Version July 2025
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) (alternative agent):
Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols. Administer as part of an appropriate combination regimen and BK virus monitoring protocol. An example regimen is provided.
Loading dose: Oral: 100 mg once daily for 5 days, followed by maintenance dose (Ref).
Maintenance dose: Oral: 40 mg once daily. Adjust dose based on active metabolite serum concentrations; usual daily dose: 20 to 60 mg/day (Ref).
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 (Ref).
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 (Ref).
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.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: The pharmacokinetics of leflunomide in kidney impairment have not been well characterized. After a single dose of 100 mg, half-life of teriflunomide (active metabolite) was similar in 3 patients on peritoneal dialysis and reduced in hemodialysis patients compared to healthy volunteers. However, the percent unbound in dialysis patients (1.51%) was higher compared to healthy volunteers (0.62%), suggesting that caution and vigilance are warranted in patients with kidney impairment (Ref).
Altered kidney function: No dosage adjustment necessary (Ref); use with caution.
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (Ref):
No dosage adjustment necessary (Ref); use with caution.
Peritoneal dialysis: Not significantly dialyzed (Ref):
No dosage adjustment necessary (Ref); use with caution.
CRRT: There are no specific dosage adjustments recommended (has not been studied); use with caution (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): There are no specific dosage adjustments recommended (has not been studied); use with caution (Ref).
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.
Skin ulcers: Consider discontinuing leflunomide and starting an accelerated drug elimination procedure in patients with suspected leflunomide-associated skin ulcer or persistent skin ulcers.
Refer to adult dosing.
(For additional information see "Leflunomide: Pediatric drug information")
Juvenile idiopathic arthritis (alternative agent): Limited data available (Ref):
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 (Ref).
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.
Severe cutaneous adverse reactions (SCARs) have been reported, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) (Ref). In patients with DRESS, diarrhea is a prominent symptom indicating digestive tract involvement (Ref). Other reported cutaneous reactions include subacute cutaneous lupus erythematosus (SCLE) (Ref), dermal ulcer (Ref), erythema multiforme-like drug eruption (Ref), lichenoid eruption (Ref), keratoacanthoma (Ref), and alopecia (Ref). Cases of alopecia areata are often reversible (Ref).
Mechanism: SCARs: Non–dose-related; immunologic. SCARs, including SJS/TEN and DRESS, are T-cell–mediated (Ref). SCLE: Non–dose-related; mechanism unknown (Ref).
Onset: Varied; SCARs, including SJS/TEN and DRESS, usually develop 1 to 8 weeks after initiation, with cases of SJS/TEN first presenting with symptoms 11 to 14 days after initiation (Ref). SCLE may develop 6 weeks to several years after initiation (Ref).
Risk factors:
• Certain genetic polymorphisms, although data are inconclusive (Ref)
Mild to moderate diarrhea has been reported early in therapy (Ref). Discontinuation for diarrhea occurred in <5% of patients in clinical studies (Ref).
Mechanism: Early-onset diarrhea: May be related to effects of leflunomide on the cell cycle of gastrointestinal epithelium (Ref). Late-onset diarrhea: Mechanism unknown; late onset diarrhea with weight loss and abdominal pain may be related to development of inflammatory colitis (Ref).
Onset: Varied; Early-onset diarrhea: Within first 3 months of initiation; may be transient (Ref). Delayed-onset diarrhea (inflammatory or collagenous colitis): Typically after 18 to 24 months of therapy, but may occur earlier or later (Ref).
Risk factors:
• Higher serum concentrations (Ref)
Pancytopenia, agranulocytosis, and thrombocytopenia have been reported with leflunomide monotherapy and occurs more frequently in patients receiving concurrent therapy with methotrexate or other immunosuppressive agents (Ref).
Onset: Varied; more common in first 12 months of therapy (Ref).
Risk factors:
• Concurrent methotrexate (Ref)
Leflunomide may cause abnormal hepatic function tests (ie, increased serum alanine aminotransferase and increased serum aspartate aminotransferase), which are typically asymptomatic and mild (Ref). Severe hepatic injury, including fatal hepatic failure, has rarely been reported. The pattern of injury ranges from cholestatic to hepatocellular (Ref). Hepatotoxicity may result in discontinuation, upon which cases typically begin to resolve within 4 to 6 weeks (Ref).
Mechanism: Dose-related; exact mechanism unknown, although several mechanisms have been proposed, including oxidative stress (Ref), mitochondrial dysfunction (Ref), metabolic idiosyncrasy (Ref), and activation of the toll-like receptor-4 mediated NFκB pathway (Ref).
Onset: Varied; has been reported within the first 6 months of treatment (Ref).
Risk factors:
• Dose >20 mg/day (Ref)
• Concurrent hepatotoxic medications
• Concurrent methotrexate (Ref)
• Preexisting acute or chronic liver disease
• Psoriatic arthritis versus rheumatoid arthritis indication (Ref)
Leflunomide may increase susceptibility to infection, including opportunistic infection (especially pneumonia due to Pneumocystis jirovecii, tuberculosis [including extrapulmonary tuberculosis], and aspergillosis). Severe infections, including sepsis (may be fatal) have been reported. Risk of severe infection requiring hospitalization in rheumatoid arthritis (RA) patients was ~8% in a retrospective review (Ref). In contrast, a meta-analysis found no association with a higher risk of infection versus placebo or comparator treatments (Ref). Another study reported no difference in incidence of local infection in patients receiving leflunomide versus similar patients not receiving leflunomide (Ref).
Mechanism: Leflunomide reduces production of activated CD4 T cells, potentially interfering with response to infectious agents (Ref).
Risk factors:
• Older age (Ref)
• Diabetes mellitus (Ref)
• Concurrent corticosteroid at higher doses (ie, prednisone ≥7.5 mg or equivalent) (Ref)
• Concurrent methotrexate (Ref)
• Severe RA (Ref)
Interstitial lung disease (ILD) and worsening of preexisting interstitial lung disease have been reported including some fatalities. Bilateral ground glass opacities and diffuse alveolar damage are the most common radiologic and histopathologic findings, respectively (Ref). ILD is also associated with rheumatoid arthritis (RA) and drugs used to treat RA, such as methotrexate; therefore, causal association is unclear. A meta-analysis and two other reviews found no association with a higher risk of ILD versus placebo or comparator treatments (Ref).
Onset: Varied; typically within 3 to 5 months of initiation of therapy (Ref).
Risk factors:
• Preexisting ILD (Ref)
• History of methotrexate use (Ref)
• Cigarette smoking (Ref)
• Low body weight (<40 kg) (Ref)
Numerous cases of sensorimotor neuropathy and sometimes painful peripheral neuropathy have been reported; most patients slowly recover after treatment discontinuation, but symptoms may persist (Ref). In one study in rheumatoid arthritis patients, new-onset and worsening of preexisting neuropathy were reported (Ref). Quantitative sensory testing has detected peripheral nerve injury more often in leflunomide patients than in matched controls (Ref).
Mechanism: Unknown; nerve biopsies have demonstrated epineural perivascular inflammation affecting large and small myelinated nerve fibers, suggesting axonopathy with features of vasculitis. Other studies have reported nonspecific axonal loss (Ref). Presentation and electrodiagnostic findings suggest direct neurotoxicity, but the site of primary nerve injury is unclear (Ref).
Onset: Varied; often after 3 to 6 months of therapy (Ref); however, a wide range (3 days to ~3 years) has been reported (Ref).
Risk factors:
• Older age (>60 years) (Ref)
• Diabetes mellitus (Ref)
• Concurrent neurotoxic medications (Ref)
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%) (table 1), skin rash (11% to 12%)
|
Drug (Leflunomide) |
Comparator (Methotrexate) |
Comparator (Sulfasalazine) |
Placebo |
Number of Patients (Leflunomide) |
Number of Patients (Methotrexate) |
Number of Patients (Sulfasalazine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
17% |
10% |
N/A |
N/A |
501 |
498 |
N/A |
N/A |
|
9% |
6% |
6% |
1% |
315 |
182 |
133 |
210 |
Gastrointestinal: Diarrhea (22% to 27%) (table 2), nausea (13%)
|
Drug (Leflunomide) |
Comparator (Methotrexate) |
Comparator (Sulfasalazine) |
Placebo |
Number of Patients (Leflunomide) |
Number of Patients (Methotrexate) |
Number of Patients (Sulfasalazine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
27% |
20% |
10% |
12% |
315 |
182 |
133 |
210 |
|
22% |
10% |
N/A |
N/A |
501 |
498 |
N/A |
N/A |
Nervous System: Headache (10% to 13%)
1% to 10%:
Cardiovascular: Hypertension (9% to 10%)
Dermatologic: Pruritus (5% to 6%)
Gastrointestinal: Abdominal pain (≤8%), gastrointestinal pain (≤8%), oral mucosa ulcer (3% to 5%), vomiting (3% to 5%)
Hepatic: Abnormal hepatic function tests (6% to 10%) (table 3), increased serum alanine aminotransferase (>3 × ULN: 2% to 4%; reversible) (table 4)
|
Drug (Leflunomide) |
Comparator (Methotrexate) |
Comparator (Sulfasalazine) |
Placebo |
Number of Patients (Leflunomide) |
Number of Patients (Methotrexate) |
Number of Patients (Sulfasalazine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
10% |
10% |
4% |
2% |
315 |
182 |
133 |
210 |
|
6% |
17% |
N/A |
N/A |
501 |
498 |
N/A |
N/A |
|
Drug (Leflunomide) |
Comparator (Methotrexate) |
Comparator (Sulfasalazine) |
Placebo |
Number of Patients (Leflunomide) |
Number of Patients (Methotrexate) |
Number of Patients (Sulfasalazine) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|---|---|
|
4% |
3% |
N/A |
3% |
182 |
182 |
N/A |
118 |
>3 × ULN |
|
3% |
17% |
N/A |
N/A |
501 |
498 |
N/A |
N/A |
>3 × ULN |
|
2% |
N/A |
2% |
1% |
133 |
N/A |
133 |
92 |
>3 × ULN |
Hypersensitivity: Hypersensitivity reaction (1% to 5%)
Nervous system: Asthenia (3% to 6%), dizziness (5% to 7%)
Neuromuscular & skeletal: Back pain (6% 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
Gastrointestinal: Anorexia, enlargement of salivary glands, flatulence, xerostomia
Genitourinary: Vulvovaginal candidiasis
Hematologic & oncologic: Leukocytosis
Hepatic: Increased gamma-glutamyl transferase, increased serum alkaline phosphatase, increased serum bilirubin
Hypersensitivity: Anaphylaxis
Infection: Abscess
Nervous system: Drowsiness, malaise
Ophthalmic: Blurred vision, eye disease, papilledema, retinal hemorrhage, retinopathy
Respiratory: Dyspnea, flu-like symptoms, pharyngitis
Postmarketing:
Cardiovascular: Necrotizing angiitis (cutaneous), vasculitis
Dermatologic: Cellulitis (Ref), cutaneous lupus erythematosus, dermal ulcer (Ref), erythema multiforme (Ref), erythroderma (Ref), exacerbation of psoriasis, lichenoid eruption (Ref), pustular psoriasis, Stevens-Johnson syndrome (Ref), toxic epidermal necrolysis (Ref), urticaria
Gastrointestinal: Cholestasis, colitis (including collagenous, microscopic colitis) (Ref), oral candidiasis (Ref), pancreatitis (Ref)
Hematologic & oncologic: Agranulocytosis (Ref), keratoacanthoma (Ref), leukopenia, neutropenia, pancytopenia (Ref), thrombocytopenia (Ref)
Hepatic: Hepatic failure (Ref), hepatic injury (acute) (Ref), hepatic necrosis (acute), hepatitis, hepatoxicity (Ref), increased serum aspartate aminotransferase (Ref), jaundice
Hypersensitivity: Angioedema, drug reaction with eosinophilia and systemic symptoms (Ref)
Infection: Aspergillosis (Ref), herpes zoster infection (disseminated) (Ref), opportunistic infection (Ref), sepsis (Ref), severe infection (Ref)
Nervous system: Peripheral neuropathy (Ref), sensorimotor neuropathy (Ref)
Neuromuscular & skeletal: Immune-mediated necrotizing myopathy (Ref), subacute cutaneous lupus erythematosus (Ref)
Renal: Pyelonephritis (Ref)
Respiratory: Interstitial lung disease (Ref), interstitial pneumonitis, pneumonia (Ref), pneumonia due to Pneumocystis jirovecii (Ref), pulmonary cryptococcosis (Ref), pulmonary fibrosis, pulmonary hypertension (Ref), tonsillitis (Ref), tuberculosis (Ref)
Known hypersensitivity (including anaphylaxis) to leflunomide or any component of the formulation; severe hepatic impairment; concomitant treatment with teriflunomide; pregnant patients.
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; patients who could become pregnant 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:
• 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.
Disease-related concerns:
• Immunodeficiency or infection: Use caution in patients with a history of new/recurrent infections, with conditions that predispose them to infections, or with chronic, latent, or localized infections. Use is not recommended in patients with severe immunodeficiency or severe, uncontrolled infections. Patients should be screened for tuberculosis (TB) (disease [active TB] and infection [latent TB]) and if necessary, treated prior to initiating leflunomide therapy. Safety has not been established in patients with TB infection.
• 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.
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. Initiate accelerated elimination procedures in patients when a severe adverse reaction occurs (eg, severe dermatologic reaction, suspected liver injury, bone marrow suppression, serious infection, interstitial lung disease, peripheral neuropathy, suspected hypersensitivity) or if pregnancy occurs during treatment. 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.
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
Tablets (Arava Oral)
10 mg (per each): $59.78
20 mg (per each): $59.78
Tablets (Leflunomide Oral)
10 mg (per each): $16.41 - $16.42
20 mg (per each): $6.00 - $16.42
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Arava: 10 mg, 20 mg, 100 mg [DSC]
Generic: 10 mg, 20 mg
Administer without regard to meals.
Oral: Administer without regard to meals.
Hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Rheumatoid arthritis: Treatment of adults with active rheumatoid arthritis.
BK virus (viremia or nephropathy; in kidney transplant recipients)
Leflunomide may be confused with lenalidomide
Substrate of BCRP; Inhibits BCRP, CYP2C8 (Moderate), OAT1/3, OATP1B1/1B3; Induces CYP1A2 (Moderate);
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Alpelisib: BCRP/ABCG2 Inhibitors may increase 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 serum concentration of Amodiaquine. Risk X: Avoid
Anagrelide: CYP1A2 Inducers (Moderate) may decrease serum concentration of Anagrelide. CYP1A2 Inducers (Moderate) may decrease active metabolite exposure of Anagrelide. Risk C: Monitor
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Atogepant. Management: For episodic migraine, the recommended atogepant dose is 10 mg or 30 mg once daily if given with OATP1B1/1B3 inhibitors. For chronic migraine, the recommended atogepant dose is 30 mg once daily with OATP1B1/1B3 inhibitors. Risk D: Consider Therapy Modification
Atrasentan: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Atrasentan. Risk X: Avoid
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of BCG Products. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Leflunomide may increase serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
Bendamustine: CYP1A2 Inducers (Moderate) may decrease 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
Bile Acid Sequestrants: May decrease active metabolite exposure 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 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
Brivudine: May increase adverse/toxic effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Caffeine and Caffeine Containing Products: CYP1A2 Inducers (Moderate) may decrease serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor
Charcoal, Activated: May decrease active metabolite exposure of Leflunomide. Specifically, concentrations of teriflunomide may decrease. Management: Unless using this combination to intentionally enhance teriflunomide elimination, consider an alternative to charcoal whenever possible. Separating drug administration is not likely to be effective at avoiding this interaction. Risk D: Consider Therapy Modification
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Chikungunya Vaccine (Live). Risk X: Avoid
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Cladribine. Risk X: Avoid
ClomiPRAMINE: CYP1A2 Inducers (Moderate) may decrease serum concentration of ClomiPRAMINE. Risk C: Monitor
CloZAPine: CYP1A2 Inducers (Moderate) may decrease serum concentration of CloZAPine. Risk C: Monitor
Coccidioides immitis Skin Test: Coadministration of Immunosuppressants (Therapeutic Immunosuppressant Agents) and Coccidioides immitis Skin Test may alter diagnostic results. 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 increase immunosuppressive effects 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 Vaccines: Leflunomide may decrease therapeutic effects of COVID-19 Vaccines. Management: Rheumatology guidelines recommend holding leflunomide for 1 to 2 weeks after vaccine administration as permitted by the underlying disease. Risk D: Consider Therapy Modification
Dabrafenib: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Dabrafenib. Risk C: Monitor
Daprodustat: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Daprodustat. Management: Reduce the daprodustat starting dose by half if combined with moderate CYP2C8 inhibitors, unless the dose is 1 mg, then no dose adjustment is required. Monitor hemoglobin and adjust daprodustat dose when starting or stopping moderate CYP2C8 inhibitors. Risk D: Consider Therapy Modification
Dasabuvir: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Dasabuvir. Risk C: Monitor
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Dengue Tetravalent Vaccine (Live). Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects 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 serum concentration of Desloratadine. Risk C: Monitor
Deucravacitinib: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
DULoxetine: CYP1A2 Inducers (Moderate) may decrease serum concentration of DULoxetine. Risk C: Monitor
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elagolix. Risk X: Avoid
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase 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 concentration of Enzalutamide. CYP2C8 Inhibitors (Moderate) may increase active metabolite exposure of Enzalutamide. Risk C: Monitor
Erlotinib: CYP1A2 Inducers (Moderate) may decrease 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
Etrasimod: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Filgotinib: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Immunosuppressants (Cytotoxic Chemotherapy): May increase immunosuppressive effects 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 increase immunosuppressive effects 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 increase immunosuppressive effects 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 decrease therapeutic effects 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 serum concentration of Lidocaine (Systemic). Risk C: Monitor
Melatonin: CYP1A2 Inducers (Moderate) may decrease serum concentration of Melatonin. Risk C: Monitor
Methotrexate: May increase adverse/toxic effects 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 serum concentration of Mexiletine. Risk C: Monitor
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Natalizumab. Risk X: Avoid
OAT1/3 Substrates (Clinically Relevant): Leflunomide may increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor
OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors): Leflunomide may increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor
OLANZapine: CYP1A2 Inducers (Moderate) may decrease serum concentration of OLANZapine. Risk C: Monitor
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the concentrations of the dasabuvir component may be increased. Risk C: Monitor
PAZOPanib: BCRP/ABCG2 Inhibitors may increase serum concentration of PAZOPanib. Risk X: Avoid
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Pidotimod. Risk C: Monitor
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Pimecrolimus. Risk X: Avoid
Pioglitazone: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Pioglitazone. Risk C: Monitor
Pirfenidone: CYP1A2 Inducers (Moderate) may decrease serum concentration of Pirfenidone. Risk C: Monitor
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Pneumococcal Vaccines. Risk C: Monitor
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase hypersensitivity effects of 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 serum concentration of Propranolol. Risk C: Monitor
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider Therapy Modification
Repaglinide: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Repaglinide. Risk C: Monitor
Resmetirom: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Resmetirom. Risk X: Avoid
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase active metabolite exposure of Revefenacin. Risk X: Avoid
RifAMPin: May increase active metabolite exposure of Leflunomide. Risk C: Monitor
Riluzole: CYP1A2 Inducers (Moderate) may decrease serum concentration of Riluzole. Risk C: Monitor
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Ritlecitinib. Risk X: Avoid
ROPINIRole: CYP1A2 Inducers (Moderate) may decrease serum concentration of ROPINIRole. Risk C: Monitor
Rosuvastatin: Leflunomide may increase serum concentration of Rosuvastatin. Management: Limit the maximum adult rosuvastatin dose to 10 mg/day in patients receiving leflunomide, and monitor for evidence of rosuvastatin toxicity (eg, muscle toxicity, elevated transaminase concentrations). Risk D: Consider Therapy Modification
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Ruxolitinib (Topical). Risk X: Avoid
Seladelpar: OAT1/3 Inhibitors may increase serum concentration of Seladelpar. Risk X: Avoid
Selexipag: CYP2C8 Inhibitors (Moderate) may increase active metabolite exposure 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 decrease therapeutic effects 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
Sulopenem Etzadroxil: OAT1/3 Inhibitors may increase serum concentration of Sulopenem Etzadroxil. Risk C: Monitor
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Tacrolimus (Topical). Risk X: Avoid
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects 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
Tasimelteon: CYP1A2 Inducers (Moderate) may decrease serum concentration of Tasimelteon. Risk C: Monitor
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Taurursodiol. Risk X: Avoid
Teriflunomide: Leflunomide may increase adverse/toxic effects of Teriflunomide. Risk X: Avoid
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Tertomotide. Risk X: Avoid
Theophylline Derivatives: CYP1A2 Inducers (Moderate) may decrease serum concentration of Theophylline Derivatives. Risk C: Monitor
TiZANidine: CYP1A2 Inducers (Moderate) may decrease serum concentration of TiZANidine. Risk C: Monitor
Tobacco (Smoked): May decrease serum concentration of Leflunomide. Risk C: Monitor
TOLBUTamide: Leflunomide may increase 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 serum concentration of Leflunomide. Specifically, tolbutamide may increase the proportion of non-protein-bound (i.e., free fraction) teriflunomide. Risk C: Monitor
Topotecan: BCRP/ABCG2 Inhibitors may increase serum concentration of Topotecan. Risk X: Avoid
Tovorafenib: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Tovorafenib. Risk X: Avoid
Treprostinil: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Treprostinil. Risk C: Monitor
Tucatinib: CYP2C8 Inhibitors (Moderate) may increase serum concentration of Tucatinib. Risk C: Monitor
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Typhoid Vaccine. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Ubrogepant: BCRP/ABCG2 Inhibitors may increase 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 (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Vaccines (Live). Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to starting immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider Therapy Modification
Vadadustat: OAT1/3 Inhibitors may increase serum concentration of Vadadustat. Risk C: Monitor
Vorasidenib: CYP1A2 Inducers (Moderate) may decrease serum concentration of Vorasidenib. Risk X: Avoid
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Voxilaprevir. Risk X: Avoid
Warfarin: Leflunomide may increase anticoagulant effects of Warfarin. Leflunomide may decrease anticoagulant effects of Warfarin. Risk C: Monitor
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Yellow Fever Vaccine. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentration of Zavegepant. Risk X: Avoid
Zoster Vaccine (Live/Attenuated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Zoster Vaccine (Live/Attenuated). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Zoster Vaccine (Live/Attenuated). Risk X: Avoid
No interactions with food have been noted.
Exclude pregnancy before starting treatment in patients who could become pregnant. Patients who could become pregnant should not receive therapy until pregnancy has been excluded, they have been counseled concerning fetal risk, and reliable contraceptive measures have been confirmed. Patients who could become pregnant should use effective contraception during leflunomide treatment and after treatment is discontinued until undetectable serum concentrations of the active metabolite teriflunomide (<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 of teriflunomide 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 patients who could become pregnant upon discontinuation of leflunomide. Without the use of the accelerated elimination procedure, it can take up to 2 years to reach undetectable plasma concentrations.
Teriflunomide is present in semen. To minimize risk to a fetus, effective contraception should be used during leflunomide therapy and until teriflunomide serum concentrations are <0.02 mg/L. 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]). Males may undergo an accelerated elimination procedure after discontinuing leflunomide, prior to planning a pregnancy.
Based on data from animal reproduction studies, in utero exposure to leflunomide may cause fetal harm; teratogenic and embryo-lethality were observed at oral doses one-tenth of the maximum recommended human dose (based on AUC).
Outcome data following in utero fetal exposure to leflunomide are available (Bérard 2018; Cassina 2012; Chambers 2010; Henson 2020; Pfaller 2020; Princk 2024; 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. Stop leflunomide and start an accelerated drug elimination procedure if pregnancy occurs during treatment. Use during pregnancy is contraindicated.
Data collection to monitor pregnancy and infant outcomes following exposure to leflunomide is ongoing. Health care providers are encouraged to enroll patients 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 patients who could become pregnant); baseline evaluation for tuberculosis (TB) disease (active TB) and screen patients for TB infection (latent TB); 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 (off-label use): 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).
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%)
Molecular weight: 270.02 (leflunomide).
