No

Antimetabolite

Treatment of active rheumatoid arthritis to reduce signs and symptoms and to retard structural damage as evidenced by x-ray erosions and joint space narrowing

X

Has been associated with teratogenic and embryolethal effects in animal models at low doses. Leflunomide is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be excluded prior to initiating treatment. Following treatment, pregnancy should be avoided until the drug elimination procedure is completed.

Pregnancy/breast-feeding; known hypersensitivity to leflunomide or any component

Hepatic disease (including seropositive hepatitis B or C patients) may increase risk of hepatotoxicity; immunosuppression may increase the risk of lymphoproliferative disorders or other malignancies; women of childbearing potential should not receive leflunomide until pregnancy has been excluded, patients have been counseled concerning fetal risk and reliable contraceptive measures have been confirmed. Caution in renal impairment. Not recommended for patients with severe immune deficiency, bone marrow dysplasia or uncontrolled infection. Has been associated with rare pancytopenia; use with caution in patients with a prior history of significant hematologic abnormalities. Discontinue if evidence of bone marrow suppression occurs, and begin procedure for accelerated removal (cholestyramine and activated charcoal, see Toxicology/Overdose). The use of live vaccines is not recommended. Leflunomide will increase uric acid excretion.

>10%:

Gastrointestinal: Diarrhea (17%)

Respiratory: Respiratory tract infection (15%)

1% to 10%:

Cardiovascular: Hypertension (10%), chest pain (2%), palpitation, tachycardia, vasculitis, vasodilation, varicose vein, edema (peripheral)

Central nervous system: Headache (7%), dizziness (4%), pain (2%), fever, malaise, migraine, anxiety, depression, insomnia, sleep disorder

Dermatologic: Alopecia (10%), rash (10%), pruritus (4%), dry skin (2%), eczema (2%), acne, dermatitis, hair discoloration, hematoma, herpes infection, nail disorder, subcutaneous nodule, skin disorder/discoloration, skin ulcer, bruising

Endocrine & metabolic: Hypokalemia (1%), diabetes mellitus, hyperglycemia, hyperlipidemia, hyperthyroidism, menstrual disorder

Gastrointestinal: Nausea (9%), abdominal pain (5%), dyspepsia (5%), weight loss (4%), anorexia (3%), gastroenteritis (3%), stomatitis (3%), vomiting (3%), cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, candidiasis (oral), enlarged salivary gland, tooth disorder, xerostomia, taste disturbance

Genitourinary: Urinary tract infection (5%), albuminuria, cystitis, dysuria, hematuria, vaginal candidiasis, prostate disorder, urinary frequency

Hematologic: Anemia

Hepatic: Abnormal LFTs (5%)

Neuromuscular & skeletal: Back pain (5%), joint disorder (4%), weakness (3%), tenosynovitis (3%), synovitis (2%), arthralgia (1%), paresthesia (2%), muscle cramps (1%), neck pain, pelvic pain, increased CPK, arthrosis, bursitis, myalgia, bone necrosis, bone pain, tendon rupture, neuralgia, neuritis

Ocular: Blurred vision, cataract, conjunctivitis, eye disorder

Respiratory: Bronchitis (7%), cough (3%), pharyngitis (3%), pneumonia (2%), rhinitis (2%), sinusitis (2%), asthma, dyspnea, epistaxis, lung disorder

Miscellaneous: Infection (4%), accidental injury (5%), allergic reactions (2%), diaphoresis

<1%: Anaphylaxis, urticaria, eosinophilia, thrombocytopenia, leukopenia, pancytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis

There is no human experience with overdosage. Leflunomide is not dialyzable. Cholestyramine and/or activated charcoal enhance elimination of leflunomide's active metabolite (MI). In cases of significant overdose or toxicity, cholestyramine 8 g every 8 hours for 1-3 days may be administered to enhance elimination. Plasma levels are reduced by approximately 40% in 24 hours and 49% to 65% after 48 hours of cholestyramine dosing.

Cytochrome P-450 2C9 enzyme inhibitor

Decreased effect: Administration of cholestyramine and activated charcoal enhance the elimination of leflunomide's active metabolite

Protect from light; store at 25°C (77°F)

Inhibits pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects

Distribution: V_d: 0.13 L/kg

Metabolism: Hepatic, to A77 1726 (MI) which accounts for nearly all pharmacologic activity; further metabolism to multiple inactive metabolites

Bioavailability: 80%

Half-life: Mean 14-15 days; enterohepatic recycling appears to contribute to the long half-life of this agent, since activated charcoal and cholestyramine substantially reduce plasma half-life

Time to peak: 6-12 hours

Elimination: Urine 43%; Feces 48%

Adults: Oral: Initial: 100 mg/day for 3 days, followed by 20 mg/day; dosage may be decreased to 10 mg/day in patients who have difficulty tolerating the 20 mg dose. Due to the long half-life of the active metabolite, plasma levels may require a prolonged period to decline after dosage reduction.

Dosing adjustment in renal impairment: No specific dosage adjustment is recommended. There is no clinical experience in the use of leflunomide in patients with renal impairment. The free fraction of MI is doubled in dialysis patients. Patients should be monitored closely for adverse effects requiring dosage adjustment.

Dosing adjustment in hepatic impairment: No specific dosage adjustment is recommended. Since the liver is involved in metabolic activation and subsequent metabolism/elimination of leflunomide, patients with hepatic impairment should be monitored closely for adverse effects requiring dosage adjustment.

Guidelines for dosage adjustment or discontinuation based on the severity and persistence of ALT elevation secondary to leflunomide have been developed. For ALT elevations >2 times the upper limit of normal, dosage reduction to 10 mg/day may allow continued administration. Cholestyramine 8 g 3 times/day for 1-3 days may be administered to decrease plasma levels. If elevations >2 times but less than or equal to 3 times the upper limit of normal persist, liver biopsy is recommended. If elevations >3 times the upper limit of normal persist despite cholestyramine administration and dosage reduction, leflunomide should be discontinued and drug elimination should be enhanced with additional cholestyramine as indicated.

Elderly: Although hepatic function may decline with age, no specific dosage adjustment is recommended. Patients should be monitored closely for adverse effects which may require dosage adjustment.

No interactions with food have been noted

Serum transaminase determinations at baseline and monthly during the initial phase of treatment; if stable, monitoring frequency may be decreased to intervals determined by the individual clinical situation

May cause dizziness, malaise, anxiety, depression, or insomnia

May rarely cause leukopenia, caution with clozapine and carbamazepine

No information available to require special precautions

1% to 10% of patients may experience stomatitis (3%), gingivitis, candidiasis (oral), enlarged salivary gland, tooth disorder, dry mouth, and taste disturbance

Take as directed; do not increase dose without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). Store medication away from light. You may experience diarrhea (buttermilk, boiled milk, or yogurt may help); nausea, vomiting, loss of appetite, and flatulence (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known). If diabetic, monitor blood sugars closely; this medication may alter glucose levels. Report chest pain, palpitations, rapid heartbeat, or swelling of extremities; persistent gastrointestinal problems; skin rash, redness, irritation, acne, ulcers, or easy bruising; frequency, painful or difficult urination, or genital itching or irritation; depression, acute headache, anxiety, or difficulty sleeping; weakness, muscle tremors, cramping or weakness, back pain, or altered gait; cough, cold symptoms, wheezing, or difficulty breathing; easy bruising/bleeding; blood in vomitus, stool, urine; or other unusual effects related to this medication. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant or have sex unless using appropriate barrier contraception while on this medication. This drug may cause severe fetal defects. Do not breast-feed.

Tablet: 10 mg, 20 mg, 100 mg

Fox RI, "Mechanism of Action of Leflunomide in Rheumatoid Arthritis," J Rheumatol, 1998, 53:20-6.

"New Drugs for Rheumatoid Arthritis," Med Lett Drugs Ther, 1998, 40(1040):110-2.

Popovic M, Stefanovic D, Pejnovic N, et al, "Comparative Study of the Clinical Efficacy of Four DMARDs (Leflunomide, Methotrexate, Cyclosporine, and Levamisole) in Patients With Rheumatoid Arthritis," Trans Proc, 1998, 30(8):4135-6.

Rozman B, "Clinical Experience With Leflunomide in Rheumatoid Arthritis," J Rheumatol, 1998, 53:27-32.

Smolen JS, Kalden JR, Scott DL, et al, "Efficacy and Safety of Leflunomide Compared With Placebo and Sulfasalazine in Active Rheumatoid Arthritis: A Double-Blind, Ramdomised, Multicentre Trial," Lancet, 1999, 353(9149):259-66.