Leflunomide 20 mg Tablet, Film Coated, 30-count
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Antirheumatic Agent class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Leflunomide is used alone or in combination with other medications to treat rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function). Leflunomide is in a class of medications called disease-modifying antirheumatic drugs (DMARDs). It works by decreasing inflammation and slowing the progress of the condition, which can help improve the physical activity of people with rheumatoid arthritis.
Read the full MedlinePlus article ↗- Leflunomide — also sold as Arava — is used to treat active rheumatoid arthritis in adults. Rheumatoid arthritis is an autoimmune condition where your immune system attacks your own...
- It can take several weeks to feel the full benefit, partly because leflunomide's active form (teriflunomide) builds up in the body gradually. Some prescribers use a short loading p...
- How long does it take for leflunomide to start working?
- The most common ones are diarrhea, nausea, headache, rash, and some hair thinning. Elevated liver enzymes can show up on your blood tests too, which is why regular monitoring is so...
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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UNII 68401960MK
Crospovidone is a synthetic polymer made from polyvinylpyrrolidone. It acts as a disintegrant, helping tablets break apart quickly in the stomach so the medicine dissolves and absorbs into the body.
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UNII EX438O2MRT
Ferric oxide yellow is a naturally occurring iron compound used as a colorant in medications. It gives tablets, capsules, and other forms a yellow or golden hue for identification and appearance.
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UNII R75537T0T4
Hypromellose 2910 is a plant-derived thickening agent made from cellulose. It serves as a binder that holds tablet ingredients together, a film-coating for pills, and a viscosity controller in liquids.
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UNII 0WZ8WG20P6
Hypromellose 2910 is a plant-based cellulose derivative that acts as a thickener, binder, and film-coating agent. It helps control how quickly the medicine dissolves and protects the tablet or capsule from moisture and light.
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UNII EWQ57Q8I5X
Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
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UNII 70097M6I30
Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
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UNII 30IQX730WE
Polyethylene glycol 6000 is a synthetic polymer made from ethylene glycol units. It acts as a binder, filler, and solubilizer in medicines to help hold ingredients together, add bulk, and improve how well active drugs dissolve and absorb.
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UNII ETJ7Z6XBU4
Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
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UNII O8232NY3SJ
A plant-based carbohydrate derived from corn kernels. It acts as a filler to add bulk, a binder to hold ingredients together, and a disintegrant to help the tablet break apart in your stomach for absorption.
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UNII 7SEV7J4R1U
A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
11 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.292 | $8.75 / 30 tablets |
| Medicaid paysCMS SDUD · 12 mo | $0.6092 | $18.28 / 30 tablets |
| Medicare drug plans payPart D · Q2 2026 | $0.5536 | $16.61 / 30 tablets |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| leflunomide 20 mg 23155-0044-03 | Heritage | 30 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mg 35573-0448-30 | Burel | 30 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mg 50268-0478-15 | AvPAK | 50 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mg 59651-0349-30 | Aurobindo | 30 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mg 60505-2503-01 | Apotex | 30 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mg 62135-0794-30 | Chartwell | 30 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mg 62332-0062-30 | Alembic | 30 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mgthis 70748-0130-06 | Lupin | 30 tablets | $0.292 | AB | Availability likely | — |
| Leflunomide 20 mg 10702-0278-03 | KVK-Tech, | 30 tablets | $0.549 | AB | FDA listed | +88% |
| Arava 20 mg 00088-2161-30 | sanofi-aventis | 30 tablets | — | AB | FDA listed | — |
| Leflunomide 20 mg 42291-0421-30 | AvKARE | 30 tablets | — | AB | FDA listed | — |
| Leflunomide 20 mg 46708-0437-30 | Alembic | 30 tablets | — | AB | FDA listed | — |
| Leflunomide 20 mg 50090-5992-00 | A-S | 30 tablets | — | AB | FDA listed | — |
| leflunomide 20 mg 50090-7537-00 | A-S | 30 tablets | — | AB | FDA listed | — |
| leflunomide 20 mg 68071-3764-09 | NuCare | 90 tablets | — | AB | FDA listed | — |
| leflunomide 20 mg 70710-1158-01 | Zydus | 100 tablets | — | AB | FDA listed | — |
| leflunomide 20 mg 70771-1492-01 | Zydus | 100 tablets | — | AB | FDA listed | — |
| Leflunomide 20 mg 71335-2256-01 | Bryant | 30 tablets | — | AB | FDA listed | — |
| leflunomide 20 mg 71335-2403-01 | Bryant | 30 tablets | — | AB | FDA listed | — |
| leflunomide 20 mg 71335-2832-01 | Bryant | 30 tablets | — | AB | FDA listed | — |
| leflunomide 20 mg 72162-2410-03 | Bryant | 30 tablets | — | AB | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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🗺️ Medicaid utilization & spend
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 70748-0130-06 You're viewing this | 1 BOTTLE in 1 CARTON (70748-130-06) / 30 TABLET, FILM COATED in 1 BOTTLE | 2020-08-31 | Active |
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY Embryo-Fetal Toxicity Leflunomide tablet 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 tablets in females of reproductive potential.
Advise females of reproductive potential to use effective contraception during leflunomide tablets treatment and during an accelerated drug elimination procedure after leflunomide tablets treatment. Stop leflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant. [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.3 ), Use in Specific Populations ( 8.1 , 8.3 )], and Clinical Pharmacology ( 12.3 )]. Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide tablets.
Leflunomide tablet is contraindicated in patients with severe hepatic impairment. Concomitant use of leflunomide tablets with other potentially hepatotoxic drugs may increase the risk of liver injury. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) >2xULN before initiating treatment, are at increased risk and should not be treated with leflunomide tablets.
Monitor ALT levels at least monthly for six months after starting leflunomide tablets, and thereafter every 6 to 8 weeks. If leflunomide-induced liver injury is suspected, stop leflunomide tablets treatment, start an accelerated drug elimination procedure, and monitor liver tests weekly until normalized. [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 , 5.3 ), Use in Specific Populations ( 8.6 )]. WARNING: EMBRYO-FETAL TOXICITY and HEPATOTOXICITY See full prescribing information for complete boxed warning.
Embryo-Fetal Toxicity • Teratogenicity and embryo-lethality occurred in animals administered leflunomide. ( 5.1 , 8.1 ) • Exclude pregnancy prior to initiating leflunomide tablets therapy. ( 5.1 , 8.3 ) • Advise use of effective contraception in females of reproductive potential during treatment and during a drug elimination procedure.
( 5.1 , 5.3 , 8.3 ) • Stop leflunomide tablets and use an accelerated drug elimination procedure if the patient becomes pregnant. ( 5.1 , 5.3 , 8.1 ) Hepatotoxicity • Severe liver injury and fatal liver failure have been reported. ( 5.2 ) • Avoid leflunomide tablets use in patients with pre-existing liver disease, or those with serum alanine aminotransferase (ALT) >2 × ULN.
( 5.2 , 8.6 ) • Use caution when leflunomide tablets are given with other potentially hepatotoxic drugs. ( 5.2 ) • Monitor ALT levels. Interrupt leflunomide tablets treatment if ALT elevation > 3-fold ULN.
If likely leflunomide-induced, start accelerated drug elimination procedure and monitor liver tests weekly until normalized. ( 5.2 , 5.3 )
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Leflunomide is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. ( 1 ) Leflunomide tablets USP are indicated for the treatment of adults with active rheumatoid arthritis (RA).
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Loading dosage for patients at low risk for leflunomide tablets -associated hepatotoxicity and leflunomide tablets-associated myelosuppression: 100 mg daily for 3 days. ( 2.1 ) Maintenance dosage: 20 mg daily. ( 2.1 ) Maximum recommended daily dosage: 20 mg once daily.
( 2.1 ) If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily. ( 2.1 ) Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting leflunomide tablets. ( 2.2 )
2.1Recommended Dosage The recommended dosage of leflunomide tablets is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of leflunomide tablets -associated hepatotoxicity and leflunomide tablets -associated myelosuppression. The loading dose provides steady-state concentrations more rapidly.
For patients who are at low risk for leflunomide tablets -associated hepatotoxicity and leflunomide tablets - associated myelosuppression, the recommended leflunomide tablets loading dose is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for leflunomide tablets - associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide tablets -associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide tablets dosage is 20 mg once daily without a loading dose [see Warnings and Precautions ( 5.2 , 5.4 )].
The maximum recommended daily dose is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1). Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide tablets, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [ see Clinical Pharmacology ( 12.3 ) ].
After stopping leflunomide tablets treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions ( 5.3 )]. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide tablets [see Clinical Pharmacology ( 12.3 )].
2.2Evaluation and Testing Prior to Starting leflunomide tablets Prior to starting leflunomide tablets treatment, the following evaluations and tests are recommended: Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions ( 5.4 )] Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions ( 5.2 , 5.4 )] For females of reproductive potential, pregnancy testing [see Warnings and Precautions ( 5.1 )] Check blood pressure [see Warnings and Precautions ( 5.11 )]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Leflunomide tablets, USP are available in two strengths: Tablets: 10 mg, supplied as white to off-white, round film coated tablet, debossed with "L" on one side and "A4" on the other side. Tablets: 20 mg, supplied as Yellow colour, film coated, round shaped tablet, debossed with "L" on one side and "A5" on the other side. Tablets: 10 mg and 20 mg. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Leflunomide tablet is contraindicated in: Pregnant women. Leflunomide tablets may cause fetal harm. If a woman becomes pregnant while taking this drug, stop leflunomide tablets, apprise the patient of the potential hazard to the fetus, and begin a drug elimination procedure [see Warnings and Precautions ( 5.1 , 5.3 ) and Use in Specific Populations ( 8.1 )].
Patients with severe hepatic impairment [see Warnings and Precautions ( 5.2 )]. Patients with known hypersensitivity to leflunomide or any of the other components of leflunomide tablets. Known reactions include anaphylaxis [see Adverse Reactions ( 6.1 )].
Patients being treated with teriflunomide [see Drug Interactions ( 7 )]. Pregnancy. ( 4 , 5.1 , 8.1 ) Severe hepatic impairment.
( 4 , 5.2 ) Hypersensitivity to leflunomide tablets or any of its inactive components. ( 4 ) Current teriflunomide treatment. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS After stopping leflunomide tablets, it is recommended that an accelerated drug elimination procedure be used to reduce the plasma concentrations of the active metabolite, teriflunomide. ( 5.3 ) Severe infections (including sepsis), pancytopenia, agranulocytosis and thrombocytopenia: Stop leflunomide tablets and use accelerated elimination procedure. Do not start leflunomide tablets in patients with active infection.
Monitor CBCs during treatment with leflunomide tablets ( 5.4 ) Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS): Stop leflunomide tablets and use accelerated elimination procedure. ( 5.5 ) Skin ulcers: If skin ulcer is suspected, discontinue leflunomide treatment and consider an accelerated drug elimination procedure. ( 5.6 ) Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy, evaluate patient and consider discontinuing leflunomide tablets.
( 5.8 ) Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide tablets and initiation of accelerated elimination procedure. ( 5.9 ) Increased blood pressure: Monitor and treat.
( 5.11 )
5.1Embryo-Fetal Toxicity Leflunomide tablets may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-lethality occurred in animal reproduction studies with leflunomide at doses lower than the human exposure level [see Use in Specific Populations ( 8.1 )]. Leflunomide tablet is contraindicated for use in pregnant women [see Contraindications ( 4 )].
Exclude pregnancy before starting treatment with leflunomide tablets in females of reproductive potential [see Dosage and Administration ( 2.2 )]. Advise females of reproductive potential to use effective contraception during leflunomide tablets treatment and during an accelerated drug elimination procedure after leflunomide tablets treatment [see Use in Specific Populations ( 8.3 )]. If a woman becomes pregnant while taking leflunomide tablets, stop treatment with leflunomide tablets, apprise the patient of the potential risk to a fetus, and perform an accelerated drug elimination procedure to achieve non detectable plasma concentrations of teriflunomide, the active metabolite of leflunomide [see Warnings and Precautions ( 5.3 )].
Upon discontinuing leflunomide tablets, it is recommended that all females of reproductive potential undergo an accelerated drug elimination procedure. Women receiving leflunomide tablets treatment who wish to become pregnant must discontinue leflunomide tablets and undergo an accelerated drug elimination procedure, which includes verification that plasma concentrations of the active metabolite of leflunomide, teriflunomide, are less than 0.02 mg/L (0.02 mcg/mL). Based on animal data, human plasma concentrations of teriflunomide of less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryo-fetal risk [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.1 )].
5.2Hepatotoxicity Severe liver injury, including fatal liver failure, has been reported in some patients treated with leflunomide tablets. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) of greater than twice the upper limits of normal (>2 × ULN) before initiating treatment, should not be treated with leflunomide tablets. Use caution when leflunomide tablets are given with other potentially hepatotoxic drugs.
Monitoring of ALT levels is recommended at least monthly for six months after starting leflunomide tablets, and thereafter every 6 to 8 weeks. If ALT elevation > 3-fold ULN occurs, interrupt leflunomide tablets therapy and investigate the cause. If likely leflunomide tablets - induced, perform the accelerated drug elimination procedure and monitor liver tests weekly until normalized [see Warnings and Precautions ( 5.3 )…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Immunosuppression [see Warnings and Precautions ( 5.4 )] Bone marrow suppression [see Warnings and Precautions ( 5.4 )] Serious infections [see Warnings and Precautions ( 5.4 )] Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms [see Warnings and Precautions ( 5.5 )] Skin ulcers [see Warnings and Precautions ( 5.6 )] Peripheral neuropathy [see Warnings and Precautions ( 5.8 )] Interstitial lung disease [see Warnings and Precautions ( 5.9 )] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide tablets treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, and dyspepsia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceutical, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with leflunomide tablets administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years.
The mean duration of RA was 6 years ranging from 0 to 45 years. Elevation of Liver Enzymes Treatment with leflunomide tablets was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤2-fold ULN) and usually resolved while continuing treatment.
Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate.
Table 1. Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3* Trial 1 Trial 2 Trial 3 * Leflunomide tablets 20mg/day (n=182) PL (n=118) MTX 7.5 to 15 mg/wk (n=182) Leflunomide tablets 20mg/day (n=133) PL (n=92) SSZ 2 mg/day (n=133) Leflunomide tablets 20mg/day (n=501) MTX 7.5 to 15 mg/wk (n=498) ALT (SGPT) >3-fold ULN (n %) 8 (4.4) 3 (2.5) 5 (2.7) 2 (1.5) 1 (1.1) 2 (1.5) 13 (2.6) 83 (16.7) Reversed to ≤ 2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0 to 3 Months 6 1 1 2 1 2 7 27 4 to 6 Months 1 1 3 - - - 1 34 7 to 9 Months 1 1 1 - - - - 16 10 to 12 Months - - - - - - 5 6 MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal *Only 10% of patients in Trial 3 received folate.
All patients in Trial 1 received folate. In a 6-month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide tablets was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo.
Most Common Adverse Reactions The most common adverse reactions in leflunomide tablets -treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year ( ≥ 5% in any leflunomide tablets treatment group). Table 2.
Percentage Of Patients With Adverse Events ≥5% In Any Leflunomide…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Drug interaction studies have been conducted with both leflunomide and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects. Effect of Potent CYP and Transporter Inducers Leflunomide is metabolized by CYP450 metabolizing enzymes.
Concomitant use of leflunomide tablets and rifampin, a potent inducer of CYP and transporters, increased the plasma concentration of teriflunomide by 40%. However, when co-administered with the metabolite, teriflunomide, rifampin did not affect its pharmacokinetics. No dosage adjustment is recommended for leflunomide tablets when coadministered with rifampin.
Because of the potential for leflunomide tablets concentrations to continue to increase with multiple dosing, caution should be used if patients are to be receiving both leflunomide tablets and rifampin [see Clinical Pharmacology ( 12.3 )]. Effect on CYP2C8 Substrates Teriflunomide is an inhibitor of CYP2C8 in vivo . In patients taking leflunomide tablets, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased.
Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology ( 12.3 )]. Effect on Warfarin Coadministration of leflunomide tablets with warfarin requires close monitoring of the international normalized ratio (INR) because teriflunomide, the active metabolite of leflunomide tablets, may decrease peak INR by approximately 25%. Effect on Oral Contraceptives Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel.
Consideration should be given to the type or dose of contraceptives used in combination with leflunomide tablets [ see Clinical Pharmacology ( 12.3 )]. Effect on CYP1A2 Substrates Teriflunomide, the active metabolite of leflunomide tablets, may be a weak inducer of CYP1A2 in vivo . In patients taking leflunomide tablets, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced.
Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology ( 12.3 )]. Effect on Organic Anion Transporter 3 (OAT3) Substrates Teriflunomide inhibits the activity of OAT3 in vivo . In patients taking leflunomide tablets, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased.
Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology ( 12.3 )]. Effect on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) Substrates Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo . For a patient taking leflunomide tablets, the dose of rosuvastatin should not exceed 10 mg once daily.
For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG- Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide tablets [see Clinical Pharmacology ( 12.3 )]. Drugs metabolized by CYP2C8 and OAT3 transporters: Monitor patients because teriflunomide may increase exposure of these drugs.
( 7 ) Teriflunomide may increase exposure of ethinylestradiol and levonorgestrel. Choose an appropriate oral contraceptive. ( 7 ) Drugs metabolized by CYP1A2: Monitor patients because teriflunomide may decrease exposure of these drugs.
( 7 ) Warfarin: Monitor INR as teriflunomide…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation: Discontinue breastfeeding. ( 8.2 ) Females and Males of Reproductive Potential: See FPI for information regarding contraception. ( 8.3 ) Safety and effectiveness in pediatric patients <12 years of age have not been established. ( 8.4 )
8.1Pregnancy Risk Summary Leflunomide tablet is contraindicated for use in pregnant women because of the potential for fetal harm. In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of, and equivalent to, the maximum recommended human dose (MRHD) based on AUC, respectively, in rats and rabbits, caused teratogenicity (rats and rabbits), and embryo-lethality (rats) [see Data]. Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of leflunomide tablets during pregnancy.
The background risk of major birth defects and miscarriage for the indicated populations is unknown. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with leflunomide tablets, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL). [see Warnings and Precautions ( 5.3 )].
Clinical Considerations Fetal/Neonatal adverse reactions Lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from leflunomide tablets. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L. [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )]. Data Animal Data In an embryofetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microphthalmia and internal hydrocephalus, were observed.
Under these exposure conditions, Leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In an embryofetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. Leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in both rats and rabbits).
In a pre- and post-natal development study, when female rats were treated with leflunomide at a dose that was approximately 1/100 of the MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival.
8.2Lactation Risk Summary Clinical lactation studies have not been conducted to assess the presence of leflunomide tablets in human milk, the effects of leflunomide tablets on the breastfed child, or the effects of leflunomide tablets on milk production. Because of the potential for serious adverse reactions in a breastfed infant from leflunomide tablets, advise a nursing woman to discontinue breastfeeding during treatment with leflunomide tablets.
8.3Females and Males of Reproductive Potential Leflunomide tablets may cause fetal harm if administered during pregnancy. [see Use in Specific Populations ( 8.1 )…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Leflunomide tablet is contraindicated for use in pregnant women because of the potential for fetal harm. In animal reproduction studies, oral administration of leflunomide during organogenesis at a dose of 1/10 of, and equivalent to, the maximum recommended human dose (MRHD) based on AUC, respectively, in rats and rabbits, caused teratogenicity (rats and rabbits), and embryo-lethality (rats) [see Data]. Pregnancy exposure registry data are not available at this time to inform the presence or absence of drug-associated risk with the use of leflunomide tablets during pregnancy.
The background risk of major birth defects and miscarriage for the indicated populations is unknown. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, stop treatment with leflunomide tablets, apprise the patient of the potential hazard to a fetus, and perform the accelerated drug elimination procedure to achieve teriflunomide concentrations of less than 0.02 mg/L (0.02 mcg/mL). [see Warnings and Precautions ( 5.3 )].
Clinical Considerations Fetal/Neonatal adverse reactions Lowering the plasma concentration of the active metabolite, teriflunomide, by instituting an accelerated drug elimination procedure as soon as pregnancy is detected may decrease the risk to the fetus from leflunomide tablets. The accelerated drug elimination procedure includes verification that the plasma teriflunomide concentration is less than 0.02 mg/L. [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )]. Data Animal Data In an embryofetal development study, pregnant rats administered leflunomide during organogenesis from gestation days 7 to 19 at a dose approximately 1/10 of the MRHD (on an AUC basis at a maternal oral dose of 15 mg/kg), teratogenic effects, most notably anophthalmia or microphthalmia and internal hydrocephalus, were observed.
Under these exposure conditions, Leflunomide also caused a decrease in the maternal body weight and an increase in embryolethality with a decrease in fetal body weight for surviving fetuses. In an embryofetal development study, pregnant rabbits administered leflunomide during organogenesis from gestation days 6 to 18 at a dose approximately equivalent to the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg), a teratogenic finding of fused, dysplastic sternebrae was observed. Leflunomide was not teratogenic in rats and rabbits at doses approximately 1/150 and 1/10 of the MRHD, respectively (on an AUC basis at maternal oral dose of 1 mg/kg in both rats and rabbits).
In a pre- and post-natal development study, when female rats were treated with leflunomide at a dose that was approximately 1/100 of the MRHD (on an AUC basis at a maternal dose of 1.25 mg/kg) beginning 14 days before mating and continuing until the end of lactation, the offspring exhibited marked (greater than 90%) decreases in postnatal survival.
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of leflunomide tablets in pediatric patients have not been established. The safety and effectiveness of leflunomide tablets in the treatment of polyarticular course juvenile idiopathic arthritis (JIA) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (JIA) as defined by the American College of Rheumatology (ACR). In this population, leflunomide tablets treatment was found not to be effective.
The safety of leflunomide tablets was studied in 74 patients with polyarticular course JIA ranging in age from 3 to 17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss.
Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, and five between 3 and 8-fold the upper limit of normal.
🧓 Geriatric Use ▾
8.5Geriatric Use Of the total number of subjects in controlled clinical trials (Trials 1, 2, and 3) of leflunomide tablets, 234 subjects were 65 years and over [see Clinical Studies ( 14 )]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is needed in patients over 65.
🆘 Overdosage ▾
10 OVERDOSAGE There have been reports of chronic overdose in patients taking leflunomide tablets at daily dose up to five times the recommended daily dose and reports of acute overdose in adults and children. Adverse events were consistent with the safety profile for leflunomide tablets [See Adverse Reactions ( 6 )]. The most frequent adverse events observed were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.
In the event of a significant overdose or toxicity, perform an accelerated drug elimination procedure to accelerate elimination [see Warnings and Precautions ( 5.3 )]. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide, the primary metabolite of leflunomide, is not dialyzable [See Clinical Pharmacology ( 12.3 )].
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
12.3Pharmacokinetics Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Plasma concentrations of the parent drug, leflunomide, have been occasionally seen at very low concentrations. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of the active metabolite, teriflunomide.
Absorption Following oral administration, peak teriflunomide concentrations occurred between 6 to 12 hours after dosing. Due to the very long half-life of teriflunomide (18 to 19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations. Without a loading dose, it is estimated that attainment of steady- state plasma concentrations would require about two months of dosing.
The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional. Effect of Food Co-administration of leflunomide tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations. Distribution Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma.
The volume of distribution is 11 L after a single intravenous (IV) administration. Elimination Teriflunomide, the active metabolite of leflunomide, has a median half-life of 18 to 19 days in healthy volunteers. The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal.
Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, due to individual variation in drug clearance [see Warnings and Precautions ( 5.3 )]. After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h. Metabolism In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in leflunomide metabolism.
In vivo , leflunomide is metabolized to one primary (teriflunomide) and many minor metabolites. In vitro , teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes. The parent compound is rarely detectable in plasma.
Excretion Teriflunomide, the active metabolite of leflunomide, is eliminated by direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces).
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that teriflunomide is not dialyzable. Specific Populations Gender. Gender has not been shown to cause a consistent change in the in vivo pharmacokinetics of teriflunomide.
Smoking. A population based pharmacokinetic analysis of the clinical trial data indicates that smokers have a 38% increase in clearance over non-smokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers. Drug Interaction Studies Drug interaction studies have been conducted with both leflunomide and with its active metabolite, teriflunomide, where the metabolite was directly administered to the test subjects.
The Potential Effect of Other Drugs on Leflunomide tablets Potent CYP and transporter inducers: Following concomitant administration of a single d…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Leflunomide Tablets, USP; 10 mg and 20 mg Strength Quantity NDC Number Description 10 mg 30 count bottle 70748-129-06 White to off-white, round film coated tablet, free from physical defects, debossed with "L" on one side and "A4" on the other side. 20 mg 30 count bottle 70748-130-06 Yellow colour, film coated, round shaped tablet, free from physical defects, debossed with "L" on one side and "A5" on the other side. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Protect from light.
📋 Description ▾
11 DESCRIPTION Leflunomide USP is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C 12 H 9 F 3 N 2 O 2 , a molecular weight of 270.2 and the following structural formula: Leflunomide USP is available for oral administration as film coated tablets containing 10 mg and 20 mg of active drug.
Combined with leflunomide are the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, corn starch, HPMC 2910/Hypromellose USP (6 mPas), Titanium Dioxide USP, Macrogol/PEG 6000 NF, Talc USP and Iron Oxide Yellow NF (20 mg tablet only). Image
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Embryo-Fetal Toxicity Advise females of reproductive potential: Of the potential for fetal harm if leflunomide tablets are taken during pregnancy. To notify their healthcare provider immediately if a pregnancy occurs or is suspected. To use effective contraception during treatment with leflunomide tablets and until the active metabolite (teriflunomide) plasma concentration is verified to be less than 0.02 mg/L [see Warnings and Precautions ( 5.1 , 5.3 ), Use in Specific Populations ( 8.1 , 8.3 ), and Clinical Pharmacology ( 12.3 )].
Serious Skin Reactions Advise patients of the possibility of rare, serious skin reactions. Instruct patients to promptly seek medical attention if they develop a skin rash, mucous membrane lesions, or skin ulcers. Lactation Advise nursing women to discontinue breastfeeding during treatment with leflunomide tablets [see Use in Specific Populations ( 8.2 )].
Investigations Advise patients of the potential hepatotoxic effects of leflunomide tablets and of the need for monitoring liver enzymes. Instruct patients to report if they develop symptoms such as unusual tiredness, abdominal pain or jaundice. Advise patients that they may develop a lowering of their blood counts and should have frequent hematologic monitoring.
This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with leflunomide tablets, who have recently discontinued such therapy before starting treatment with leflunomide tablets, or who have had a history of a significant hematologic abnormality. Instruct patients to promptly report if they notice symptoms consistent with pancytopenia, such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness. Inform patients about the early warning signs of interstitial lung disease and ask them to contact their physician promptly if these symptoms appear or worsen during therapy.