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Leflunomide

Pronunciation

Class: Disease-modifying Antirheumatic Drugs
Chemical Name: 5-Methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide
Molecular Formula: C12H9F3N2O2
CAS Number: 75706-12-6
Brands: Arava

Warning(s)

  • Pregnancy
  • Contraindicated in pregnant women and women of childbearing potential who are not using a reliable form of contraception.1 (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

  • Pregnancy must be excluded prior to initiation of therapy.1

  • Pregnancy must be avoided while the woman is receiving leflunomide and prior to completion of the drug elimination procedure following discontinuance of the drug.1 (See Drug Elimination Procedures Following Leflunomide Discontinuance under Dosage and Administration.)

  • Hepatotoxicity
  • Severe liver injury, including fatal liver failure, reported.1

  • Do not use in patients with preexisting liver disease or baseline ALT >2 times ULN; use with caution in patients receiving other potentially hepatotoxic drugs.1

  • Regular monitoring of ALT during therapy required; ALT >3 times ULN warrants interruption of therapy while cause is investigated.1 (See Hepatic Effects under Cautions.)

Introduction

Immunomodulating agent and disease-modifying antirheumatic drug (DMARD).1 2 3 4 5 6 7 8 12 13 14 15 17 Considered a prodrug since it is rapidly and almost completed metabolized to an active metabolite (A77 1726; commercially available as teriflunomide).2 3 4 8 12 13 14 15 72

Uses for Leflunomide

Rheumatoid Arthritis in Adults

Used to manage the signs and symptoms of rheumatoid arthritis, to improve physical function, and to retard structural damage associated with the disease.1 2 3 4 5 6 7 8 12 13 14 15 16 46 47 56 57 Efficacy comparable to that of methotrexate or sulfasalazine.2 5 6 16 56 57 58 59 64

Slideshow: Drug Treatment for Rheumatoid Arthritis - What Are Your Options?

Has been used with methotrexate in a limited number of adults.1 3 48 70 Used concomitantly with aspirin, NSAIAs, or low dosages of oral corticosteroids (e.g., prednisone 10 mg daily) in clinical studies.1 5 6

Solid Organ Transplantation

Has been used for the prevention of acute and chronic rejection in recipients of solid organ transplants (designated an orphan drug by FDA for this use).54 Evaluated in a limited number of renal or hepatic transplant recipients.60

Leflunomide Dosage and Administration

General

Drug Elimination Procedures Following Leflunomide Discontinuance

  • Plasma concentrations of the active metabolite of leflunomide (A77 1726; commercially available as teriflunomide) may be detectable in plasma for up to 2 years following discontinuance of the drug.44 45 72 Manufacturer recommends use of a drug elimination procedure whenever more rapid elimination is indicated or desirable.1

  • An 11-day cholestyramine regimen is recommended whenever leflunomide is discontinued in women of childbearing potential and should be considered in men who wish to father a child after discontinuing the drug; this regimen reduces plasma concentrations of A77 1726 to undetectable levels.1

  • A shorter regimen of cholestyramine or activated charcoal (≥1 day) can be used to hasten elimination of A77 1726 in other patients (see Prolonged Leflunomide Exposure following Discontinuance under Cautions).1 In patients who discontinued leflunomide because of hypersensitivity reaction, a more prolonged regimen may be necessary to achieve rapid and sufficient clearance of A77 1726.1

11-Day Cholestyramine Drug-Elimination Procedure

  • Cholestyramine 8 g orally 3 times daily for 11 days; the 11 days do not need to be consecutive unless plasma concentrations need to be reduced rapidly.1

  • Following completion of regimen, determine plasma concentrations of A77 1726 twice (≥14 days apart) to verify that concentrations are undetectable.1 If plasma concentrations exceed 0.02 mcg/mL, administer additional cholestyramine.1

Shorter Cholestyramine or Activated Charcoal Regimen

  • Cholestyramine (8 g 3 times daily) given orally for 24 hours reduces plasma concentrations of A77 1726 by approximately 40% in 24 hours and 49–65% in 48 hours.1

  • Alternatively, suspension of activated charcoal (50 g every 6 hours) given for 24 hours either orally or via nasogastric tube reduces plasma concentrations of A77 1726 by approximately 37% in 24 hours and 48% in 48 hours.1

  • Repeat the elimination procedure if clinically necessary.1

Concomitant Therapy for Rheumatoid Arthritis

  • Aspirin, NSAIAs, and low-dose corticosteroids may be continued.1 5 6

  • Used concomitantly with methotrexate in a limited number of patients.3 48 70 Manufacturer states that concomitant use with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold has not been adequately studied.1

Administration

Oral Administration

Usually administered orally as a single daily dose, without regard to meals.1

Dosage

Adults

Rheumatoid Arthritis in Adults
Oral

100 mg once daily for 3 days, then 20 mg once daily.1 2 5 6 If this dosage is not tolerated, decrease to 10 mg once daily.1 Discontinuance may be required in patients who experience hepatotoxicity.1 (See Hepatic Effects under Cautions.)

Eliminating the 3-day loading dose may decrease the risk of adverse effects (see Plasma Concentrations under Pharmacokinetics).1 Elimination of loading dose may be especially important for patients at increased risk of hematologic or hepatic toxicity.1

Solid Organ Transplantation
Renal or Hepatic Transplant Recipients
Oral

Initial loading dosage of 1.2–1.4 g (administered in divided doses over 5–7 days), then 10–120 mg daily.60

Prescribing Limits

Adults

Rheumatoid Arthritis in Adults
Oral

Maintenance therapy: Maximum 20 mg daily.1 Dosage of 25 mg daily associated with higher incidence of alopecia, weight loss, and increases in serum liver enzyme concentrations.1

Special Populations

Hepatic Impairment

Not recommended in patients with preexisting acute or chronic liver disease (including those who are seropositive for hepatitis B or C) or in patients with baseline ALT >2 times the ULN.1 2 68 (See Hepatic Impairment and also Hepatic Effects, under Cautions.)

Geriatric Patients

Routine dosage adjustment based on age is not necessary in patients >65 years of age.1

Cautions for Leflunomide

Contraindications

  • Known hypersensitivity to leflunomide or any ingredient in the formulation.1

  • Do not initiate leflunomide in pregnant women or women of childbearing potential unless the possibility of pregnancy has been excluded and an effective method of contraception has been started.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Warnings

Hepatic Effects

Possible hepatic reactions (e.g., hepatitis, jaundice/cholestasis); severe liver injury (e.g., liver failure, acute hepatic necrosis), sometimes fatal, reported rarely.1 55 64 68 Reactions generally occur within first 6–12 months of initiating therapy.55 68

Increased risk of liver injury in patients with preexisting liver disease and those receiving other hepatotoxic agents concomitantly.68 Do not use in patients with preexisting liver disease or baseline ALT >2 times ULN; use with caution in patients receiving other potentially hepatotoxic drugs.1 68

Monitor closely for hepatotoxicity.1 Determine serum ALT concentrations prior to initiation of therapy, at least once monthly during the first 6 months, and (if ALT concentrations remain stable) every 6–8 weeks thereafter.1 If leflunomide is used concomitantly with methotrexate, also follow American College of Rheumatology (ACR) guidelines for monitoring for methotrexate liver toxicity.1

Increases in serum concentrations of ALT and/or AST 1 2 5 6 7 8 generally are mild (≤2 times the ULN) and resolve despite continued administration.1 5 6 8

If ALT concentrations are >3 times the ULN, interrupt leflunomide therapy and investigate cause of ALT elevation.1 If leflunomide is the probable cause, administer cholestyramine to hasten drug elimination and monitor serum ALT concentration weekly until value is normal.1 If leflunomide is considered an unlikely cause of ALT elevation because another probable cause is found, may consider resuming leflunomide therapy.1

Infectious Complications

Opportunistic infections (e.g., Pneumocystis jiroveci pneumonia, tuberculosis [including extrapulmonary disease], aspergillosis) and serious infection, including sepsis and death, reported rarely.1 Most serious infections occurred in patients receiving concomitant therapy with immunosuppressive agents and/or with comorbid illness that, in addition to rheumatoid arthritis, could have predisposed them to infections.1

Interrupt leflunomide therapy and administer cholestyramine or charcoal if serious infection develops.1

Not recommended in patients with severe immunodeficiency or severe uncontrolled infections.1

Not evaluated in patients with latent tuberculosis infection; safety in such patients is not known.1 Evaluate all patients for latent tuberculosis prior to initiation of therapy.1 When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to leflunomide therapy.1

Hematologic Effects

Pancytopenia,1 2 53 61 agranulocytosis,1 and thrombocytopenia1 7 reported; these effects reported most frequently when leflunomide was given with or immediately after methotrexate or another immunosuppressive agent.1 Some patients had a history of clinically important hematologic abnormality.1

Anemia (including iron deficiency anemia), 1 ecchymosis,1 eosinophilia,1 leukopenia,1 2 8 neutropenia1 reported.

Monitor for hematologic toxicity.1 Determine platelet count, leukocyte count, and hemoglobin concentration or hematocrit prior to initiating therapy, once monthly during the first 6 months, then every 6–8 weeks.1 If used in conjunction with methotrexate or another immunosuppressive agent, determine platelet count, leukocyte count, and hemoglobin concentration or hematocrit once monthly throughout therapy.1 Consider continued monitoring in patients who discontinue leflunomide and receive subsequent therapy with a drug with known potential for hematological suppression.1

Discontinue leflunomide if evidence of bone marrow suppression occurs; consider use of a drug elimination procedure.1

Not recommended in patients with bone marrow dysplasia.1

Fetal/Neonatal Morbidity and Mortality

Can cause fetal toxicity.1 Because the risks clearly outweigh any possible benefits, leflunomide is contraindicated in pregnant women.1 10

Do not initiate in a woman of childbearing potential until pregnancy is excluded and use of a reliable form of contraception is confirmed.1 11

Pregnancy must be avoided during leflunomide therapy and prior to completion of the drug-elimination procedure following discontinuance of the drug.1

Discontinue leflunomide if the drug is administered inadvertently during pregnancy or if the patient becomes pregnant while receiving the drug.1 Use of a drug-elimination procedure to rapidly lower plasma concentrations of A77 1726 to undetectable concentrations early in pregnancy (i.e., at the first delay in menses) may decrease risk to fetus.1

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.1 11 To minimize risk, men wishing to father a child should consider discontinuing leflunomide therapy and undergoing an 11-day cholestyramine drug-elimination procedure.1

Malignancy

Increased risk of malignancy, particularly lymphoproliferative disorders, in patients receiving some immunosuppressant drugs.1 While an increased incidence of malignancies or lymphoproliferative disorders has not been observed in patients receiving leflunomide in clinical trials, long-term studies are needed to establish the precise risk.1 2

Sensitivity Reactions

Dermatologic Reactions

Stevens-Johnson syndrome,1 53 toxic epidermal necrolysis,1 53 and erythema multiforme1 53 reported rarely.

If severe skin reaction occurs, discontinue immediately; use of a drug-elimination procedure recommended.1

General Precautions

Prolonged Leflunomide Exposure following Discontinuance

Up to 2 years may be required for plasma concentrations of the active metabolite (A77 1726; commercially available as teriflunomide) to decrease to undetectable concentrations (<0.02 mcg/mL) following discontinuance of leflunomide.44 45 72 Manufacturer recommends a drug-elimination procedure when more rapid elimination of A77 1726 is indicated or desirable (see Drug Elimination Procedures Following Leflunomide Discontinuance under Dosage and Administration).1

Adverse effects or drug interactions associated with leflunomide may continue to occur after the patient is no longer receiving the drug.44 45

Manufacturer recommends a drug-elimination procedure following discontinuance in women of childbearing potential; procedure should be considered in men who wish to father a child after discontinuing the drug.1

A drug-elimination procedure also recommended 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, serious infection).1

A drug-elimination procedure may be appropriate in patients who will receive a drug with known potential for hematologic suppression following discontinuance of leflunomide.1

Pulmonary Effects

Interstitial lung disease (e.g., pneumonitis, pulmonary fibrosis) reported, including fatalities.1 In patients experiencing new or worsening pulmonary symptoms (e.g., cough, dyspnea) with or without fever, consider discontinuing leflunomide.1 If discontinuance is warranted, consider use of a drug elimination procedure.1

Cardiovascular Effects

Hypertension reported; evaluate BP at baseline and periodically during therapy.1

Specific Populations

Pregnancy

Category X.1

Pregnancy registry at 877-311-8972.1 (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Lactation

Do not use in nursing women; either proceed with nursing or initiate therapy with leflunomide, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy in pediatric patients not fully evaluated.1 Leflunomide has been used for treatment of polyarticular course juvenile rheumatoid arthritis in a limited number of children and adolescents 3–17 years of age;1 66 however, appropriate dosing in pediatric patients is not clear.66 67 Adverse effects observed in children were similar to those in adults.1 66

Geriatric Use

No overall differences in efficacy or safety relative to younger adults, but increased sensitivity cannot be ruled out.1

No difference in pharmacokinetics based on adult age; routine dosage adjustment is not needed.1

Hepatic Impairment

Use not recommended in patients with preexisting acute or chronic liver disease or baseline serum ALT concentrations >2 times the ULN because of possible increased risk of hepatotoxicity and liver’s role in formation of active metabolite and in recirculation and elimination of the drug.1 2 Not recommended in patients who are seropositive for hepatitis B or C.2 68 (See Hepatic Effects under Cautions.)

Renal Impairment

Use with caution; not evaluated in this population.1

Common Adverse Effects

Diarrhea, increased serum AST/ALT concentrations, alopecia, rash.1 5 6 7 8

Interactions for Leflunomide

Leflunomide's active metabolite, A77 1726 (commercially available as teriflunomide), inhibits CYP2C9.1 72

Drug interactions may continue to occur after patient no longer is receiving the drug.44 45

Drugs Affecting Hepatic Microsomal Enzymes

CYP2C9 substrates: Potential pharmacokinetic interaction (increased plasma concentrations of CYP2C9 substrate).1

Vaccines

Data not available regarding administration of vaccines in patients receiving leflunomide.1

Do not administer live vaccines to patients receiving leflunomide.1 49 Consider the long half-life of A77 1726 when administration of a live vaccine is being considered.1

Hepatotoxic Agents

Increase in adverse hepatic effects expected.1 68 Use with caution.1 68

DMARDs

Used concomitantly with methotrexate in a limited number of patients with rheumatoid arthritis (see Specific Drugs under Interactions).3 48 70 Manufacturer states that concomitant administration with antimalarials, azathioprine, methotrexate, penicillamine, or oral or injectable gold not adequately studied.1

Specific Drugs

Drug

Interaction

Comments

Anticoagulants

Increases in INR reported rarely in patients receiving warfarin;1 possible increases in plasma warfarin concentrations1

Monitor carefully1

Charcoal, activated

Decreased plasma concentrations and hastened elimination of A77 17261

Used for drug elimination1

Cholestyramine

Decreased plasma concentrations and hastened elimination of A77 17261

Used for drug elimination1

Cimetidine

Interaction unlikely1

Contraceptives, oral triphasic

Interaction unlikely1

Methotrexate

Pharmacokinetic interaction unlikely;1 increased incidence of adverse effects and increases in serum ALT1 3 70

Caution advised; monitor closely for hepatotoxicity (see Hepatic Effects under Cautions)1

NSAIAs

Used without any evidence of any change in effect;1 increased free fraction of diclofenac and ibuprofen1

Clinical importance of pharmacokinetic changes unknown1

Phenytoin

Possible increased plasma phenytoin concentration1

Clinical importance unknown1

Rifampin

Increased peak plasma concentrations of A77 17261

Caution advised1

Tolbutamide

Increased free fraction of tolbutamide1

Clinical importance unknown1

Leflunomide Pharmacokinetics

Absorption

Bioavailability

Following oral administration, leflunomide is rapidly converted to the active metabolite A77 1726 (commercially available as teriflunomide) in the GI mucosa and liver; peak plasma concentrations of A77 1726 usually occur within 6–12 hours.1 2 8 12 15 44 72

Food

High-fat meal does not appear to affect absorption of A77 1726.1

Plasma Concentrations

Therapy usually initiated with a loading dosage so that steady-state plasma concentrations are achieved relatively rapidly.1 Steady-state plasma concentrations of A77 1726 likely would not be attained for at least 2 months in the absence of the initial loading dosage used for rheumatoid arthritis.1

Distribution

Extent

Not fully characterized.1

A77 1726 distributes into milk in rats; not known whether distributed into human milk.1 72

Plasma Protein Binding

A77 1726: >99% (albumin).1 2 4 12 The percentage of unbound A77 1726 is slightly higher in those with rheumatoid arthritis.1 2

Special Populations

In patients undergoing CAPD or hemodialysis, percentage of unbound A77 1726 is twice that in healthy adults (1.51 versus 0.62%).1

Elimination

Metabolism

Specific enzyme(s) involved in the principal metabolism of leflunomide have not been determined; however, hepatic cytosolic and microsomal cellular fractions are sites of metabolism.1 2 8

Elimination Route

Excreted in urine principally as glucuronides and an oxanilic acid derivative of A77 1726 and by direct biliary excretion as A77 1726.1

Half-life

A77 1726: 14–18 days.1 2 4 12

Special Populations

Clearance decreased in children weighing ≤40 kg compared with adults and children weighing >40 kg.1 67

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Protect from light.1

Actions

  • A pharmacologically active metabolite (A77 1726; commercially available as teriflunomide) is responsible for essentially all of leflunomide’s activity in vivo.1 2 3 4 8 12 13 14 15 72

  • Mechanism of action in rheumatoid arthritis appears to principally involve regulation of autoimmune lymphocytes.2 5 8 12 14 15 18

  • Reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase.1 2 3 4 5 6 7 8 12 13 14 15 17 18 Inhibition of dihydroorotate dehydrogenase prevents production of ribonucleotide uridine monophosphate (rUMP) by the de novo pathway, which leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest.2 12 15 Thus, leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells.12 18

Advice to Patients

  • Risk of birth defects.1 Importance of clinicians informing women of childbearing potential 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 completed a drug-elimination procedure following discontinuance of the drug.1 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.1

  • Risk of rare, serious skin reactions.1 Importance of promptly reporting rash or mucous membrane lesions to their clinician.1

  • Potential for hepatotoxic effects; need for monitoring of liver enzymes.1 Importance of reporting symptoms such as unusual tiredness, abdominal pain, or jaundice to their clinician.1

  • Potential for hematologic toxicity; need for frequent hematologic monitoring.1 Importance of promptly reporting symptoms such as easy bruising or bleeding, recurrent infections, fever, paleness, or unusual tiredness to their clinician.1

  • Risk of interstitial lung disease.1 Importance of reporting any new or worsening respiratory symptoms.1

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.1

  • Importance of women informing clinicians if they are breast-feeding or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Leflunomide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

10 mg*

Arava

Sanofi-Aventis

Leflunomide Tablets

20 mg*

Arava

Sanofi-Aventis

Leflunomide Tablets

100 mg

Arava

Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Arava 10MG Tablets (SANOFI-AVENTIS U.S.): 30/$694.42 or 60/$1,376.88

Arava 20MG Tablets (SANOFI-AVENTIS U.S.): 30/$739.02 or 60/$1,425.02

Leflunomide 10MG Tablets (SANDOZ): 30/$64.99 or 90/$188.91

Leflunomide 20MG Tablets (PRASCO LABORATORIES): 30/$39.99 or 90/$110.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 2, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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45. Reviewers’ comments (personal observations).

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49. Immunex, Seattle, WA: Personal communication on etanercept.

50. Reviewers’ comments (personal observations) on etanercept.

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