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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(le FLOO noh mide)
U.S. Brand Names
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of active rheumatoid arthritis; indicated to reduce signs and symptoms, and to inhibit structural damage and improve physical function
Use: Unlabeled/Investigational
Treatment of cytomegalovirus (CMV) disease in transplant recipients; prevention of acute and chronic rejection in recipients of solid organ transplants
Pregnancy Risk Factor
X
Pregnancy Considerations
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. [U.S. Boxed Warning]: Women of childbearing potential should not receive therapy until pregnancy has been excluded, they have been counseled concerning fetal risk, and reliable contraceptive measures have been confirmed. Following treatment, pregnancy should be avoided until undetectable serum concentrations (<0.02 mg/L) are verified. This may be accomplished by the use of an enhanced drug elimination procedure using cholestyramine. Serum concentrations <0.02 mg/L should be verified by two separate tests performed at least 14 days apart. If serum concentrations are >0.02 mg/L, additional cholestyramine treatment should be considered. Pregnant women exposed to leflunomide should be registered with the pregnancy registry (877-311-8972). It is not known if males taking leflunomide may contribute to fetal toxicity. Males taking leflunomide who wish to father a child should consider discontinuing therapy and using the cholestyramine procedure to eliminate the medication.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known whether leflunomide is secreted in human milk. Because the potential for serious adverse reactions exists in the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Contraindications
Hypersensitivity to leflunomide or any component of the formulation; pregnancy
Warnings/Precautions
Boxed warnings:
• Women of childbearing potential: See “Special populations” below.
Concerns related to adverse effects:
• Dermatologic reactions: Rare cases of dermatologic reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported; discontinue if evidence of severe dermatologic reaction occurs, and begin procedure to enhance elimination (cholestyramine or activated charcoal).
• Hepatotoxicity: Use has been associated with rare reports of hepatotoxicity, hepatic failure, and death. Multiple risk factors for hepatotoxicity including hepatic disease (including seropositive hepatitis B or C patients) and/or concurrent exposure to other hepatotoxins may increase the risk of hepatotoxicity. Most severe cases occur within 6 months of initiation; monitoring of hepatic function is required. Dose adjustment or discontinuation with the enhanced elimination protocol may be needed based on the persistence and severity of ALT elevation.
• Immunosuppression: May increase susceptibility to infection, including opportunistic pathogens. Severe infections, sepsis, and fatalities have been reported. Not recommended in patients with severe immunodeficiency.
• Infections: Caution should be exercised when considering the use in patients with a history of new/recurrent infections, with conditions that predispose them to infections, or with chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued and drug elimination procedures initiated.
• Interstitial lung disease: Use has been associated (rarely) with interstitial lung disease; discontinue in patients who develop new onset or worsening of pulmonary symptoms. Enhanced elimination procedures should be considered if interstitial lung disease occurs; fatal outcomes have been reported.
• Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma.
Disease-related concerns:
• Hematologic disorders: Use with caution in patients with a prior history of significant hematologic abnormalities; avoid use with bone marrow dysplasia. Use has been associated with rare pancytopenia, agranulocytosis, and thrombocytopenia, generally when given concurrently or recently with methotrexate or other immunosuppressive agents. Monitoring of hematologic function is required; discontinue if evidence of bone marrow suppression and begin procedure to enhance elimination (cholestyramine or activated charcoal).
• Hepatic disease: Due to risk of toxicity, use in patients with hepatic impairment or evidence of hepatitis B or C infection is not recommended.
• Renal impairment: Use with caution in patients with renal impairment.
• Tuberculosis: Safety and efficacy have not been established in patients with latent tuberculosis infection. Patients should be screened for tuberculoses and if necessary, treated prior to initiating therapy.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
• Women of childbearing potential: [U.S. Boxed Warning]: Women of childbearing potential should not receive therapy until pregnancy has been excluded, they have been counseled concerning fetal risk and reliable contraceptive measures have been confirmed.
Other warnings/precautions:
• Enhanced elimination procedure: Due to variations in clearance, it may take up to 2 years to reach low levels of leflunomide metabolite serum concentrations. A drug elimination procedure using cholestyramine or activated charcoal is recommended when a more rapid elimination is needed.
• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of live vaccines in patients receiving therapy.
Adverse Reactions
>10%:
Gastrointestinal: Diarrhea (17%)
Respiratory: Respiratory tract infection (4% to 15%)
1% to 10%:
Cardiovascular: Hypertension (10%), chest pain (2%), edema (peripheral), palpitation, tachycardia, vasodilation, varicose vein, vasculitis
Central nervous system: Headache (7%), dizziness (4%), pain (2%), fever, malaise, migraine, anxiety, depression, insomnia, sleep disorder, vertigo
Dermatologic: Alopecia (10%), rash (10%), pruritus (4%), dry skin (2%), eczema (2%), acne, bruising, dermatitis, hair discoloration, hematoma, nail disorder, skin disorder/discoloration, skin ulcer, subcutaneous nodule
Endocrine & metabolic: Hypokalemia (1%), diabetes mellitus, hyperglycemia, hyperlipidemia, hyperthyroidism, menstrual disorder
Gastrointestinal: Nausea (9%), abdominal pain (5% to 6%), dyspepsia (5%), weight loss (4%), anorexia (3%), gastroenteritis (3%), stomatitis (3%), vomiting (3%), candidiasis (oral), colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, mouth ulcer, salivary gland enlarged, taste disturbance, tooth disorder, xerostomia
Genitourinary: Urinary tract infection (5%), albuminuria, cystitis, dysuria, prostate disorder, urinary frequency, vaginal candidiasis
Hematologic: Anemia
Hepatic: Abnormal LFTs (5%), cholelithiasis
Local: Abscess
Neuromuscular & skeletal: Back pain (5%), joint disorder (4%), weakness (3%), tenosynovitis (3%), synovitis (2%), paresthesia (2%), arthralgia (1%), leg cramps (1%), arthrosis, bone necrosis, bone pain, bursitis, CPK increased, myalgia, neck pain, neuralgia, neuritis, pelvic pain, tendon rupture
Ocular: Blurred vision, cataract, conjunctivitis, eye disorder
Renal: Hematuria
Respiratory: Bronchitis (7%), cough (3%), pharyngitis (3%), pneumonia (2%), rhinitis (2%), sinusitis (2%), asthma, dyspnea, epistaxis
Miscellaneous: Accidental injury (5%), infection (4%), allergic reactions (2%), cyst, diaphoresis, flu-like syndrome, hernia, herpes infection
<1%, postmarketing and/or case reports: Agranulocytosis, anaphylaxis, angioedema, cholestasis, cutaneous necrotizing vasculitis, eosinophilia, erythema multiforme; hepatotoxicity (rare, including hepatic necrosis and hepatic failure, some fatalities reported); hepatitis, interstitial lung disease, jaundice, leukopenia, necrolysis, neutropenia, opportunistic infection, pancreatitis, pancytopenia, peripheral neuropathy, pneumonitis (interstitial), pulmonary fibrosis, sepsis, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, urticaria
Metabolism/Transport Effects
Inhibits CYP2C9 (weak)
Drug Interactions
Bile Acid Sequestrants: May decrease serum concentrations of the active metabolite(s) of Leflunomide. Management: Unless using this combination to intentionally enhance leflunomide elimination, consider an alternative to the bile acid sequestrants when possible. Separating drug administration is not likely to be effective at avoiding this interaction. Risk D: Consider therapy modification
Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Risk C: Monitor therapy
Charcoal, Activated: May decrease serum concentrations of the active metabolite(s) of Leflunomide. Management: Unless using this combination to intentionally enhance leflunomide elimination, consider an alternative to charcoal when possible. Separating drug administration is not likely to be effective at avoiding this interaction. Risk D: Consider therapy modification
CYP2C9 Substrates (High risk): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Immunosuppressants: May enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Methotrexate: May enhance the adverse/toxic effect of Leflunomide. Particular concerns are an increased risk of pancytopenia and/or hepatotoxicity. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Rifampin: May increase serum concentrations of the active metabolite(s) of Leflunomide. Risk C: Monitor therapy
TOLBUTamide: Leflunomide may increase the serum concentration of TOLBUTamide. Specifically, the active metabolite of leflunomide (M1) may both increase total tolbutamide concentrations and increase the free fraction (i.e., non-protein bound) of tolbutamide. TOLBUTamide may increase the serum concentration of Leflunomide. Specifically, tolbutamide may increase the proportion of non-protein-bound (i.e., free fraction) M1, which is the active metabolite of leflunomide. Risk C: Monitor therapy
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live virus vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Leflunomide may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: No interactions with food have been noted.
Herb/Nutraceutical: Echinacea may diminish the therapeutic effect of leflunomide.
Storage
Store at 25°C (77°F). Protect from light.
Mechanism of Action
Leflunomide is an immunodulatory agent that inhibits pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. Leflunomide is a pro-drug; the active metabolite is responsible for activity. For CMV, may interfere with virion assembly.
Pharmacodynamics/Kinetics
Distribution: Vd: Active metabolite A77 1726 (M1): 0.13 L/kg
Protein binding: M1: >99% to albumin
Metabolism: Hepatic to an active metabolite M1, which accounts for nearly all pharmacologic activity; further metabolism to multiple inactive metabolites; undergoes enterohepatic recirculation
Bioavailability: 80%
Half-life elimination: M1: 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: M1: 6-12 hours
Excretion: Feces (48%); urine (43%)
Dosage
Oral:
Adults:
Rheumatoid arthritis: Loading dose: 100 mg/day for 3 days, followed by 20 mg/day; Note: The loading dose may be omitted in patients at increased risk of hepatic or hematologic toxicity (eg, recent concomitant methotrexate). 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, serum concentrations may require a prolonged period to decline after dosage reduction.
CMV (unlabeled use): Some authors recommend 200 mg/day for 7 days, followed by 40-60 mg/day (Avery, 2004). Others have utilized the standard arthritis dosing (John, 2004). Adjust dose based on serum concentrations and adverse events (Avery, 2008; Williams, 2002).
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.
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; not recommended for use in patients with significant hepatic impairment. 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.
Dosing adjustment in hepatic toxicity: Dosage adjustment or discontinuation based on the severity and persistence of ALT elevation secondary to leflunomide:
ALT elevations >2 times but ?3 times ULN: Reduce dose to 10 mg/day, and monitor closely.
ALT elevations persist or if elevations >3 times ULN: Discontinue leflunomide and initiate cholestyramine to enhance elimination.
Enhanced elimination procedure:
To achieve nondetectable serum concentrations (<0.02 mg/L) of leflunomide: Cholestyramine 8 g 3 times/day for 11 days. The 11 days do not need to be consecutive unless plasma concentrations need to be lowered rapidly. Verify serum concentrations by 2 separate tests ?14 days apart. If plasma concentrations are still high, additional cholestyramine treatment may be considered.
In healthy volunteers, cholestyramine 8 g 3 times/day for 24 hours decreased M1 concentrations by 40% in 24 hours and 49% to 65% in 48 hours. Activated charcoal 50 g every 6 hours for 24 hours was shown to decrease plasma concentrations of M1 by 37% in 24 hours and 48% in 48 hours.
Administration: Oral
Administer without regard to meals.
Monitoring Parameters
A complete blood count (WBC, hemoglobin, hematocrit, and platelet count), serum phosphate, as well as serum transaminase determinations should be monitored at baseline and monthly during the initial 6 months of treatment; if stable, monitoring frequency may be decreased to every 6-8 weeks thereafter (continue monthly when used in combination with other immunosuppressive agents). In addition, monitor for signs/symptoms of severe infection, abnormalities in hepatic function tests, symptoms of hepatotoxicity, and blood pressure. If coadministered with methotrexate, monthly transaminase and serum albumin levels are recommended. Screen for tuberculosis and pregnancy prior to therapy.
Dietary Considerations
May be taken without regard to meals.
Patient Education
Take as directed; do not increase dose without consulting prescriber. Maintain adequate hydration unless instructed to restrict fluid intake. Store medication away from light. Do not receive any vaccinations unless approved by prescriber. You may experience diarrhea; nausea, vomiting, loss of appetite, and flatulence (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known). If you have diabetes, monitor blood sugars closely; this medication may alter glucose levels. If you experience symptoms such as nausea, vomiting, stomach pain or swelling, jaundice, dark urine, or unusual tiredness, report these to your prescriber immediately. Report chest pain, palpitations, rapid heartbeat, or swelling of extremities; persistent GI problems; skin rash, mucous membrane lesions, redness, irritation, acne, ulcers; frequent, painful, or difficult urination, or genital itching or irritation; depression, acute headache, anxiety, or difficulty sleeping; muscle tremors, cramping or weakness, back pain, or altered gait; cough, cold symptoms, wheezing, or respiratory difficulty; 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. This drug should not be used in the 2nd or 3rd trimester of pregnancy. Do not get pregnant or have sex unless using appropriate contraception while on this medication. This drug may cause severe fetal defects. Consult prescriber if you suspect you might be pregnant. Do not breast-feed.
Geriatric Considerations
In Phase III studies, no difference in safety and effectiveness were seen between older and younger adults. No dosage reduction necessary based on age alone; monitor in renal and hepatic impairment.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), stomatitis, oral candidiasis, abnormal taste, tooth disorder, enlarged salivary gland, esophagitis, and gingivitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness, malaise, anxiety, depression, or insomnia
Mental Health: Effects on Psychiatric Treatment
May rarely cause leukopenia, caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. Assess results of laboratory tests, therapeutic effectiveness, and adverse reactions. Do not administer live vaccines. Monitor for signs and symptoms of severe infection, hypertension, or hepatic dysfunction. Monitor for new onset or worsening of pulmonary symptoms. Pregnancy risk factor X: Determine that patient is not pregnant before starting therapy. Do not give to sexually-active female patients unless capable of complying with contraceptive use. Breast-feeding is contraindicated.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 10 mg, 20 mg
Arava®: 10 mg, 20 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Arava)
10 mg (30): $595.35
20 mg (30): $621.32
Tablets (Leflunomide)
10 mg (30): $64.00
20 mg (30): $40.01
References
Avery RK, Bolwell BJ, Yen-Lieberman B, et al, “Use of Leflunomide in an Allogenic Bone Marrow Tranplant Recipient With Refractory Cytomegalovirus Infection,” Bone Marrow Transplant, 2004, 34(12):1071-5.
Avery RK, “Update in Management of Ganciclovir-Resistant Cytomegalovirus Infection,” Curr Opin Infect Dis, 2008, 21(4):433-7.
Fox RI, “Mechanism of Action of Leflunomide in Rheumatoid Arthritis,” J Rheumatol, 1998, 53:20-6.
John GT, Manivannan J, Chandy S, et al, “Leflunomide Therapy for Cytomegalovirus Disease in Renal Allograft Recipients,” Transplantation, 2004, 77(9):1460-1.
“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,” Transplant 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.
Williams JW, Mital D, Chong A, et al, "Experiences With Leflunomide in Solid Organ Transplantation," Transplantation, 2002, 73(3):358-66.
International Brand Names
Lexi-Comp.com
Last full review/revision November 2009
Content last modified November 2009
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