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Leflunomide

Pronunciation

Pronunciation

(le FLOO noh mide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Arava: 10 mg, 20 mg

Generic: 10 mg, 20 mg

Brand Names: U.S.

  • Arava

Pharmacologic Category

  • Antirheumatic, Disease Modifying

Pharmacology

Leflunomide is an immunomodulatory agent that inhibits pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. Leflunomide is a prodrug; the active metabolite is responsible for activity. For CMV, may interfere with virion assembly.

Distribution

Vd: Teriflunomide: 11 L

Metabolism

Hepatic to an active metabolite teriflunomide, which accounts for nearly all pharmacologic activity; further metabolism to multiple inactive metabolites; undergoes enterohepatic recirculation

Excretion

Feces (37.5%); urine (22.6%)

Time to Peak

Teriflunomide: 6 to 12 hours

Half-Life Elimination

Teriflunomide: Mean: 18 to 19 days; enterohepatic recycling appears to contribute to the long half-life of this agent, since activated charcoal and cholestyramine substantially reduce plasma half-life

Protein Binding

Teriflunomide: >99% to albumin

Use: Labeled Indications

Rheumatoid arthritis: Treatment of adults with active rheumatoid arthritis (RA).

Use: Unlabeled

Treatment of cytomegalovirus (CMV) disease in transplant recipients resistant to standard antivirals; prevention of acute and chronic rejection in recipients of solid organ transplants

Contraindications

Hypersensitivity to leflunomide or any component of the formulation; severe hepatic impairment; concomitant treatment with teriflunomide; pregnant women.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to teriflunomide; moderate to severe renal impairment; immunodeficiency states; impaired bone marrow function or significant anemia, leukopenia, neutropenia, or thrombocytopenia due to causes other than rheumatoid arthritis; serious infections; impaired liver function; severe hypoproteinemia; women of childbearing potential who are not using reliable contraception before, during, and for a period of 2 years after treatment with leflunomide (or as long as plasma levels of the active metabolite are above 0.02 mg/L); breast-feeding; patients younger than 18 years of age

Dosing: Adult

Rheumatoid arthritis: Oral: Loading dose: 100 mg once daily for 3 days; maintenance dose: 20 mg once daily, may reduce dose to 10 mg once daily if higher dose is not tolerated (maximum dose: 20 mg once daily). Note: The loading dose may be omitted in patients at increased risk of hepatic or hematologic toxicity (eg, recent concomitant methotrexate or other immunosuppressive agents). Due to the long half-life of the active metabolite, serum concentrations may require a prolonged period to decline after dosage reduction.

CMV disease, resistant to standard antivirals (off-label use): Oral: Some authors recommend 100 to 200 mg/day for 5 to 7 days, followed by 40 to 60 mg/day (Avery 2004; Avery 2010). Others have utilized the standard rheumatoid arthritis dosing (John 2004). Adjust dose based on serum concentrations of metabolite and adverse events (Avery 2008; Avery 2010; Williams 2002).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Juvenile idiopathic arthritis (off-label use) (Silverman 2005): Children ≥3 years and Adolescents: Oral:

<20 kg: 100 mg as a single dose followed by 10 mg every other day

20 kg to 40 kg: 100 mg once daily for 2 days followed by 10 mg once daily

>40 kg: 100 mg once daily for 3 days followed by 20 mg once daily

Dosing: Renal Impairment

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Canadian labeling:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Moderate to severe impairment: Use is contraindicated.

Dosing: Hepatic Impairment

US labeling: Not recommended for use in patients with preexisting liver disease or those with baseline ALT >2 times ULN; monitor liver function closely. Use is contraindicated in severe hepatic impairment.

Canadian labeling: Use is contraindicated.

Dosing: Adjustment for Toxicity

Hepatic toxicity:

US labeling: ALT elevations >3 x ULN: Discontinue drug therapy and investigate probable cause; if leflunomide-induced, initiate accelerated drug elimination process and monitor liver tests weekly until normalized.

Canadian labeling:

ALT elevations 2 to 3 x ULN: May reduce maintenance dose to 10 mg once daily; monitor ALT weekly.

Persistent ALT elevations >2 x ULN or ALT elevations >3 x ULN: Discontinue treatment and initiate drug elimination procedures.

Drug elimination procedure: To achieve nondetectable serum concentrations (<0.02 mg/L) of the active metabolite (teriflunomide) administer the following:

Cholestyramine: 8 g 3 times daily for 11 days. If plasma concentrations are still high, additional cholestyramine treatment may be considered.

Activated charcoal: 50 g (made into suspension) every 12 hours for 11 days. If plasma concentrations are still high, additional activated charcoal treatment may be considered. Note: As an alternative, the Canadian labeling recommends activated charcoal 50 g 4 times daily for 11 days (may modify duration based on clinical response or laboratory results).

Administration

Administer without regard to meals.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

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. Consider therapy modification

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. 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. Consider therapy modification

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). 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. Exceptions: Cytarabine (Liposomal). Consider therapy modification

Methotrexate: May enhance the adverse/toxic effect of Leflunomide. Particular concerns are an increased risk of pancytopenia and/or hepatotoxicity. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

RifAMPin: May increase serum concentrations of the active metabolite(s) of Leflunomide. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Teriflunomide: Leflunomide may enhance the adverse/toxic effect of Teriflunomide. Leflunomide may increase the serum concentration of Teriflunomide. Avoid combination

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

TOLBUTamide: Leflunomide may increase the serum concentration of TOLBUTamide. Specifically, the active metabolite of leflunomide (teriflunomide) 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) teriflunomide. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Leflunomide may enhance the adverse/toxic effect of Vaccines (Live). Leflunomide may diminish the therapeutic effect of Vaccines (Live). Management: The ACIP guidelines state that live-attenuated vaccines should generally be avoided for at least 3 months after cessation of immunosuppressant therapy. However, the ACR does not recommend avoiding live vaccines in patients being treated with leflunomide. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Leflunomide may diminish the anticoagulant effect of Vitamin K Antagonists. Leflunomide may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Headache (7% to 13%)

Dermatologic: Alopecia (9% to 17%), skin rash (10% to 12%)

Gastrointestinal: Diarrhea (17% to 27%), nausea (9% to 13%)

Respiratory: Respiratory tract infection (15% to 27%)

1% to 10%:

Cardiovascular: Hypertension (9% to 10%; new onset 1% to 2%), chest pain (1% to 4%), angina pectoris (1% to <3%), palpitations (1% to <3%), peripheral edema (1% to <3%), tachycardia (1% to <3%), varicose veins (1% to <3%), vasculitis (1% to <3%), vasodilatation (1% to <3%)

Central nervous system: Dizziness (4% to 7%), paresthesia (2% to 4%), pain (1% to 4%), anxiety (1% to <3%), depression (1% to <3%), insomnia (1% to <3%), malaise (1% to <3%), migraine (1% to <3%), neuralgia (1% to <3%), neuritis (1% to <3%), sleep disorder (1% to <3%), vertigo (1% to <3%)

Dermatologic: Pruritus (4% to 6%), dry skin (2% to 3%), eczema (2% to 3%), acne vulgaris (1% to <3%), contact dermatitis (1% to <3%), cutaneous nodule (1% to <3%), dermal ulcer (1% to <3%), dermatological disease (1% to <3%), diaphoresis (1% to <3%), fungal dermatitis (1% to <3%), hair discoloration (1% to <3%), maculopapular rash (1% to <3%), nail disease (1% to <3%), skin discoloration (1% to <3%), subcutaneous nodule (1% to <3%)

Endocrine & metabolic: Weight loss (2% to 4%); hypokalemia (1% to 3%), albuminuria (1% to <3%), diabetes mellitus (1% to <3%), hyperglycemia (1% to <3%), hyperlipidemia (1% to <3%), hyperthyroidism (1% to <3%), menstrual disease (1% to <3%)

Gastrointestinal: Gastrointestinal pain (5% to 8%), abdominal pain (5% to 6%), dyspepsia (5% to 6%), oral mucosa ulcer (3% to 5%), vomiting (3% to 5%), anorexia (3%), gastroenteritis (3%), cholelithiasis (1% to <3%), colitis (1% to <3%), constipation (1% to <3%), dysgeusia (1% to <3%), enlargement of salivary glands (1% to <3%), esophagitis (1% to <3%), flatulence (1% to <3%), gastritis (1% to <3%), gingivitis (1% to <3%), hernia (1% to <3%), melena (1% to <3%), oral candidiasis (1% to <3%), stomatitis (1% to <3%), xerostomia (1% to <3%)

Genitourinary: Urinary tract infection (5%), cystitis (1% to <3%), dysuria (1% to <3%), hematuria (1% to <3%), pelvic pain (1% to <3%), prostatic disease (1% to <3%), urinary frequency (1% to <3%), vulvo candidiasis (1% to <3%)

Hematologic & oncologic: Anemia (1% to <3%), ecchymoses (1% to <3%), hematoma (1% to <3%)

Hepatic: Abnormal hepatic function tests (5% to 10%), increased serum ALT (>3 x ULN 2% to 4%; reversible)

Hypersensitivity: Hypersensitivity reaction (1% to 5%)

Infection: Abscess (1% to <3%), herpes simplex infection (1% to <3%), herpes zoster (1% to <3%)

Neuromuscular & skeletal: Back pain (5% to 8%), arthropathy (4% to 8%), weakness (3% to 6%), tenosynovitis (2% to 5%), synovitis (2% to 4%), arthralgia (≤4%), leg cramps (≤4%), bursitis (1% to <3%), increased creatine phosphokinase (1% to <3%), muscle cramps (1% to <3%), myalgia (1% to <3%), neck pain (1% to <3%), ostealgia (1% to <3%), osteoarthritis (1% to <3%), osteonecrosis (1% to <3%), rupture of tendon (1% to <3%)

Ophthalmic: Blurred vision (1% to <3%), cataract (1% to <3%), conjunctivitis (1% to <3%), eye disease (1% to <3%)

Respiratory: Bronchitis (5% to 8%), cough (3% to 5%), rhinitis (2% to 5%), flu-like symptoms (≤4%), upper respiratory tract infection (≤4%), pharyngitis (2% to 3%), pneumonia (2% to 3%), asthma (1% to <3%), dyspnea (1% to <3%), epistaxis (1% to <3%), pulmonary disease (1% to <3%), sinusitis (1% to 2%)

Miscellaneous: Accidental injury (5% to 7%), cyst (1% to <3%), fever (1% to <3%)

<1% (Limited to important or life-threatening): Agranulocytosis, cholestasis, cutaneous lupus erythematosus, DRESS syndrome, eosinophilia, erythema multiforme, exacerbation of psoriasis, hepatitis, hepatotoxicity (rare, including hepatic necrosis and hepatic failure), hypophosphaturia, interstitial pulmonary disease, necrotizing angiitis (cutaneous), opportunistic infection, pancreatitis, pancytopenia, peripheral neuropathy, pustular psoriasis, sepsis, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, uricosuria

ALERT: U.S. Boxed Warning

Embryofetal toxicity:

Leflunomide is contraindicated in pregnant women because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals administered leflunomide at doses lower than the human exposure level. Exclude pregnancy before the start of treatment with leflunomide in females of reproductive potential. Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated elimination procedure after leflunomide treatment. Stop leflunomide and use an accelerated drug elimination procedure if the patient becomes pregnant.

Hepatotoxicity:

Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide. Leflunomide is contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with preexisting acute or chronic liver disease, or those with ALT more than twice the upper limit of normal (ULN) before initiating treatment, are at increased risk and should not be treated with leflunomide. Monitor ALT levels at least monthly for 6 months after starting leflunomide, and thereafter every 6 to 8 weeks. If leflunomide-induced liver injury is suspected, stop leflunomide treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized.

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic reactions: Rare cases of dermatologic reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported; discontinue if evidence of severe dermatologic reaction occurs, and begin accelerated drug elimination procedures.

• Hepatotoxicity: [US Boxed Warning]: Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide. Leflunomide is contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with preexisting acute or chronic liver disease, or those with ALT more than twice the upper limit of normal (ULN) before initiating treatment, are at increased risk and should not be treated with leflunomide. Monitor ALT levels at least monthly for 6 months after starting leflunomide, and thereafter every 6 to 8 weeks. If ALT elevation >3-fold the ULN occurs, interrupt therapy and investigate the cause. If leflunomide-induced liver injury is suspected, stop leflunomide treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized. If leflunomide-induced liver injury is unlikely because another cause has been found, resumption of leflunomide therapy may be considered. If given concomitantly with methotrexate, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.

• Hematologic toxicities: Pancytopenia, agranulocytosis, and thrombocytopenia have been reported with leflunomide therapy alone; most frequently hematologic toxicity occurs in patients receiving concomitant therapy with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies. In some cases, patients had a history of a significant hematologic abnormality. All patients should have platelet, white blood cell count (WBC), and hemoglobin or hematocrit monitored at baseline and monthly for 6 months following therapy initiation and then every 6 to 8 weeks thereafter. If used with concomitant methotrexate or other potential immunosuppressive agents, increase chronic monitoring to monthly. If evidence of bone marrow suppression occurs, stop treatment and initiate an accelerated drug elimination procedure.

• Hypertension: Blood pressure elevations have been observed; assess blood pressure at baseline and monitor periodically during therapy.

• Infections: May increase susceptibility to infection, including opportunistic pathogens (especially Pneumocystis jiroveci pneumonia, tuberculosis [including extrapulmonary tuberculosis], and aspergillosis). Severe infections, sepsis, and fatalities have been reported. Not recommended in patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled 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; consider interrupting therapy and initiating accelerated drug elimination procedures if infection is serious.

• Interstitial lung disease: Use has been associated with interstitial lung disease and worsening of preexisting interstitial lung disease (with some fatalities reported). The risk is increased in patients with a history of interstitial lung disease. Further investigate etiology in patients who develop new-onset or worsening of pulmonary symptoms (eg, cough and dyspnea, with or without associated fever). Accelerated drug elimination procedures should be considered if leflunomide is discontinued due to interstitial lung disease.

• Malignancy: Use of some immunosuppressive medications may increase the risk of malignancies, especially lymphoproliferative disorders; impact of leflunomide on the development and course of malignancies is not fully defined.

• Peripheral neuropathy: Cases of peripheral neuropathy have been reported; most patients recover after treatment discontinuation, but symptoms may persist in some patients. Use with caution in patients >60 years of age, receiving concomitant neurotoxic medications or patients with diabetes; discontinue if evidence of peripheral neuropathy occurs and begin accelerated drug elimination procedures.

Disease-related concerns:

• Hematologic disorders: Use with caution in patients with a history of significant hematologic abnormalities; avoid use with bone marrow dysplasia. The Canadian labeling contraindicates use with impaired bone marrow function or significant anemia, leukopenia, neutropenia, or thrombocytopenia due to causes other than rheumatoid arthritis. 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 accelerated drug elimination procedures.

• Hepatic impairment: Use is not recommended due to risk of increased hepatotoxicity.

• Renal impairment: Use with caution in patients with renal impairment. The Canadian labeling contraindicates use in moderate to severe impairment.

• Tuberculosis: Safety has not been established in patients with latent tuberculosis infection. Patients should be screened for tuberculosis and if necessary, treated prior to initiating leflunomide therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunosuppressants: If coadministered with other potential immunosuppressive agents, increased monitoring for hematological adverse effects is necessary.

• Immunizations: No clinical data are available on the efficacy and safety of vaccinations during leflunomide treatment. Vaccination with live vaccines is not recommended; consider the long elimination half-life of the leflunomide active metabolite (eg, teriflunomide) when considering live vaccine administration after leflunomide discontinuation.

Special populations:

• Women of reproductive potential: [US Boxed Warning]: Leflunomide is contraindicated in pregnant women because of the potential for fetal harm. Adverse events were observed in animal reproduction studies with doses lower than the expected human exposure. Exclude pregnancy before the start of treatment in females of reproductive potential. Advise females of reproductive potential to use effective contraception during treatment and during an accelerated elimination procedure after treatment is discontinued. Discontinue therapy and use an accelerated elimination procedure if pregnancy occurs during treatment. Women of reproductive potential should also undergo drug elimination procedures following therapy discontinuation. The Canadian labeling contraindicates use in women of childbearing potential who are not using reliable contraception before, during, and for a period of 2 years after treatment with leflunomide (or as long as plasma levels of the active metabolite are above 0.02 mg/L).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Drug elimination procedure: Due to variations in clearance, it may take up to 2 years to reach low levels of leflunomide metabolite (eg, teriflunomide) serum concentrations. An accelerated drug elimination procedure using cholestyramine or activated charcoal is recommended when a more rapid elimination is needed (eg, severe adverse reaction, suspected hypersensitivity or pregnancy). Refer to dosing for detailed accelerated elimination procedure. Verify plasma teriflunomide concentrations are less than 0.02 mg/L by tests at least 14 days apart. If concentrations are greater than 0.02 mg/L, repeat the accelerated elimination procedure. Use of accelerated drug elimination may potentially result in return of disease activity if the patient has been responding to leflunomide treatment.

Monitoring Parameters

Pregnancy test to rule out pregnancy prior to initiating therapy; baseline evaluation for active tuberculosis and screen patients for latent tuberculosis; blood pressure (baseline and periodically thereafter); complete blood count (WBC, platelet count, hemoglobin or hematocrit) at baseline and monthly during the initial 6 months of treatment; if stable, monitoring frequency may be decreased to every 6 to 8 weeks thereafter (continue monthly when used in combination with other immunosuppressive agents [eg, methotrexate]); hepatic function (transaminases) at least monthly for the first 6 months of treatment, then every 6 to 8 weeks thereafter (discontinue if ALT >3 x ULN, treat with accelerated elimination procedure, and monitor liver function at least weekly until normal). If coadministered with methotrexate, monitor transaminases (ALT, AST) and serum albumin levels consistent with the American College of Rheumatology (ACR) guidelines; signs/symptoms of severe infection or pulmonary symptoms (eg, cough, dyspnea).

When used for CMV disease, monitor serum trough concentrations of active metabolite (also see Reference Range).

Pregnancy Considerations

[US Boxed Warning]: Leflunomide is contraindicated in pregnant women because of the potential for fetal harm. Adverse events were observed in animal reproduction studies with doses lower than the expected human exposure. Exclude pregnancy before the start of treatment in females of reproductive potential. Advise females of reproductive potential to use effective contraception during treatment and during an accelerated elimination procedure after treatment is discontinued. Discontinue therapy and use an accelerated elimination procedure if pregnancy occurs during treatment. Women of reproductive 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 2 separate tests performed at least 14 days apart. If serum concentrations are >0.02 mg/L, additional cholestyramine treatment should be considered. As an alternative to cholestyramine, the Canadian labeling recommends that activated charcoal may be used to enhance drug elimination.

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. The Canadian labeling recommends avoiding use in males capable of fathering a child and who are not using reliable contraception during and for a total of 2 years after treatment unless an elimination procedure is used; for men receiving treatment and desiring to father a child, serum concentrations of the active metabolite should be verified by 2 separate tests performed at least 14 days apart. If levels <0.02 mg/L are confirmed with the second test, an additional waiting period of 3 months is recommended.

Health care providers are encouraged to enroll women exposed to leflunomide during pregnancy in the Pregnancy Registry (877-311-8972 or http://www.pregnancystudies.org/participate-ina-study/).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, hair loss, abdominal pain, back pain, or dizziness. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), burning or numbness feeling, severe headache, pale skin, loss of strength and energy, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), or signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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