Two medicines, side by side
Leflunomide vs methotrexate
Leflunomide and methotrexate are both labeled for rheumatoid arthritis. Drugs@FDA records approvals of leflunomide since 1998 and of methotrexate since 1953. Pharmacies paid $0.324 per leflunomide 10 mg tablet and $0.158 per methotrexate 2.5 mg tablet (NADAC, October 7, 2026); the strengths differ, so the two prices are not like for like. Methotrexate's other strengths are brand-only: $21.76 per mL (Xatmep 2.5 mg/mL oral solution). In FDA's classes, leflunomide is an antirheumatic agent and methotrexate a folate analog metabolic inhibitor.
Check it at the source: the leflunomide FDA label on DailyMed (effective June 4, 2025); the methotrexate FDA label on DailyMed (effective May 27, 2026).
Highlights of the leflunomide record
Leflunomide (Arava) · label of June 4, 2025
EMBRYO-FETAL TOXICITY and HEPATOTOXICITY 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 ARAVA therapy. ( 5.1 , 8.3 ) Advise use of effective contraception in females of reproductive potential during treatment and during a drug elimination procedure.
Used for
From the label: indicationsARAVA is indicated for the treatment of adults with active rheumatoid arthritis (RA). ARAVA is a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis.
On the market
- Earliest approval on file
- September 10, 1998
- Generic labelers
- 16 labelers
- Pharmacy cost
- $0.324 per tablet
Supply and safety
- Shortage
- A presentation being discontinued
- Recalls
- 2
Highlights of the methotrexate record
Methotrexate (Rasuvo) · label of May 27, 2026
EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, SEVERE ADVERSE REACTIONS, and RISK OF MEDICATION ERRORS Methotrexate Tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Tablets is contraindicated in pregnancy. For neoplastic diseases, advise females and males of reproductive potential to use effective contraception [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 , 8.3) ].
Used for
From the label: indicationsMethotrexate tablets is a dihydrofolate reductase inhibitor indicated for the: Treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen ( 1.1 ) Treatment of adults with mycosis fungoides ( 1.1 ) Treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a metronomic combination regimen ( 1.1 ) Treatment of adults […]
On the market
- Earliest approval on file
- December 7, 1953
- Generic labelers
- 29 labelers
- Pharmacy cost
- $0.158 per tablet
Supply and safety
- Shortage
- In shortage
- Recalls
- 8
Source: FDA drug labels via openFDA (Leflunomide label of June 4, 2025, Methotrexate label of May 27, 2026); NDC Directory, Drugs@FDA, NADAC, FDA shortages and recalls (October 8, 2026)
How do leflunomide and methotrexate differ on the record?
In FDA's classes, leflunomide is an antirheumatic agent and methotrexate a folate analog metabolic inhibitor.
How each works, in its label's words: Leflunomide, “Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity.”; Methotrexate, “Methotrexate inhibits dihydrofolic acid reductase.”
Half-life, in each label's words: Leflunomide, “Due to the very long half-life of teriflunomide (18–19 days), a loading dose of 100 mg for 3 days was used in clinical …”; Methotrexate, “Elimination The elimination half-life of methotrexate is approximately 3 to 10 hours.”
Both labels carry a boxed warning; the records quote them.
Generics: leflunomide since 2005; methotrexate since 1979 (Drugs@FDA).
| Leflunomide | Methotrexate | |
|---|---|---|
| Labeled for | Rheumatoid arthritis | Rheumatoid arthritis, Psoriasis, Leukemia, lymphoma and myeloma, Breast cancer |
| Pharmacologic class | Antirheumatic Agent | Folate Analog Metabolic Inhibitor |
| How it works (label) | Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. | Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. |
| Half-life (label) | Due to the very long half-life of teriflunomide (18–19 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. | Elimination The elimination half-life of methotrexate is approximately 3 to 10 hours. |
| Earliest approval on file (Drugs@FDA) | September 10, 1998 | December 7, 1953 |
| First generic approved | September 13, 2005 | September 5, 1979 |
| Generic labelers (NDC) | 16 labelers | 29 labelers |
| Pharmacy cost (NADAC, each one's most listed form; strengths differ) | $0.324 per tablet (Leflunomide 10 mg tablet) | $0.158 per tablet (Methotrexate 2.5 mg tablet) |
| 12-month price change | -7% | -4% |
| Boxed warning | Yes | Yes |
| Shortage now | A presentation being discontinued | In shortage |
| Recalls recorded | 2 | 8 |
| FAERS reports (a report is not proof of cause; counts follow how widely a medicine is used) | 104,036 | 489,791 |
| DEA schedule | none | none |
Source: Drugs@FDA, FDA NDC Directory, CMS NADAC of October 7, 2026, FDA shortages and recalls, FAERS via openFDA (FDA files October 8, 2026)
Do their labels mention each other?
Leflunomide label, warnings and precautionsIf ARAVA and methotrexate are given concomitantly, follow the American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity with ALT, AST, and serum albumin testing.
Source: FDA drug labels via openFDA
What do the labels say about using others of their kind?
Methotrexate label, drug interactionsOral antibiotics (including neomycin) Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Oral or intravenous penicillin or sulfonamide antibiotics Aspirin and other nonsteroidal anti-inflammatory drugs Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Hepatotoxic products Proton pump inhibitors Weak acids (e.g. …
Source: FDA drug labels via openFDA
What next?
- Alternatives to leflunomide
- every medicine labeled for the same conditions