pharmacopeia
GET
/api/v1/drug/leflunomide

Boxed warning

EMBRYO-FETAL TOXICITY and HEPATOTOXICITY Embryo-Fetal Toxicity 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. Advise females of reproductive potential to use effective contraception during leflunomide treatment and during an accelerated drug elimination procedure after leflunomide 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. 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 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.

2D structure
5-methyl-N-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide
SMILES CC1=C(C=NO1)C(=O)NC2=CC=C(C=C2)C(F)(F)F
InChIKey VHOGYURTWQBHIL-UHFFFAOYSA-N

Mechanism of action

Sourced from openFDA

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.

Nucleic Acid Synthesis

Indications

Sourced from openFDA
  • Leflunomide Tablets, USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Leflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis.ICD-10: M06.9

Contraindications

Sourced from openFDA
  • Leflunomide tablets are contraindicated in: Pregnant women. Leflunomide may cause fetal harm.contraindicated

Dosage & administration

Sourced from openFDA

Loading dosage for patients at low risk for leflunomide -associated hepatotoxicity and leflunomide -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 ) 2.1 Recommended Dosage The recommended dosage of Leflunomide is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of leflunomide -associated hepatotoxicity and leflunomide associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly. For patients who are at low risk for leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression the recommended leflunomide loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide dosage is 20 mg once daily without a loading dose [see Warnings and Precautions ( 5.2 , 5.4 )]. The maximum recommended daily dosage is 20 mg once per day.

Warnings & precautions

Sourced from openFDA

After stopping leflunomide, 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 and use accelerated elimination procedure. Do not start leflunomide in patients with active infection. Monitor CBCs during treatment with leflunomide. ( 5.4 ) Stevens-Johnson syndrome and toxic epidermal necrolysis: Stop leflunomide and use accelerated elimination procedure. ( 5.5 ) Peripheral neuropathy: If patient develops symptoms consistent with peripheral neuropathy evaluate patient and consider discontinuing leflunomide. ( 5.7 ) Interstitial lung disease: May be fatal. New onset or worsening symptoms may necessitate discontinuation of leflunomide and initiation of accelerated elimination procedure. ( 5.8 ) Increased blood pressure: Monitor and treat. ( 5.10 ) 5.1 Embryo-Fetal Toxicity Leflunomide 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 is contraindicated for use in pregnant women [see Contraindications (4) ] . Exclude pregnancy before starting treatment with leflunomide in females of reproductive potential [see Dosage and Administration (2.2) ] .

Adverse reactions

Sourced from openFDA

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) ] Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.5) ] Peripheral neuropathy [see Warnings and Precautions (5.7) ] Interstitial lung disease [see Warnings and Precautions (5.8) ] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical 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 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.

Use in specific populations

Sourced from openFDA

Lactation: Discontinue breastfeeding. ( 8.2 ) Safety and effectiveness in pediatric patients <12 years of age has not been established. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to leflunomide during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-877-311-8972 or visit http://www.pregnancystudies.org/participate-in a-study/. Risk Summary Leflunomide 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 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.

Pharmacokinetics

Sourced from openFDA
Metabolism
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.

Overdosage

Sourced from openFDA

There have been reports of chronic overdose in patients taking leflunomide 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 [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) ].

Approval history

Sourced from openFDA
  • Sep 10, 1998NDANDA020905Sanofi Aventis Us
  • Sep 13, 2005ANDAANDA077086Heritage
  • Sep 13, 2005ANDAANDA077090Apotex
  • Nov 21, 2011ANDAANDA091369Alembic Pharms Ltd
  • Apr 24, 2019ANDAANDA212308Zydus Lifesciences
  • Jun 3, 2019ANDAANDA212453Abhai Llc
  • Feb 4, 2020ANDAANDA211863Lupin
  • Mar 29, 2021ANDAANDA213652Aurobindo Pharma

FDA shortages

View JSON

Reference statistics from the openFDA drug-shortage dataset. For a live view, consult the FDA database directly. Not clinical guidance.

  • Arava, Tablet, 10 mg (NDC 0088-2160-30)To be discontinued
    Sponsor: Sanofi-Aventis U.S. LLC
    Updated
  • Arava, Tablet, 100 mg (NDC 0088-2162-33)To be discontinued
    Sponsor: Sanofi-Aventis U.S. LLC
    Updated
  • Arava, Tablet, 20 mg (NDC 0088-2161-30)To be discontinued
    Sponsor: Sanofi-Aventis U.S. LLC
    Updated
  • Leflunomide, Tablet, 10 mg (NDC 0955-1735-30)To be discontinued
    Sponsor: Sanofi-Aventis U.S. LLC
    Updated
  • Leflunomide, Tablet, 20 mg (NDC 0955-1737-30)To be discontinued
    Sponsor: Sanofi-Aventis U.S. LLC
    Updated

FAERS reports

View JSON
Reference statistics only. FAERS reports are voluntarily submitted and are not incidence rates, safety signals, or causal evidence. Counts reflect reporting volume — how often a reaction was reported, not how often it occurs. For decision-grade use, consult openFDA and the FAERS Public Dashboard directly.
102,952 total reports matchedLatest report Share = reports listing the reaction ÷ total matched reports. Rows can sum to >100% because a single report often lists multiple reactions.
  1. 1Drug Ineffective37,15036%
  2. 2Rheumatoid Arthritis25,09524%
  3. 3Pain20,24920%
  4. 4Arthralgia17,14217%
  5. 5Drug Intolerance15,73515%
  6. 6Joint Swelling15,73015%
  7. 7Fatigue15,54715%
  8. 8Rash13,49813%
  9. 9Off Label Use11,97512%
  10. 10Abdominal Discomfort11,87212%
  11. 11Alopecia11,84012%
  12. 12Contraindicated Product Administered11,76711%
  13. 13Arthropathy10,91511%
  14. 14Condition Aggravated10,50310%
  15. 15Swelling10,37510%

Literature

View JSON

Recent PubMed references pinned to Leflunomide as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

Clinical trials

View JSON

The 10 most recently updated of 137 ClinicalTrials.gov registrations naming Leflunomide as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

Frequently asked questions

How does Leflunomide work?
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.
What is Leflunomide used for?
According to FDA labeling, Leflunomide carries indications including: Leflunomide Tablets, USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Leflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.
What class of drug is Leflunomide?
Leflunomide is classified as Dihydroorotate dehydrogenase (DHODH) inhibitors, Antirheumatic Agent, Nucleic Acid Synthesis Inhibitors, Immunologic Activity Alteration.
What are the brand names for Leflunomide?
Leflunomide is marketed under brand names including Arava.
What are the contraindications for Leflunomide?
Leflunomide labeling lists contraindications including: Leflunomide tablets are contraindicated in: Pregnant women. Leflunomide may cause fetal harm.. Always consult the full prescribing information and a clinician.
Note. Data for leflunomide is illustrative MVP content compiled from public sources. pharmacopeia is for educational and informational use only and is not a substitute for professional medical advice.

Search pharmacopeia

Search drugs, classes, and ingredients