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.
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 serum ALT >2 times 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.
BK virus (viremia or nephropathy), in kidney transplant recipients (off-label use; based on limited data): Oral: Loading dose: 100 mg/day for 5 days; Maintenance: 40 mg/day (AST-IDCOP [Hirsch 2019]; Nesselhauf 2016) or Loading dose: 60 mg/day for 2 days; Maintenance: 20 mg/day (Kable 2017); consider adjusting dose based on active metabolite serum concentrations (AST-IDCOP [Hirsch 2019]; Kable 2017; Nesselhauf 2016).
Cytomegalovirus disease, in transplant recipients resistant to standard antivirals, adjunctive therapy (off-label use; based on limited data): Oral: 100 mg once daily for 3 to 5 days, followed by 20 to 40 mg/day (Avery 2010; Chon 2015; Gokarn 2019; Silva 2018; Wang 2018); consider adjusting dose based on active metabolite serum concentrations and/or adverse events (Avery 2010; Wang 2018).
Rheumatoid arthritis:
Note: May be used as an alternative to methotrexate in disease-modifying antirheumatic drug–naive patients with moderate to high disease activity, or as adjunctive therapy in patients whose treatment targets have not been met despite maximally tolerated methotrexate therapy (ACR [Fraenkel 2021]; EULAR [Smolen 2020]).
Loading dose (optional): Oral: 100 mg once daily for 3 days. Note: Loading dose may be omitted to reduce the risk of adverse effects (eg, diarrhea), particularly in patients at increased risk of hepatic or hematologic toxicity (eg, recent concomitant methotrexate or other immunosuppressive agents); onset of action may be delayed (Maddison 2005; Osiri 2003).
Maintenance dose: Oral: 20 mg once daily; may reduce maintenance dose to 10 mg once daily if needed based on tolerability (maximum: 20 mg once daily).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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.
Hepatic function impairment at baseline:
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.
Hepatoxicity during treatment:
US labeling: ALT elevations >3 times 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 times ULN: May reduce maintenance dose to 10 mg once daily; monitor ALT weekly.
Persistent ALT elevations >2 times ULN or ALT elevations >3 times ULN: Discontinue treatment and initiate drug elimination procedures.
(For additional information see "Leflunomide: Pediatric drug information")
Juvenile idiopathic arthritis (alternative agent): Limited data available (Alcântara 2014; Ayaz 2019; Foeldvari 2010; Silverman 2005):
Children and Adolescents:
<20 kg: Oral: 10 mg every other day.
20 to 40 kg: Oral: 10 mg once daily.
>40 kg: Oral: 20 mg once daily.
Note: While loading doses of 100 mg/dose were used in early clinical trials, they may be associated with toxicity; more recent studies omit the loading dose (Silverman 2006).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
There are no pediatric-specific recommendations; based on experience in adult patients, dosage adjustment or avoidance suggested for baseline liver impairment or development of toxicity during therapy; use is contraindicated in severe hepatic impairment.
Refer to adult dosing.
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
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Arava: 10 mg, 20 mg, 100 mg
Generic: 10 mg, 20 mg
Administer without regard to meals.
Oral: Administer without regard to meals.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Rheumatoid arthritis: Treatment of adults with active rheumatoid arthritis.
BK virus (viremia or nephropathy; in kidney transplant recipients); Cytomegalovirus disease (in transplant recipients resistant to standard antivirals)
Leflunomide may be confused with lenalidomide
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Alopecia (9% to 17%), skin rash (10% to 12%)
Gastrointestinal: Diarrhea (17% to 27%), nausea (9% to 13%)
Nervous System: Headache (7% to 13%)
1% to 10%:
Cardiovascular: Hypertension (9% to 10%)
Dermatologic: Pruritus (4% to 6%)
Gastrointestinal: Abdominal pain (≤8%), gastrointestinal pain (≤8%), oral mucosa ulcer (3% to 5%), vomiting (3% to 5%)
Hepatic: Abnormal hepatic function tests (5% to 10%), increased serum ALT (>3 x ULN: 2% to 4%; reversible)
Hypersensitivity: Hypersensitivity reaction (1% to 5%)
Nervous system: Dizziness (4% to 7%)
Neuromuscular & skeletal: Asthenia (3% to 6%), back pain (5% to 8%), tenosynovitis (2% to 5%)
Respiratory: Bronchitis (5% to 8%), rhinitis (2% to 5%)
Frequency not defined:
Cardiovascular: Chest pain, leg thrombophlebitis, palpitations, varicose veins
Endocrine & metabolic: Increased gamma-glutamyl transferase
Gastrointestinal: Anorexia, enlargement of salivary glands, flatulence, sore throat, xerostomia
Genitourinary: Vulvovaginal candidiasis
Hematologic & oncologic: Leukocytosis, thrombocytopenia
Hepatic: Hyperbilirubinemia, increased serum alkaline phosphatase, increased serum aspartate aminotransferase
Hypersensitivity: Anaphylaxis
Infection: Abscess
Nervous system: Drowsiness, malaise
Ophthalmic: Blurred vision, eye disease, papilledema, retinal hemorrhage, retinopathy
Respiratory: Dyspnea, flu-like symptoms
Postmarketing:
Cardiovascular: Necrotizing angiitis (cutaneous), vasculitis
Dermatologic: Dermal ulcer, cutaneous lupus erythematosus, erythema multiforme, exacerbation of psoriasis, pustular psoriasis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Gastrointestinal: Cholestasis, colitis (including microscopic colitis), pancreatitis
Hematologic & oncologic: Agranulocytosis, leukopenia, neutropenia, pancytopenia
Hepatic: Hepatic failure, hepatic injury (acute), hepatic necrosis (acute), hepatitis, hepatoxicity, jaundice
Hypersensitivity: Angioedema
Immunologic: Drug reaction with eosinophilia and systemic symptoms
Infection: Aspergillosis, opportunistic infection, sepsis, severe infection
Nervous system: Peripheral neuropathy
Respiratory: Interstitial pneumonitis, interstitial pulmonary disease, pneumonia due to Pneumocystis jirovecii, pulmonary fibrosis, pulmonary hypertension
Known hypersensitivity (including anaphylaxis) to leflunomide or any component of the formulation; severe hepatic impairment; concomitant treatment with teriflunomide; pregnant females.
Canadian labeling: Additional contraindications (not in the 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; females of reproductive 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); breastfeeding; patients <18 years of age.
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) 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 >2 times the 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 times 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 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, 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. Avoid use in patients with bone marrow dysplasia.
• 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 jirovecii pneumonia, tuberculosis [including extrapulmonary tuberculosis], and aspergillosis). Severe infections, sepsis, and fatalities have been reported. Not recommended in patients with severe immunodeficiency 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. Patients should be screened for tuberculosis (active and latent) and if necessary, treated prior to initiating leflunomide therapy. Safety has not been established in patients with latent tuberculosis infection.
• Interstitial lung disease: Interstitial lung disease and worsening of preexisting interstitial lung disease have been reported (with some fatalities). 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. The risk for peripheral neuropathy may be increased in patients >60 years of age, receiving concomitant neurotoxic medications or patients with diabetes. If peripheral neuropathy occurs, consider discontinuing leflunomide and consider accelerated drug elimination procedures.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• 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:
• Females of reproductive potential: [US Boxed Warning]: Leflunomide is contraindicated in pregnant females because of the potential for fetal harm. Adverse events were observed in animal reproduction studies with doses lower than the expected human exposure. Discontinue leflunomide and use an accelerated elimination procedure if pregnancy occurs during treatment. 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.
Other warnings/precautions:
• Drug elimination procedure: Due to slow elimination and 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 the manufacturer's labeling for detailed accelerated elimination procedure. Verify plasma teriflunomide concentrations are <0.02 mg/L by tests at least 14 days apart. If concentrations are >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.
Substrate of BCRP/ABCG2; Inhibits BCRP/ABCG2, CYP2C8 (moderate), OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3); Induces CYP1A2 (moderate)
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Risk D: Consider therapy modification
Amodiaquine: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Amodiaquine. Risk X: Avoid combination
Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Risk X: Avoid combination
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Atogepant. Management: The recommended dose of atogepant when coadministered with OATP1B1/1B3 inhibitors is 10 mg once daily or 30 mg once daily. Risk D: Consider therapy modification
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bendamustine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Bendamustine. Concentrations of active metabolites may be increased. Management: Consider alternatives to moderate CYP1A2 inducers during therapy with bendamustine due to the potential for decreased bendamustine plasma concentrations and reduced efficacy. Risk D: Consider therapy modification
Berotralstat: BCRP/ABCG2 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with BCRP inhibitors. Risk D: Consider therapy modification
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
Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification
Caffeine and Caffeine Containing Products: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Caffeine and Caffeine Containing Products. 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
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
ClomiPRAMINE: CYP1A2 Inducers (Moderate) may decrease the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy
CloZAPine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): May enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as systemic corticosteroids. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: In the US, after receipt of the single dose COVID-19 adenovirus vector vaccine (Janssen), administer an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose, in patients taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider administration of a 3rd dose of COVID-19 vaccine, at least 28 days after completion of the primary 2-dose series, in patients 5 years of age and older taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
Dabrafenib: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Dabrafenib. Risk C: Monitor therapy
Dasabuvir: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Dasabuvir. Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Desloratadine: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Desloratadine. Risk C: Monitor therapy
Dichlorphenamide: OAT1/3 Inhibitors may increase the serum concentration of Dichlorphenamide. Risk C: Monitor therapy
DULoxetine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of DULoxetine. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Risk D: Consider therapy modification
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Risk X: Avoid combination
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid combination
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Risk D: Consider therapy modification
Enzalutamide: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Enzalutamide. CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Enzalutamide. Risk C: Monitor therapy
Erlotinib: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Erlotinib. Management: Avoid the concomitant use of erlotinib and moderate CYP1A2 inducers if possible. If concomitant use is unavoidable, increase the erlotinib dose by 50 mg increments at 2-week intervals to a maximum of 300 mg. Risk D: Consider therapy modification
Immunosuppressants (Cytotoxic Chemotherapy): May enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification
Immunosuppressants (Miscellaneous Oncologic Agents): May enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Immunosuppressants (Therapeutic Immunosuppressant Agents): May enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Lidocaine (Systemic): CYP1A2 Inducers (Moderate) may decrease the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy
Melatonin: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Melatonin. Risk C: Monitor therapy
Methotrexate: May enhance the adverse/toxic effect of Leflunomide. Specifically, the risks of hepatoxicity and hematologic toxicity may be increased. Management: If leflunomide is coadministered with methotrexate, initiate leflunomide 20 mg once daily without use of a loading dose. Monitor for methotrexate-induced hepatic toxicity frequently (see monograph for details) and monitor blood counts monthly. Risk D: Consider therapy modification
Mexiletine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Mexiletine. Risk C: Monitor therapy
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
OLANZapine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of OLANZapine. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the concentrations of the dasabuvir component may be increased. Risk C: Monitor therapy
PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pioglitazone: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Pioglitazone. Risk C: Monitor therapy
Pirfenidone: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Pirfenidone. Risk C: Monitor therapy
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Propranolol: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Propranolol. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification
Repaglinide: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination
RifAMPin: May increase serum concentrations of the active metabolite(s) of Leflunomide. Risk C: Monitor therapy
Riluzole: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Riluzole. Risk C: Monitor therapy
ROPINIRole: CYP1A2 Inducers (Moderate) may decrease the serum concentration of ROPINIRole. Risk C: Monitor therapy
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. Management: Reduce the selexipag dose to once daily when combined with moderate CYP2C8 inhibitors. Revert back to twice daily selexipag dosing upon stopping the moderate CYP2C8 inhibitor. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tasimelteon: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Tasimelteon. Risk C: Monitor therapy
Teriflunomide: Leflunomide may enhance the adverse/toxic effect of Teriflunomide. Leflunomide may increase the serum concentration of Teriflunomide. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Theophylline Derivatives: CYP1A2 Inducers (Moderate) may decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
TiZANidine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of TiZANidine. Risk C: Monitor therapy
Tobacco (Smoked): May decrease the serum concentration of Leflunomide. Risk C: Monitor therapy
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. Risk C: Monitor therapy
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Treprostinil: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Treprostinil. Risk C: Monitor therapy
Tucatinib: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Tucatinib. Risk C: Monitor therapy
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Risk D: Consider therapy modification
Vaccines (Inactivated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Leflunomide may enhance the anticoagulant effect of Vitamin K Antagonists. Leflunomide may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
No interactions with food have been noted.
[US Boxed Warning]: 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.
Females 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. Use of the accelerated elimination procedure is recommended in all females of reproductive potential upon discontinuation of leflunomide. Without the use of the accelerated elimination procedure, it can take up to 2 years to reach undetectable plasma concentrations.
Use of leflunomide may be considered for males with rheumatic and musculoskeletal diseases who are planning to father a child (recommendation based on limited human data) (ACR [Sammaritano 2020]).
[US Boxed Warning]: Leflunomide is contraindicated for use in pregnant women because of the potential for fetal harm. Teratogenicity and embryo-lethality 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. Stop leflunomide and use an accelerated drug elimination procedure if the patient becomes pregnant.
Outcome information following in utero fetal exposure to leflunomide is limited (Bérard 2018; Cassina 2012; Chambers 2010; Henson 2020; Pfaller 2020; Weber-Schoendorfer 2017). Based on available data, no consistent pattern of congenital abnormalities has been observed (Henson 2020; Pfaller 2020). The accelerated elimination procedure may decrease potential risks to the fetus by decreasing the plasma concentration teriflunomide, of the active metabolite of leflunomide. Following treatment, pregnancy should be avoided until undetectable serum concentrations (<0.02 mg/L) are verified.
Data collection to monitor pregnancy and infant outcomes following exposure to leflunomide is ongoing. Health care providers are encouraged to enroll women exposed to leflunomide during pregnancy in the Pregnancy Registry (1-877-311-8972 or http://www.pregnancystudies.org/participate-ina-study/).
It is not known whether leflunomide is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends discontinuing breastfeeding during leflunomide treatment. Leflunomide is not recommended for use in patients with rheumatic and musculoskeletal diseases who are breastfeeding (ACR [Sammaritano 2020]).
Rheumatoid arthritis:
Manufacturer's labeling: Pregnancy test to rule out pregnancy prior to initiating therapy (in females of reproductive potential); baseline evaluation for active tuberculosis and screen patients for latent tuberculosis; blood pressure (baseline and periodically thereafter); signs/symptoms of severe infection or pulmonary symptoms (eg, cough, dyspnea); CBC (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 times ULN, treat with accelerated elimination procedure, and monitor liver function at least weekly until normal).
Alternate recommendations: CBC, serum creatinine, serum transaminases: Baseline and every 2 to 4 weeks during the initial 3 months after initiation or following dose increases, then every 8 to 12 weeks during 3 to 6 months of treatment, followed by every 12 weeks beyond 6 months of treatment; monitor more frequently if clinically indicated (ACR [Singh 2016]; ACR [Fraenkel 2021]).
BK virus and cytomegalovirus disease (off-label uses): Monitor serum trough concentrations of active metabolite (also see Reference Range) (AST-IDCOP [Hirsch 2019]; Kable 2017; Nesselhauf 2016).
BK virus (viremia or nephropathy):
Timing of serum samples: Every 2 to 4 weeks (AST-IDCOP [Hirsch 2019]; Nesselhauf 2016).
Therapeutic concentration: Active metabolite (teriflunomide): Trough: 40 to 100 mcg/mL (AST-IDCOP [Hirsch 2019]) or 50 to 100 mcg/mL (Kable 2017; Nesselhauf 2016).
Cytomegalovirus disease:
Timing of serum samples: Initial: Obtain 24 hours after last dose of loading regimen and periodically thereafter.
Therapeutic concentration: Active metabolite (teriflunomide): Trough: 50 to 80 mcg/mL (Avery 2010) or up to 100 mcg/mL (Williams 2002).
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
Protein binding: Teriflunomide: >99% to albumin
Metabolism: Hepatic to an active metabolite teriflunomide, which accounts for nearly all pharmacologic activity; further metabolism to multiple inactive metabolites; undergoes enterohepatic recirculation
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
Time to peak: Teriflunomide: 6 to 12 hours
Excretion: Feces (37.5%); urine (22.6%)
Tablets (Arava Oral)
10 mg (per each): $57.04
20 mg (per each): $57.04
Tablets (Leflunomide Oral)
10 mg (per each): $16.41 - $16.42
20 mg (per each): $6.00 - $16.42
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