Pronunciation: le-FLOO-noe-mide
Class: Antirheumatic agent

Trade Names

Arava
- Tablet, oral 10 mg
- Tablet, oral 20 mg
- Tablet, oral 100 mg

Apo-Leflunomide (Canada)
PMS-Leflunomide (Canada)
Sandoz Leflunomide (Canada)

Pharmacology

Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase and has antiproliferative and anti-inflammatory activity.

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Pharmacokinetics

Absorption

The T _max of the active metabolite is 6 to 12 h. Without a loading dose (100 mg per 3 days), steady-state plasma concentration would require nearly 2 mo of dosing. Bioavailability is approximately 80%.

Distribution

Steady-state Vd is 0.13 L/kg. More than 99.3% protein bound.

Metabolism

The specific site of metabolism is unknown. The major active metabolite responsible for all activity is A77 1726 (M1); 4-trifluor-methylaniline is the minor metabolite.

Elimination

The half-life is approximately 2 wk. Renally excreted, as well as by direct biliary excretion. Renal excretion is more significant in the first 96 h. Eliminated in urine (43%) and feces (48%). Primary urinary metabolites are leflunomide glucuronide and oxanilic acid derivative of M1. Primary fecal metabolite is M1. Cl of M1 is 31 mL/h.

Special Populations

Renal Function Impairment

In patients with chronic renal insufficiency requiring either continuous ambulatory peritoneal dialysis or hemodialysis, neither had a significant impact on circulating levels of M1. Free fraction of M1 was almost doubled, but mechanism for this is unknown. Because the kidney plays a role in drug elimination, use with caution.

Hepatic Function Impairment

Studies have not been done; however, leflunomide is not recommended in these patients.

Children

Children weighing 40 kg or less have a reduced Cl of M1 relative to adults.

Gender

Gender has not been shown to cause a consistent change in the pharmacokinetics of M1.

Tobacco use

Tobacco use has a 38% increase in Cl over nonsmokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.

Indications and Usage

Treatment of active rheumatoid arthritis (RA) in adults to reduce signs and symptoms, inhibit structural damage, and improve physical function.

Unlabeled Uses

Juvenile idiopathic arthritis.

Contraindications

Pregnancy; hypersensitivity to leflunomide or any components of the product.

Dosage and Administration

Rheumatoid Arthritis
Adults

PO 100 mg once daily for 3 days, followed by 20 mg once daily (max, 20 mg/day). If dosing at 20 mg/day is not well tolerated, the dosage may be decreased to 10 mg/day; carefully observe the patient because it may take several weeks for metabolite levels to decline.

General Advice

• Administer orally with or without food.
• Do not administer until baseline liver enzymes have been evaluated.

Storage/Stability

Store between 59° and 86°F. Protect from light.

Drug Interactions

Cholestyramine and charcoal

Decreased plasma levels of leflunomide. Unless being used to treat leflunomide toxicity or hypersensitivity, avoid cholestyramine in patients receiving leflunomide.

Hepatotoxic drugs

May potentiate the hepatotoxicity of leflunomide. Close clinical and laboratory monitoring (LFTs, CBC with differential and platelets) is indicated during coadministration.

NSAIDs and tolbutamide

Free-fraction serum concentrations were increased by leflunomide. The clinical importance of this finding is unknown. Monitor the clinical response. If an interaction is suspected, adjust the dose of these agents as needed.

Rifampin

May increase leflunomide serum levels. Coadminister with caution and provide close clinical and laboratory monitoring.

Vaccines, live

Vaccination with live vaccines is not recommended. Consider the long half-life of leflunomide when contemplating giving a live vaccine after discontinuing leflunomide.

Warfarin

Increased INR has been reported rarely during coadministration. Closely monitor coagulation parameters when starting, stopping, or changing the dose of leflunomide and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Hypertension (10%); chest pain (4%); angina pectoris, palpitation, tachycardia, varicose vein, vasculitis, vasodilation (1% to less than 3%).

CNS

Headache (13%); dizziness (7%); asthenia (6%); paresthesia (4%); anxiety, depression, insomnia, malaise, migraine, neuralgia, neuritis, sleep disorder, vertigo (1% to less than 3%); peripheral neuropathy (postmarketing).

Dermatologic

Alopecia (17%); rash (12%); pruritus (6%); dry skin, eczema (3%); acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, skin ulcer, subcutaneous nodule, sweating increased (1% to less than 3%); urticaria; erythema multiforme, Stevens-Johnson syndrome, TEN, vasculitis (including cutaneous necrotizing vasculitis) (postmarketing).

EENT

Rhinitis (5%); pharyngitis (3%); blurred vision, cataract, conjunctivitis, eye disorder, taste perversion (1% to less than 3%).

Endocrine

Diabetes mellitus, hyperthyroidism (1% to less than 3%).

GI

Diarrhea (27%); nausea (13%); dyspepsia (10%); GI/abdominal pain (8%); mouth ulcer, vomiting (5%); anorexia, gastroenteritis (3%); cholelithiasis, colitis, constipation, dry mouth, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, salivary gland enlarged, stomatitis/aphthous stomatitis, tooth disorder (1% to less than 3%); pancreatitis (postmarketing).

Genitourinary

UTI (5%); albuminuria, cystitis, dysuria, hematuria, menstrual disorder, pelvic pain, prostate disorder, urinary frequency, vaginal moniliasis (1% to less than 3%).

Hematologic-Lymphatic

Anemia (including iron deficiency anemia), ecchymosis (1% to less than 3%); eosinophilia; leukopenia less than 2,000 WBC/mm ³ (rare); transient thrombocytopenia (rare); agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia (postmarketing).

Hepatic

Abnormal liver enzymes (10%); hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis (postmarketing).

Hypersensitivity

Allergic reaction (5%); anaphylaxis, angioedema (postmarketing).

Metabolic-Nutritional

Weight loss (4%); hypokalemia (3%); CPK increased, peripheral edema, hyperglycemia, hyperlipidemia (1% to less than 3%).

Musculoskeletal

Back pain, joint disorder (8%); tenosynovitis (5%); arthralgia, leg cramps, synovitis (4%); arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, neck pain, tendon rupture (1% to less than 3%).

Respiratory

Respiratory tract infection (27%); bronchitis (8%); increased cough, sinusitis (5%); upper respiratory tract infection (4%); pneumonia (3%); asthma, dyspnea, epistaxis, lung disorder (1% to less than 3%); interstitial lung disease including interstitial pneumonitis and pulmonary fibrosis (postmarketing).

Miscellaneous

Injury accident (7%); flu syndrome, pain (4%); abscess, cyst, fever, hernia (1% to less than 3%); opportunistic infections, severe infections including sepsis (postmarketing).

Precautions

Warnings Pregnancy Contraindicated during pregnancy. Pregnancy must be excluded prior to initiation of therapy. Ensure reliable use of contraception in women of childbearing potential during therapy. Patients must avoid pregnancy prior to completion of the drug elimination procedure after leflunomide treatment. Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported. Do not use leflunomide in patients with preexisting acute or chronic liver disease or those with ALT more than twice the ULN before initiating treatment. Use caution when coadministering with other potentially hepatotoxic drugs.

Monitor CV Check BP before starting therapy and periodically thereafter. Hematologic Monitor Hgb or Hct, platelets, and WBC at baseline and monthly for 6 mo after starting therapy, and every 6 to 8 wk thereafter (monthly if used with concomitant methotrexate and/or other potential immunosuppressive agents). Hepatic Monitor ALT at least monthly for 6 mo after starting therapy, and every 6 to 8 wk thereafter. If methotrexate is given concurrently, American College of Rheumatology guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month. If ALT elevation greater than 3-fold the ULN occurs, interrupt leflunomide therapy while investigating the probable cause of the elevation. If the elevation is likely leflunomide-induced, initiate cholestyramine washout and monitor LFTs weekly until normalized. Consider resumption of leflunomide if leflunomide-induced liver injury is unlikely because another probable cause has been found.

Pregnancy

Category X . May cause fetal death or teratogenic effects. Contraindicated in women who are or may become pregnant. Do not start women of childbearing potential on leflunomide until pregnancy is excluded and it is confirmed that they are using reliable contraception. Advise men wishing to father a child to consider discontinuing the use of leflunomide and taking cholestyramine 8 g 3 times daily for 11 days.

Lactation

Undetermined. Do not use in breast-feeding women.

Children

Safety and efficacy in children have not been fully evaluated.

Hypersensitivity

Rare cases of Stevens-Johnson syndrome and TEN have been reported. If these conditions occur, stop leflunomide and initiate a drug elimination procedure.

Renal Function

Use with caution.

Hepatic Function

Use is not recommended in patients with hepatic impairment.

Drug elimination procedure

Without the drug elimination procedure, it may take up to 2 y to reach plasma M1 metabolite levels less than 0.02 mg/L because of individual variation in drug Cl. The following procedure is recommended to achieve nondetectable plasma levels (less than 0.02 mg/L) after stopping treatment:

• Administer cholestyramine 8 g 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.)
• Verify plasma levels less than 0.02 mg/L by 2 separate tests at least 14 days apart. If plasma levels are more than 0.02 mg/L, consider additional cholestyramine treatment.

If hypersensitivity is suspected, more prolonged administration of cholestyramine or charcoal may be needed to achieve rapid and sufficient Cl. Duration may be modified based on the clinical status of the patient.

Hematologic effects

Agranulocytosis, pancytopenia, and thrombocytopenia have been reported rarely. If evidence of bone marrow suppression occurs, stop treatment with leflunomide and administer cholestyramine or charcoal.

Immunosuppression

Not recommended for use in patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. May cause patients to become more susceptible to infections, including opportunistic infections (eg, aspergillosis, Pneumocystis jiroveci pneumonia, tuberculosis). Severe infections, including sepsis, which may be fatal, have been reported. If a severe infection occurs, it may be necessary to interrupt leflunomide and administer cholestyramine or charcoal.

Latent tuberculosis

Screen patients for latent tuberculosis infection with a tuberculin skin test prior to initiation of leflunomide.

Malignancy

Risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications, including leflunomide.

Renal effects

Leflunomide has a uricosuric effect. A separate effect of hypophosphaturia is seen in some patients.

Respiratory effects

Interstitial lung disease associated with fatal outcomes has been reported. Consider discontinuation of therapy in patients with new onset or worsening of pulmonary symptoms (eg, cough, dyspnea) with or without associated fever.

Overdosage

Symptoms

Abdominal pain, anemia, diarrhea, elevated LFTs, leukopenia.

Patient Information

• Advise patient that drug may be taken without regard to meals.
• Remind patient that other medications for RA may still be taken while taking this drug.
• Advise women that this drug may cause birth defects.
• Advise women to use effective contraception during treatment and not to attempt to become pregnant after stopping the drug until they have gone through the drug elimination procedure.
• Advise men wishing to father a child not to do so unless they have stopped the drug and have taken cholestyramine (part of drug elimination procedure) for 11 days.
• Advise patient to avoid live vaccines while taking this drug.
• Advise patient that diarrhea, headache, indigestion, and nausea are common adverse reactions and to inform health care provider if they occur and are intolerable.
• Advise patients of the possibility of rare, serious skin reactions. Instruct patients to inform their health care provider promptly if they develop a skin rash or mucous membrane lesions.
• Advise patients of the potential hepatotoxic effects and the need for monitoring of liver enzymes. Instruct patients to notify their health care provider if they develop symptoms such as abdominal pain, jaundice, or unusual tiredness.
• Advise patients that they may develop a lowering of their blood cell counts and advise them to have frequent hematologic monitoring. Instruct patients to notify their health care provider if they notice symptoms of easy bruising or bleeding, fever, paleness, recurrent infections, or unusual tiredness.
• Inform patients about the early warning signs of interstitial lung disease and advise them to contact their health care provider as soon as possible if these symptoms appear or worsen during therapy.

Copyright © 2009 Wolters Kluwer Health.