAIAs), metabolized by this isoenzyme. In vitro studies indicate that A77 1726 inhibits metabolism of diclofenac to 4'-hydroxydiclofenac; however, the clinical importance of this finding is unknown.(See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Hepatotoxic Agents

Concomitant administration of leflunomide with hepatotoxic drugs is expected to result in an increase in adverse hepatic effects. Increased serum concentrations of liver enzymes are frequently observed in patients receiving leflunomide concomitantly with methotrexate.(See Drug Interactions: Methotrexate.) The possibility of an increased incidence in adverse effects should be considered if hepatotoxic drugs are administered in patients who previously received leflunomide, and use of a drug elimination procedure may be considered following discontinuance of leflunomide to minimize the risk of overlapping toxicity.

Anticoagulants

Results of in vitro studies indicate that warfarin does not affect protein binding of A77 1726. However, increases in the international normalized ratio (INR) have been reported rarely in patients receiving leflunomide in conjunction with warfarin.

Cholestyramine and Activated Charcoal

Administration of cholestyramine or activated charcoal in leflunomide-treated individuals reduces the plasma concentration and hastens elimination of A77 1726. In a limited number of healthy individuals, administration of cholestyramine 8 g 3 times daily for 24 hours reduced plasma A77 1726 concentrations 40 or 49-65% in 24 or 48 hours, respectively. Administration of a suspension containing activated charcoal 50 g every 6 hours for 24 hours orally or via a nasogastric tube reduced plasma A77 1726 concentrations 37 or 48% in 24 or 48 hours, respectively. Because it can take up to 2 years for plasma A77 1726 concentrations to fall to 0.02 mcg/mL following discontinuance of leflunomide, the manufacturer recommends administration of cholestyramine or activated charcoal when it is advisable to hasten elimination of A77 1726. An 11-day regimen of cholestyramine has been recommended to decrease plasma A77 1726 to undetectable concentrations (less than 0.02 mcg/mL).(See Dosage and Administration: Drug Elimination Procedures.)

Methotrexate

In clinical studies, concomitant use of leflunomide and methotrexate did not affect the pharmacokinetics of either drug. Limited data from patients receiving leflunomide in combination with methotrexate indicate that concomitant therapy generally is well tolerated and that the adverse effect profile is similar to that reported in patients receiving either leflunomide or methotrexate alone. However, increased serum concentrations of liver enzymes are observed frequently in such patients. In a 6-month study that evaluated addition of leflunomide or placebo in patients (with normal liver function test values at study entry) with persistent active rheumatoid arthritis despite ongoing methotrexate therapy, substantial increases in serum ALT (3 times the ULN or greater) occurred in 3.8 or 0.8% of patients receiving leflunomide and methotrexate or methotrexate and placebo, respectively. In a 1-year clinical study, 5 of 30 patients receiving concomitant leflunomide and methotrexate therapy experienced mild to moderate increases in liver enzyme concentrations (2-3 times the upper limit of normal [ULN]) and 5 patients experienced substantial increases in liver enzyme concentrations (exceeding 3 times the ULN); all increases resolved with continued therapy or discontinuance of leflunomide. Liver biopsy in 3 patients did not reveal evidence of marked fibrosis or cirrhosis. Early cirrhosis was reported in one patient who received combination therapy with leflunomide and methotrexate in a clinical study; the patient, who had received methotrexate for about 4 years prior to the study, received methotrexate for a total of 7.5 years (total cumulative dose of about 4.5 g) and leflunomide for 3.5 years (total cumulative dose of 12.9 g). Increases in serum aminotransferase concentrations occurred intermittently during the first 18 months following initiation of combination therapy. In addition, decreases in the platelet count occurred after 9 months of combination therapy; low platelet counts (92,000-133,000/mm) persisted for the duration of the study (3.5 years). Liver biopsy at study end showed diffuse marked fibrous septal formation with architectural distortions consistent with early micronodular cirrhosis and mild steatosis, and nuclear variation without periseptal or lobular inflammation; the biopsy was interpreted as Roenigk IV. There have been rare reports of pancytopenia, agranulocytosis, or thrombocytopenia in patients who received leflunomide concomitantly with or immediately following methotrexate.(See Cautions: Hematologic Effects.)

Nonsteroidal Anti-inflammatory Agents

Patients enrolled in clinical studies evaluating leflunomide have received concomitant NSAIAs without evidence of any change in effect. However, the possibility of a drug interaction cannot be ruled out since A77 1726 inhibits CYP2C9 and also affects protein binding of some NSAIAs. Although the clinical importance is unclear, results of in vitro studies using clinically relevant drug concentrations indicate that A77 1726 increases the free fraction of diclofenac and ibuprofen by 13-50%.

Rifampin

Administration of a single 100-mg oral dose of leflunomide in individuals receiving rifampin (600 mg once daily for 8 days) resulted in a 40% increase in peak plasma concentration of A77 1726. Because of the potential for substantial increases in plasma A77 1726 concentrations with continued administration of leflunomide, caution is advised if rifampin and leflunomide are used concomitantly.

Vaccines

Data are not available to date regarding administration of vaccines in patients receiving leflunomide. Although leflunomide is an immunomodulating agent, it is unclear whether the drug would affect the immune response to vaccines or the incidence and severity of adverse effects reported with vaccines. The manufacturer of leflunomide states that live vaccines should not be administered to patients receiving leflunomide. The long half-life of A77 1726 should be taken into account when administration of a live vaccine is being considered in a patient who previously received leflunomide.

Other Drugs

Although the clinical importance is unclear, in vitro studies indicate that A77 1726 increases protein binding of tolbutamide by 13-50%.

Results of drug interaction studies indicate that concomitant administration of leflunomide with triphasic oral contraceptives or cimetidine does not result in clinically important interactions.

Pharmacokinetics

Leflunomide is considered a prodrug since it is rapidly and almost completely metabolized in vivo to A77 1726, a pharmacologically active metabolite (commercially available as teriflunomide; also called M1). Because leflunomide generally is undetectable in plasma, pharmacokinetic studies of the drug mainly have focused on A77 1726.

The pharmacokinetics of leflunomide have been studied in healthy adults and in adults with rheumatoid arthritis. Studies in adults have not revealed differences in the pharmacokinetics of the drug based on gender or age. Limited information is available on pharmacokinetics of leflunomide in patients with renal impairment; the drug has not been studied in patients with hepatic impairment.

Absorption

Following oral administration of leflunomide, the drug is rapidly converted to A77 1726 in the GI mucosa and liver. Following oral administration of leflunomide tablets, peak plasma concentrations of A77 1726 usually occur within 6-12 hours. Leflunomide therapy usually is initiated with a loading dosage (100 mg once daily for 3 days) so that steady-state plasma concentrations are achieved relatively rapidly. It has been estimated that steady-state plasma concentrations of A77 1726 would not be attained for at least 2 months in the absence of this initial loading dosage.

Following oral administration of a single 50- or 100-mg dose of leflunomide in adults with rheumatoid arthritis, plasma A77 1726 concentrations of 4 or 8.4-8.5 mcg/mL, respectively, were obtained 24 hours after the dose. Following oral administration of leflunomide 100 mg once daily for 3 days followed by 10 or 25 mg once daily thereafter, plasma concentrations of A77 1726 at steady state were 18 or 63 mcg/mL, respectively, 24 hours after a dose. Studies using single doses (50-100 mg) and multiple doses (5-25 mg daily) indicate that plasma concentrations of A77 1726 are dose proportional.

Oral bioavailability of A77 1726 is not affected by concomitant administration of a high-fat meal. Oral bioavailability following oral administration of leflunomide tablets is 80% of that following administration of leflunomide oral solution (not commercially available in the US).

Distribution

Distribution of A77 1726 into body tissue and fluids has not been fully characterized. A77 1726 has a volume of distribution at steady state of 0.13 L/kg.

In healthy adults, A77 1726 is greater than 99% bound to albumin. While A77 1726 is highly protein bound in both healthy individuals and those with rheumatoid arthritis, the proportion of unbound A77 1726 is slightly higher in those with rheumatoid arthritis. In patients undergoing chronic ambulatory peritoneal dialysis (CAPD) or hemodialysis, the percent of unbound A77 1726 was twice that in healthy adults (1.51 versus 0.62%).

It is not known whether A77 1726 crosses the placenta in humans. A77 1726 distributes into milk in rats; it is not known whether A77 1726 distributes into human milk.

Elimination

Following oral administration of leflunomide, the drug is rapidly metabolized in the GI mucosa and liver to A77 1726, the cyanoacetic acid metabolite (commercially available as teriflunomide), and to many minor metabolites. A77 1726 represents more than 90% of leflunomide's metabolites. Of the minor metabolites, only 4-trifluoromethylaniline (TFMA) is present in sufficient quantity to be detected in low concentrations in the plasma of some patients. Although specific enzyme(s) involved in the principal metabolism of leflunomide have not been determined, hepatic cytosolic and microsomal cellular fractions have been identified as sites of metabolism.

The plasma elimination half-life of A77 1726 is 14-18 days (range: 5-40 days). The long half-life of A77 1726 results from the high level of protein binding of A77 1726 and the hepatobiliary recirculation of this metabolite. Following IV administration of A77 1726, clearance was estimated to be 31 mL/hour. Data from phase 3 studies indicate that clearance of A77 1726 is increased 38% in cigarette smokers compared with nonsmokers; there was no evidence that this increase affected efficacy. Analysis of population pharmacokinetic data from studies of oral leflunomide in children and adolescents 3-17 years of age with juvenile rheumatoid arthritis indicates that clearance of A77 1726 is decreased in children weighing 40 kg or less; clearance of A77 1726 was estimated to be 18 mL/hour in children weighing 40 kg or less compared with 26 mL/hour in those weighing more than 40 kg.(See Cautions: Pediatric Precautions.)

Leflunomide is excreted in urine as glucuronide conjugates; A77 1726 also is excreted in urine as metabolites and by direct biliary excretion. Renal elimination is the predominant route over the first 96 hours of leflunomide therapy, after which fecal elimination becomes the major route. In a 28-day drug elimination study using a single oral dose of radiolabeled leflunomide, about 43% of the dose was excreted in urine and 48% in feces. Leflunomide glucuronides and oxanilic acid derivatives of A77 1726 were the principal metabolites in urine, and A77 1726 was the principal metabolite identified in feces.

Because it can take up to 2 years for plasma A77 1726 concentrations to decrease to undetectable concentrations (less than 0.02 mcg/mL) following discontinuance of leflunomide, the manufacturer recommends use of a drug elimination procedure when it is advisable to hasten elimination of A77 1726. Since A77 1726 is reabsorbed via enterohepatic recirculation, oral administration of cholestyramine or charcoal can hasten the removal of A77 1726 from the body. In a limited number of healthy adults, administration of cholestyramine 8 g 3 times daily for 24 hours reduced plasma A77 1726 concentrations 40 or 49-65% in 24 or 48 hours, respectively. Administration of activated charcoal (as a suspension) 50 g every 6 hours for 24 hours orally or via a nasogastric tube reduced plasma A77 1726 concentrations 37 or 48% in 24 or 48 hours, respectively. An 11-day regimen of oral cholestyramine (8 g 3 times daily) decreases A77 1726 to undetectable concentrations.(See Dosage and Administration: Drug Elimination Procedures.)

A77 1726 is not substantially removed by CAPD or hemodialysis.

Write Your Own Review

Your meds on autopilot. Forever.