Leflunomide: Drug information

For additional information see "Leflunomide: Patient drug information" and "Leflunomide: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table

ALERT: US Boxed Warning

Embryofetal toxicity:

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

Hepatotoxicity:

Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide. Leflunomide is contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with preexisting acute or chronic liver disease, or those with 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.

Brand Names: US

Arava

Brand Names: Canada

ACCEL-Leflunomide;
APO-Leflunomide;
Arava;
SANDOZ Leflunomide;
TEVA-Leflunomide

Pharmacologic Category

Antirheumatic, Disease Modifying

Dosing: Adult

BK virus, in kidney transplant recipients

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 (Ref) or Loading dose: 60 mg/day for 2 days; Maintenance: 20 mg/day (Ref); consider adjusting dose based on active metabolite serum concentrations (Ref).

Cytomegalovirus disease, in transplant recipients resistant to standard antivirals, adjunctive therapy

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 (Ref); consider adjusting dose based on active metabolite serum concentrations and/or adverse events (Ref).

Rheumatoid arthritis

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.

Dosing: Kidney Impairment: Adult

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).

Dosing: Hepatic Impairment: Adult

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.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Leflunomide: Pediatric drug information")

Juvenile idiopathic arthritis

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.

Dosing: Kidney Impairment: Pediatric

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

Dosing: Hepatic Impairment: Pediatric

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.

Adverse Reactions (Significant): Considerations

Dermatologic reactions

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)

Diarrhea

Mild to moderate diarrhea is commonly 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)

Hematologic toxicity

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)

Hepatotoxicity

Leflunomide may cause abnormal hepatic function tests (ie, increased serum alanine aminotransferase and increased serum aspartate aminotransferase) in ~15% of patients, 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; 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)

Infection

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

Interstitial pulmonary disease (ILD) and worsening of preexisting interstitial pulmonary 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)

Peripheral neuropathy

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)

Adverse Reactions

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)Alopecia, skin rash (11% to 12%)

**Leflunomide: Adverse Reaction: Alopecia**
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)Diarrhea, nausea (13%)

**Leflunomide: Adverse Reaction: Diarrhea**
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)Abnormal Hepatic Function Tests, increased serum alanine aminotransferase (>3 × ULN: 2% to 4%; reversible) (table 4)

**Leflunomide: Adverse Reaction: Abnormal Hepatic Function Tests**
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

**Leflunomide: Adverse Reaction: Increased Serum Alanine Aminotransferase**
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, sore throat, xerostomia

Genitourinary: Vulvovaginal candidiasis

Hematologic & oncologic: Leukocytosis

Hepatic: Hyperbilirubinemia, increased gamma-glutamyl transferase, increased serum alkaline phosphatase

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: Cellulitis (Yoo 2013), cutaneous lupus erythematosus, dermal ulcer (Di Nuzzo 2009), erythema multiforme (Fischer 2003), erythroderma (Shastri 2006), exacerbation of psoriasis, lichenoid eruption (May 2017), pustular psoriasis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Wang 2021), urticaria

Gastrointestinal: Cholestasis, colitis (including microscopic colitis), oral candidiasis (Yoo 2013), pancreatitis (Cannon 2004)

Hematologic & oncologic: Agranulocytosis (Qu 2017), keratoacanthoma (Tidwell 2016), leukopenia, neutropenia, pancytopenia (McEwan 2007), thrombocytopenia (Shields 2021)

Hepatic: Hepatic failure (van Roon 2004), hepatic injury (acute) (van Roon 2004), hepatic necrosis (acute), hepatitis, hepatoxicity (van Roon 2004), increased serum aspartate aminotransferase (van Roon 2004), jaundice

Hypersensitivity: Angioedema, drug reaction with eosinophilia and systemic symptoms (Adwan 2017)

Infection: Aspergillosis (Yoo 2013), herpes zoster infection (disseminated) (Yoo 2013), opportunistic infection (Yoo 2013), sepsis (Yoo 2013), severe infection (Yoo 2013)

Nervous system: Peripheral neuropathy (Bonnel 2004), sensorimotor neuropathy (Bonnel 2004)

Neuromuscular & skeletal: Subacute cutaneous lupus erythematosus (Chan 2005)

Renal: Pyelonephritis (Yoo 2013)

Respiratory: Interstitial lung disease (Raj 2013), interstitial pneumonitis, pneumonia (Yoo 2013), pneumonia due to Pneumocystis jirovecii (Yoo 2013), pulmonary cryptococcosis (Yoo 2013), pulmonary fibrosis, pulmonary hypertension (Collini 2022), tonsillitis (Yoo 2013), tuberculosis (Yoo 2013)

Contraindications

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.

Warnings/Precautions

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.

Dosage Forms: US

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

Generic Equivalent Available: US

Yes

Pricing: US

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.

Dosage Forms: Canada

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

Administration: Adult

Administer without regard to meals.

Administration: Pediatric

Oral: Administer without regard to meals.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 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 2016; 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.

Use: Labeled Indications

Rheumatoid arthritis: Treatment of adults with active rheumatoid arthritis.

Use: Off-Label: Adult

BK virus (viremia or nephropathy; in kidney transplant recipients); Cytomegalovirus disease (in transplant recipients resistant to standard antivirals)

Medication Safety Issues

Sound-alike/look-alike issues:

Leflunomide may be confused with lenalidomide

Metabolism/Transport Effects

Substrate of BCRP/ABCG2; Inhibits BCRP/ABCG2, CYP2C8 (moderate), OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3); Induces CYP1A2 (moderate)

Drug Interactions

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 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

Anagrelide: CYP1A2 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Anagrelide. CYP1A2 Inducers (Moderate) may decrease the serum concentration of Anagrelide. Risk C: Monitor therapy

Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the 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

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

BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Leflunomide may increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

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

Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

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. 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 enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination

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 Vaccines: Leflunomide may diminish the therapeutic effect 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 the serum concentration of Dabrafenib. Risk C: Monitor therapy

Daprodustat: CYP2C8 Inhibitors (Moderate) may increase the 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 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

Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

DULoxetine: CYP1A2 Inducers (Moderate) may decrease the serum concentration of DULoxetine. Risk C: Monitor therapy

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

Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

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

Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- 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 Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination

Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

OAT1/3 Substrates (Clinically Relevant): Leflunomide may increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy

OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors): Leflunomide may increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

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 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 the serum concentration of Repaglinide. Risk C: Monitor therapy

Resmetirom: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Resmetirom. Risk X: Avoid combination

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

Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination

ROPINIRole: CYP1A2 Inducers (Moderate) may decrease the serum concentration of ROPINIRole. Risk C: Monitor therapy

Rosuvastatin: Leflunomide may increase the 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 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

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

Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination

Teriflunomide: Leflunomide may enhance the adverse/toxic effect 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

Tovorafenib: CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Tovorafenib. 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 (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect 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 the serum concentration of Vadadustat. Risk C: Monitor therapy

Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination

Warfarin: Leflunomide may enhance the anticoagulant effect of Warfarin. Leflunomide may diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

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

Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Zavegepant. Risk X: Avoid combination

Food Interactions

No interactions with food have been noted.

Reproductive Considerations

[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]).

Pregnancy Considerations

[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/).

Breastfeeding Considerations

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]).

Monitoring Parameters

Rheumatoid arthritis:

Manufacturer's labeling: Pregnancy test to rule out pregnancy prior to initiating therapy (in females of reproductive potential); 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 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).

Reference Range

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).

Mechanism of Action

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.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: V_d: 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%)

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Apo-leflunomide | Arava;
(AR) Argentina: Afiancen | Apo leflunomida | Arava | Filartros | Fludart | Fluxap | Inmunoartro | Lefluar | Leflulep | Leflunomida sc;
(AT) Austria: Arava | Leflunomid medac | Leflunomid Stada;
(AU) Australia: Apo-leflunomide | Arabloc | Arava | Ataris | Leflunomide an | Leflunomide ga | Leflunomide gh | Leflunomide sandoz | Lunava;
(BD) Bangladesh: Arolef | Dimar | Leflu | Lera | Nodia;
(BE) Belgium: Arava | Leflunomide ab | Leflunomide apotex | Leflunomide jenson | Leflunomide Mylan | Leflunomide sandoz;
(BG) Bulgaria: Arava | Leflunomide Teva;
(BR) Brazil: Arava | Leflunomida | Lfm leflunomida | Reumian;
(CH) Switzerland: Arava | Leflunomid Gebro | Leflunomid Mepha | Leflunomid sandoz | Leflunomid spirig hc | Leflunomide Zentiva;
(CL) Chile: Arava | Artrotin;
(CN) China: Ai ruo hua | Guan ping | He pai | Tuo shu | Ya bang sang ke | You tong;
(CO) Colombia: Arava | Immunex | Leflava | Leflunex | Leflunomida | Lefluvitae | Lerada | Zoratomin;
(CZ) Czech Republic: Arava | Leflon | Leflugen | Leflunomid Apotex | Leflunomid sandoz | Leflunomide medac | Leflunopharm | Repso;
(DE) Germany: Arava | Leflon | Leflunomid | Leflunomid 1 A Pharma | Leflunomid al | Leflunomid Aristo | Leflunomid bluefish | Leflunomid CT | Leflunomid heumann | Leflunomid hexal | Leflunomid medac | Leflunomid Ratiopharm | Leflunomid Stada | Leflunomid tillomed | Leflunomid Winthrop | Leflunomid Zentiva | Leflunomide medac;
(DO) Dominican Republic: Arava;
(EC) Ecuador: Arava | Leflunomida;
(EE) Estonia: Arava | Leflunomide sandoz;
(EG) Egypt: Apetoid | Arthfree | Avara | Leflumine | Rafix | Vamid;
(ES) Spain: Arava | Lefluartil | Leflunomida Apotex | Leflunomida aurovitas | Leflunomida cinfa | Leflunomida Medac | Leflunomida mylan | Leflunomida Normon | Leflunomida Ratiopharm | Leflunomida stada | Leflunomida tecnigen;
(FI) Finland: Arava | Leflunomide medac | Leflunomide orion | Leflunomide ratiopharm | Leflunomide stada;
(FR) France: Arava | Leflunomide biogaran | Leflunomide eg | Leflunomide Mylan | Leflunomide ratiopharm | Leflunomide winthrop;
(GB) United Kingdom: Arava | Leflunomide Mylan | Leflunomide tillomed;
(GR) Greece: Arava | Lefid | Lefluonia;
(HK) Hong Kong: Arava;
(HR) Croatia: Alfimid | Arava;
(HU) Hungary: Arava | Leflunomid Apotex | Leflunomid sandoz | Leflunomide Mylan | Repso;
(ID) Indonesia: Arava;
(IE) Ireland: Arava | Leflunomide medac;
(IL) Israel: Arava;
(IN) India: Arava | Cleft | Feluno | Fluna | Lefday | Leflar | Lefno | Lefra | Lefsum | Leftab | Lefumide | Lefumod | Lefutoid | Leorch | Lisifen | Lunamide | O left | Rhulef | Rumalef;
(IS) Iceland: Arava;
(IT) Italy: Arava | Leflunomide aurobindo | Leflunomide Mylan | Leflunomide sandoz | Leflunomide tecnigen;
(JO) Jordan: Arava | Arotan;
(JP) Japan: Arava;
(KE) Kenya: Arotan | Lefra | Lefumide | Lunomide;
(KR) Korea, Republic of: Alvogen leflunomide | Arava | Arey | Aris | Burova | Duroba | Durova | Kimara | Lefilo | Lefl | Leflu | Lefmid | Lefru | Lefva | Leluba | Lenava | Lualba | Myungmoon leflunomide | R a | Rheumakin | Rheumide;
(KW) Kuwait: Arava;
(LB) Lebanon: Arava | Arotan | Arthfree;
(LT) Lithuania: Arava | Leflunomid sandoz | Leflunomide sandoz;
(LU) Luxembourg: Arava;
(LV) Latvia: Arava | Leflunomid sandoz | Leflunomide sandoz;
(MA) Morocco: Arava;
(MX) Mexico: Almura | Arava | Avattor | Deladex | Filarin | Galdione | Iguanos | Imagine | Koralix | Leflunomida | Leflunomida corne | Lerivril | Ramtener;
(MY) Malaysia: Arava;
(NL) Netherlands: Arava | Leflunomide apotex | Leflunomide aurobindo | Leflunomide CF | Leflunomide Mylan | Leflunomide ratiopharm | Leflunomide sandoz | Leflunomide tillomed;
(NO) Norway: Arava | Leflunomide medac | Leflunomide Zentiva;
(NZ) New Zealand: Aft Leflunomide | Apo-leflunomide | Arava;
(PE) Peru: Almora | Arava | Aravida | Artroflu | Etodolo | Filartros | Flexagin | Flumidar | Leflumard | Leflumide | Leflunomida | Lemida;
(PH) Philippines: Arava;
(PK) Pakistan: Aidra | Ariva | Cara | Cynova | Defumide | Dimara | Eflun | Lefanor | Lefid | Leflonid | Leflu | Lefluno | Lefodil | Lefomide | Lefora | Leforex | Lenomide | Life | Lufid | Lunamid | Movelef | Ra mide | Rhomed | Rhulef;
(PL) Poland: Arava | Leflunomid bluefish | Leflunomide medac | Leflunomide orion | Leflunomide sandoz;
(PR) Puerto Rico: Arava;
(PT) Portugal: Arava | Leflunomida farmoz | Leflunomida Medac | Leflunomida pentafarma;
(PY) Paraguay: Arava | Artrotin | Fluxet | Imaxetil | Leflumix | Leflunomida ac | Leflunomida cipla | Leflunomida natrodale | Leflunomida prosalud | Leflux;
(QA) Qatar: Arava;
(RO) Romania: Arava | Leflon;
(RU) Russian Federation: Arava | Arresto | Ehlafra | Leflaid | Lefomid | Ralef;
(SA) Saudi Arabia: Apo-leflunomide | Arava;
(SE) Sweden: Arava | Leflunomid bluefish | Leflunomide medac | Leflunomide Zentiva;
(SG) Singapore: Arava;
(SI) Slovenia: Arava | Leflunomid medac;
(SK) Slovakia: Arava | Leflon | Leflunomid sandoz | Leflunomid Winthrop | Leflunomide medac;
(TH) Thailand: Arava | Lareya;
(TN) Tunisia: Arava;
(TR) Turkey: Aramid | Arava | Bageda | Lefumix | Ralef | Reumil;
(TW) Taiwan: Arava | Arheuma | Pharnomide;
(UA) Ukraine: Arava | Leflutab | Lefno;
(UG) Uganda: Arthfree | Lefra;
(UY) Uruguay: Arava | Kevadon | Kinetos | Reumine;
(VE) Venezuela, Bolivarian Republic of: Arava | Lefra;
(VN) Viet Nam: Osbifin;
(ZA) South Africa: Arava | Lunar | Ravalef | Rheumalef;
(ZM) Zambia: Lefra;
(ZW) Zimbabwe: Lefra

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Leflunomide: Drug information