Leflunomide
Arava
Indications for Leflunomide
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Active rheumatoid arthritis | Adults | Monotherapy or combination with methotrexate | FDA Approved |
Leflunomide is a conventional synthetic DMARD that has demonstrated efficacy comparable to methotrexate and sulfasalazine in phase III trials for RA. It is positioned in the ACR 2021 guidelines as a suitable monotherapy alternative when methotrexate is contraindicated or not tolerated, or as combination therapy with methotrexate for patients with an inadequate response to methotrexate alone. Its unique mechanism of pyrimidine synthesis inhibition differentiates it from other DMARDs and makes it a valuable option in multi-drug strategies. Leflunomide has also shown efficacy in slowing radiographic progression in RA.
Psoriatic arthritis — effective as monotherapy; endorsed by GRAPPA and EULAR guidelines (evidence quality: Moderate).
BK virus nephropathy in renal transplant — adjunctive immunomodulation (evidence quality: Low).
CMV infection in transplant — antiviral properties via DHODH inhibition (evidence quality: Low).
Granulomatosis with polyangiitis (Wegener’s) — maintenance therapy after induction (evidence quality: Low).
Systemic lupus erythematosus — steroid-sparing, limited evidence (evidence quality: Low).
Dosing for Leflunomide
Adult — Rheumatoid Arthritis
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| RA — monotherapy, low hepatotoxicity risk | Loading: 100 mg daily × 3 days | 20 mg once daily | 20 mg/day | Loading dose achieves steady state faster (~3 days vs ~2 months) Omit loading dose if higher risk for hepatotoxicity or myelosuppression (FDA PI 2024) |
| RA — monotherapy, without loading dose | 20 mg once daily | 20 mg once daily | 20 mg/day | Preferred by many rheumatologists to reduce early GI and hepatic side effects Steady state reached in ~2 months; slower onset but better tolerated |
| RA — dose reduction for tolerability | 10 mg once daily | 10 mg once daily | 20 mg/day | If 20 mg not tolerated (GI effects or LFT elevation 2–3× ULN) May attempt re-escalation after adverse effect resolves |
| RA — add-on to methotrexate (combination DMARD) | 10 mg once daily (no loading dose) | 10–20 mg once daily | 20 mg/day | Start low due to additive hepatotoxicity risk Monthly ALT mandatory; follow ACR methotrexate hepatotoxicity monitoring guidelines |
Accelerated Drug Elimination Procedure (Washout)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Serious toxicity, pregnancy, or pre-conception planning | Cholestyramine 8 g TID × 11 days | Verify teriflunomide <0.02 mg/L on 2 separate tests ≥14 days apart | N/A | Alternative: activated charcoal 50 g orally every 6 hours for 24 hours (may repeat course if needed) Without washout, teriflunomide may take up to 2 years to reach non-detectable levels due to enterohepatic recycling |
The 100 mg × 3 day loading dose was used in pivotal trials to accelerate therapeutic onset, but it is widely associated with increased early adverse effects — particularly diarrhea, liver enzyme elevations, and alopecia. Most Australian and many US rheumatologists now omit the loading dose entirely, starting directly at 20 mg/day. The current FDA label (2024) explicitly states that treatment may be initiated with or without a loading dose depending on the patient’s risk profile. Clinical response without loading begins at approximately 4–6 weeks with full benefit by 3–6 months.
Pharmacology of Leflunomide
Mechanism of Action
Leflunomide is a prodrug that is rapidly converted in the gastrointestinal wall and liver to its active metabolite teriflunomide (A771726, also designated M1). Teriflunomide reversibly inhibits mitochondrial dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway. Rapidly proliferating lymphocytes — particularly activated T cells — depend on de novo pyrimidine synthesis for DNA and RNA production, making them selectively vulnerable to DHODH inhibition. Resting cells and most other cell types can meet their pyrimidine needs through the salvage pathway and are therefore relatively spared. By depleting pyrimidine pools in activated lymphocytes, teriflunomide suppresses T-cell proliferation, reduces B-cell immunoglobulin production, and inhibits the inflammatory cascade driving synovial destruction in RA. Additional anti-inflammatory effects include inhibition of tyrosine kinase signalling and NF-kB activation, though these are considered secondary to DHODH inhibition.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed; Tmax of M1: 6–12 h; bioavailability ~80% (tablet); high-fat meals do not significantly affect M1 levels | Can be taken with or without food; loading dose achieves therapeutic M1 levels within 3 days |
| Distribution | Vd ~0.13 L/kg (M1); >99.3% bound to plasma albumin; parent compound rarely detectable in plasma | Very high protein binding means free fraction can double in hypoalbuminaemia or renal impairment, increasing toxicity risk |
| Metabolism | Parent leflunomide rapidly converted to M1 (teriflunomide) in GI wall and liver; minor metabolite: 4-trifluoromethylaniline (TFMA); M1 undergoes enterohepatic recycling | Enterohepatic recycling prolongs effective half-life; cholestyramine interrupts this cycle, enabling accelerated drug elimination |
| Elimination | Terminal t½ of M1: ~2 weeks (range 14–18 days); renal excretion ~43%, faecal ~48% of total dose; M1 is dose-proportional | Without washout, teriflunomide may persist for up to 2 years; cholestyramine 8 g TID × 11 days reduces M1 by 40% in 24 h and 49–65% by 48 h |
Side Effects of Leflunomide
The following incidence data are from phase III clinical trials (Trials 1, 2, and 3) involving 1,865 patients treated with leflunomide as monotherapy or in combination, as reported in the FDA-approved prescribing information. Side effects are most likely to occur in the first six months and tend to diminish over time.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 17–27% | Most common side effect; higher with loading dose; usually resolves within first weeks; mechanism unknown; may respond to dose reduction or loperamide |
| Respiratory infection (upper respiratory tract) | ~15% | Comparable to placebo rates in some trials; minor infections more frequent than serious infections |
| Nausea | 9–13% | Take with food; usually self-limiting within the first month of therapy |
| Headache | ~13% | Not clearly dose-related; manageable with standard analgesics |
| Abnormal liver enzymes (ALT/AST elevation) | 10–13.5% | ALT >3× ULN in 2–3.8% of patients; most elevations are transient; monitor monthly for first 6 months |
| Rash | ~10% | Usually maculopapular and pruritic; may resolve without discontinuation; distinguish from severe cutaneous reactions |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Alopecia (diffuse hair thinning) | 6–10% | Dose-dependent; usually mild to moderate, diffuse thinning; typically reversible on dose reduction or discontinuation |
| Hypertension (new or worsened) | 2–5% | May appear 2–4 weeks after initiation; monitor BP regularly; treat with standard antihypertensives |
| Dyspepsia and abdominal pain | 5–10% | Take with food to minimize; usually self-limiting |
| Weight loss | ~7% | May not correlate with GI symptoms; mechanism unclear — possible mitochondrial uncoupling effect |
| Back pain | ~5% | Distinguish from disease-related musculoskeletal symptoms |
| Dizziness | ~4% | Usually self-limiting |
| Urinary tract infection | ~5% | Consistent with mild immunosuppressive effect; treat promptly |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe hepatotoxicity (including fatal liver failure) | ~1 in 1,000–5,000 | Usually within first 6 months; risk factors: pre-existing liver disease, alcohol, concomitant hepatotoxic drugs | Stop leflunomide immediately; initiate cholestyramine washout; monitor LFTs weekly until normalized; hepatology consultation if ALT >3× ULN or jaundice |
| Pancytopenia / agranulocytosis / thrombocytopenia | Rare | Variable; higher risk with concurrent myelosuppressive agents or recent methotrexate | Stop leflunomide; cholestyramine washout; supportive care including G-CSF if needed; evaluate for concomitant causes |
| Interstitial lung disease | Rare (potentially fatal) | Any time during therapy; may worsen pre-existing ILD | Discontinue immediately; initiate accelerated elimination; chest imaging; pulmonology referral; corticosteroids may be considered |
| Peripheral neuropathy (axonal, predominantly sensory) | Uncommon | Months to years; up to 18% of RA patients report paraesthesia from any cause | Evaluate with EMG/NCS; consider discontinuation — neuropathy may not be fully reversible; washout recommended |
| Stevens-Johnson syndrome / TEN / DRESS | Very rare | Days to weeks after initiation | Immediate discontinuation; accelerated elimination procedure; emergency dermatologic care |
| Skin ulcers | Uncommon (FDA label updated 2024) | Variable | Discontinue leflunomide if suspected; consider washout; assess wound healing before any decision to resume |
| Embryo-fetal toxicity | High risk if exposed | During pregnancy | Absolute contraindication; exclude pregnancy before treatment; cholestyramine washout mandatory before conception; verify teriflunomide <0.02 mg/L on 2 tests ≥14 days apart |
| Severe infections (including sepsis, opportunistic infections) | Uncommon | Any time | Do not start in active infection; stop leflunomide and washout if serious infection develops; screen for TB before initiation |
Severe liver injury, including fatal cases, has prompted a boxed warning. Most cases occur within the first 6 months and involve patients with pre-existing risk factors (liver disease, alcohol use, concomitant hepatotoxic drugs). Monitor ALT at least monthly for the first 6 months, then every 6–8 weeks. For confirmed ALT 2–3× ULN: reduce to 10 mg/day and monitor closely. For ALT >3× ULN: stop leflunomide, start cholestyramine washout, and monitor weekly until normalized. If combined with methotrexate, follow monthly ALT with serum albumin per ACR guidelines. Advise patients to minimise alcohol consumption.
Drug Interactions with Leflunomide
Leflunomide’s active metabolite teriflunomide is an inhibitor of CYP2C8, OAT3, BCRP, and OATP1B1/B3 transporters. It is also an inducer of CYP1A2. These properties underlie clinically significant interactions with several commonly used medications. Teriflunomide’s extremely long half-life means interactions may persist for weeks after stopping leflunomide.
Monitoring for Leflunomide
-
ALT (and AST)
Baseline, then monthly × 6 months, then q6–8 weeks
Routine Critical monitoring parameter. If ALT 2–3× ULN: reduce to 10 mg/day. If ALT >3× ULN: stop leflunomide and start cholestyramine washout. If combined with MTX: monthly ALT + albumin per ACR guidelines -
CBC with differential
Baseline, then monthly × 6 months, then q6–8 weeks
Routine Screen for pancytopenia, agranulocytosis, thrombocytopenia; risk increased with concurrent myelosuppressive agents or recent DMARD switch without washout -
Blood pressure
Baseline, then regularly
Routine New or worsened hypertension in 2–5% of patients; treat before starting if BP >140/90 on two readings; monitor at each visit -
Pregnancy test
Baseline (mandatory)
Routine Exclude pregnancy in all females of reproductive potential before initiation; confirm effective contraception; washout required before conception -
TB screening
Baseline
Routine Screen for active and latent tuberculosis before starting leflunomide per FDA PI recommendations -
Pulmonary symptoms
Any new cough, dyspnoea, or fever
Trigger-based ILD is rare but potentially fatal; low threshold for chest imaging and pulmonary function testing; stop leflunomide and initiate washout if suspected -
Peripheral neuropathy assessment
If new paraesthesia or weakness
Trigger-based Evaluate with EMG/NCS; distinguish from RA-associated entrapment neuropathy; may not be fully reversible -
Teriflunomide level
During washout procedure
Trigger-based Confirm <0.02 mg/L on two separate tests at least 14 days apart after cholestyramine washout, particularly before conception or after serious toxicity
Contraindications & Cautions for Leflunomide
Absolute Contraindications
- Pregnancy — teratogenic and embryolethal in animal studies; exclude pregnancy before initiating; mandatory washout if pregnancy occurs
- Severe hepatic impairment — leflunomide is hepatically metabolized and can cause fatal liver injury
- Pre-existing ALT >2× ULN — patients at increased risk for hepatotoxicity
- Known hypersensitivity to leflunomide or any excipient
- Current teriflunomide treatment — same active metabolite; additive exposure
Relative Contraindications (Specialist Input Recommended)
- Active infection — do not start leflunomide until infection is resolved
- Significant immunodeficiency — risk of severe or opportunistic infections
- Pre-existing bone marrow suppression — additive myelosuppressive risk
- Pre-existing interstitial lung disease — leflunomide may worsen ILD
- Concurrent use of other hepatotoxic drugs — increased liver injury risk; if combined with MTX, requires enhanced monitoring
Use with Caution
- Renal impairment — free fraction of M1 doubles in dialysis patients; no formal dose adjustment but increased vigilance required
- Elderly patients — reduced renal and hepatic reserve; lower body weight may increase drug exposure
- Alcohol use — additive hepatotoxicity risk; counsel to minimise or abstain
- Recent or planned vaccination — avoid live vaccines; immunosuppressive effect persists until teriflunomide is eliminated
Embryo-fetal toxicity: Teratogenicity and embryo-lethality occurred in animals at exposures below the human therapeutic level. Exclude pregnancy before initiation. Use effective contraception during treatment and during a washout procedure. If the patient becomes pregnant, stop leflunomide immediately and initiate the accelerated drug elimination procedure.
Hepatotoxicity: Severe liver injury, including fatal liver failure, has been reported. Most cases occurred within the first 6 months and in patients with multiple hepatotoxicity risk factors. Monitor ALT at least monthly for 6 months then every 6–8 weeks. Do not start leflunomide in patients with pre-existing liver disease or ALT >2× ULN. If ALT elevation >3× ULN occurs, stop leflunomide and start cholestyramine washout.
Patient Counselling for Leflunomide
Purpose of Therapy
Explain that leflunomide works by calming the overactive immune cells responsible for joint damage in rheumatoid arthritis. It is not a painkiller — it works to slow the disease itself. Full benefit develops over several weeks to months, and it is important to continue taking it even when feeling well. Regular blood tests are essential because the medication can affect the liver and blood counts, usually without any symptoms.
How to Take
Take leflunomide once daily, with or without food (taking with food may reduce stomach upset). Swallow the tablet whole. If a loading dose is prescribed (100 mg for 3 days), understand that this may cause more side effects initially but helps the drug work faster. Most patients start at 20 mg/day without a loading dose.
Sources
- Arava (leflunomide) — Full Prescribing Information. Sanofi-Aventis U.S. LLC. Revised May 2025. DailyMed Primary source for approved indication, dosing (including loading dose guidance), boxed warnings, adverse reactions with incidence rates, drug interactions, and washout protocol.
- Arava (leflunomide) — FDA Label 2024 revision. FDA Label PDF Contains 2024 label update adding skin ulcers warning and updated guidance on loading dose decisions based on risk assessment.
- Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med. 1999;159(21):2542-2550. DOI US Phase III trial (Trial 1) comparing leflunomide 20 mg to MTX and placebo in RA; established leflunomide’s efficacy including radiographic outcomes.
- Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2000;39(6):655-665. DOI European Phase III trial (Trial 2) demonstrating comparable efficacy of leflunomide and methotrexate in RA over 12 months.
- Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis. Lancet. 1999;353(9149):259-266. DOI European Phase III trial (Trial 3) comparing leflunomide to sulfasalazine and placebo; source for comparative adverse event rates.
- Schultz M, Keeling SO, Katz SJ, et al. Clinical effectiveness and safety of leflunomide in inflammatory arthritis: a report from the RAPPORT database. Clin Rheumatol. 2017;36(7):1471-1478. DOI Real-world observational data on leflunomide retention, effectiveness, and adverse event rates in clinical practice.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924-939. DOI ACR RA guideline positioning leflunomide as an alternative monotherapy when MTX is contraindicated and in combination DMARD strategies.
- Smolen JS, Landewe RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18. DOI EULAR RA management recommendations including leflunomide as a csDMARD option in the treatment algorithm.
- Breedveld FC, Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2000;59(11):841-849. DOI Comprehensive review of leflunomide’s mechanism via DHODH inhibition and its selective effects on activated lymphocytes.
- Rozman B. Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet. 2002;41(6):421-430. DOI Key PK reference for teriflunomide including half-life, protein binding, Vd, bioavailability, and enterohepatic recycling data.
- Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Saf. 2009;32(12):1123-1134. DOI 10-year post-licensing review of leflunomide safety including hepatotoxicity, ILD, and neuropathy data with clinical practice context.
- Jones PB, White DH. Reappraisal of the clinical use of leflunomide in rheumatoid arthritis and psoriatic arthritis. Open Access Rheumatol. 2010;2:53-71. DOI Comprehensive reappraisal covering clinical efficacy, safety profile, loading dose controversies, combination strategies, and real-world retention data.
- Suissa S, Hudson M, Ernst P. Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum. 2006;54(5):1435-1439. DOI Epidemiologic study quantifying ILD risk with leflunomide, informing clinical monitoring recommendations for pulmonary toxicity.