pharmacopeia
GET
/api/v1/drug/methotrexate

Boxed warning

EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, and SEVERE ADVERSE REACTIONS • Methotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are 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)]. • Methotrexate tablets are contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [Contraindications (4), Warnings and Precautions (5.2)]. • Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate [Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7, 5.8)]. WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, and SEVERE ADVERSE REACTIONS See full prescribing information for complete boxed warning. • Methotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate tablets are contraindicated in pregnancy.

2D structure
(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid
SMILES CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
InChIKey FBOZXECLQNJBKD-ZDUSSCGKSA-N

Mechanism of action

Sourced from openFDA

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.

Dihydrofolate ReductaseFolic Acid MetabolismThymidylate Synthetase

Indications

Sourced from openFDA
  • Methotrexate tablets are a diydrofolate 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 with rheumatoid arthritis (1.2) • Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) (1.3) • Treatment of adults with severe psoriasis (1.4) 1.1 Neoplastic Diseases Methotrexate tablets are indicated for the: • treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen • treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent or as part of a combination chemotherapy regimen • treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of a metronomic combination chemotherapy regimen 1.2 Rheumatoid Arthritis Methotrexate tablets are indicated for the treatment of adults with rheumatoid arthritis.ICD-10: C85.90, C95.90, L40.9, M06.9

Contraindications

Sourced from openFDA
  • Methotrexate tablets are contraindicated in: • Pregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]. • Patients with a history of severe hypersensitivity reactions, including anaphylaxis, to methotrexate.contraindicated

Dosage & administration

Sourced from openFDA

• Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. (2.1, 5.9) • Verify pregnancy status in females of reproductive potential before starting methotrexate tablets. (4, 5.1) • ALL: The recommended dosage is 20 mg/m 2 orally once weekly as a part of a combination chemotherapy maintenance regimen. (2.2) • Mycosis fungoides: The recommended dosage is 25 to 75 mg orally once weekly as monotherapy; 10 mg/m 2 orally twice weekly as part of combination chemotherapy. (2.2) • Relapsed or refractory non-Hodgkin lymphoma: The recommended dosage is 2.5 mg orally two to four times per week as part of metronomic combination chemotherapy. (2.2) • Rheumatoid Arthritis: The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response. (2.3) • pJIA: The recommended starting dosage is 10 mg/m 2 orally once weekly; adjust dose to achieve an optimal response. (2.4) • Psoriasis: The recommended dosage is 10 to 25 mg orally once weekly until adequate response is achieved. (2.5) 2.1 Important Dosage and Safety Information Verify pregnancy status in females of reproductive potential before starting methotrexate tablets [see Contraindications (4), Warnings and Precautions (5.1)]. Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths [see Warnings and Precautions (5.9)].

Warnings & precautions

Sourced from openFDA

• Serious Infections : Monitor patients for infection during and after treatment with methotrexate. Withhold or discontinue methotrexate for serious infections as appropriate. (5.11) • Neurotoxicity : Monitor patients for neurotoxicity and withhold or discontinue methotrexate as appropriate. (5.12) • Secondary Malignancies : Can occur with methotrexate. (5.13) • Tumor Lysis Syndrome : Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate (5.14) • Immunizations and Risk Live Vaccines : Immunizations with live vaccines is not recommended. Follow current vaccination practice guidelines. (5.15) • Infertility : Can cause impairment of fertility, oligospermia, and menstrual dysfunction. (5.16, 8.3) 5.1 Embryo-Fetal Toxicity Based on published reports and its mechanism of action, methotrexate can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate is contraindicated for use in pregnant women receiving methotrexate for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate treatment and for 3 months after the final dose [see Contraindications (4), Use in Specific Populations (8.1, 8.3)].

Adverse reactions

Sourced from openFDA

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Myelosuppression [see Warnings and Precautions (5.3)] Gastrointestinal Toxicity [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Pulmonary Toxicity [see Warnings and Precautions (5.6)] Dermatologic Reactions [see Warnings and Precautions (5.7)] Renal Toxicity [see Warnings and Precautions (5.8)] Serious Infections [see Warnings and Precautions (5.11)] Neurotoxicity [see Warnings and Precautions (5.12)] Secondary Malignancies [see Warnings and Precautions (5.13)] Tumor Lysis Syndrome [see Warnings and Precautions (5.14)] Increased Risk of Adverse Reactions Due to Third-Space Accumulation [see Warnings and Precautions (5.17)] Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, abdominal distress. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness.

Use in specific populations

Sourced from openFDA

Lactation : Instruct not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Methotrexate is contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4)]. Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)] , methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment.

Pharmacokinetics

Sourced from openFDA
Metabolism
Absorption At doses of 30 mg/m 2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to 6 hours following oral administration.

Overdosage

Sourced from openFDA

Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5. 9)] . Manifestations Manifestations of methotrexate overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported. Management Leucovorin and levoleucovorin are indicated for diminishing the methotrexate adverse reactions of methotrexate overdosage. Administer leucovorin or levoleucovorin as soon as possible after methotrexate overdosage). Monitor serum creatinine and methotrexate levels to guide leucovorin or levoleucovorin therapy. Refer to the leucovorin or levoleucovorin prescribing information for additional dosage information.

Approval history

Sourced from openFDA
  • Aug 10, 1959NDANDA011719Hospira
  • Sep 16, 1986ANDAANDA089343Hikma
  • Sep 16, 1986ANDAANDA089340Hikma
  • Sep 16, 1986ANDAANDA089341Hikma
  • Oct 11, 2013NDANDA204824Assertio Speclty
  • Jul 10, 2014NDANDA205776Medexus
  • Apr 25, 2017NDANDA208400Azurity
  • Nov 29, 2022NDANDA212479Shorla

FDA shortages

View JSON

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

  • Methotrexate Sodium Preservative Free, Injection, 25 mg/1 mL (NDC 0703-3671-01)Active
    Sponsor: Teva Pharmaceuticals USA, Inc.
    Updated
  • Methotrexate Sodium Preservative Free, Injection, 25 mg/1 mL (NDC 0703-3675-01)Active
    Sponsor: Teva Pharmaceuticals USA, Inc.
    Updated
  • Methotrexate Sodium Preservative Free, Injection, 25 mg/1 mL (NDC 0703-3678-01)Active
    Sponsor: Teva Pharmaceuticals USA, Inc.
    Updated
  • Methotrexate Sodium Preservative Free, Injection, 25 mg/1 mL (NDC 16729-277-30)Active
    Sponsor: Accord Healthcare Inc. · Reason: Shortage of an active ingredient
    Updated
  • Methotrexate Sodium Preservative Free, Injection, 25 mg/1 mL (NDC 16729-277-35)Active
    Sponsor: Accord Healthcare Inc. · Reason: Shortage of an active ingredient
    Updated
  • Methotrexate Sodium, Injection, 1 g/40 mL (25 mg/mL) (NDC 61703-124-40)Active
    Sponsor: Hospira, Inc., a Pfizer Company
    Updated
  • Methotrexate Sodium, Injection, 1 g/40 mL (25 mg/mL) (NDC 61703-408-25)Active
    Sponsor: Hospira, Inc., a Pfizer Company
    Updated
  • Methotrexate Sodium, Injection, 1 g/40 mL (25 mg/mL) (NDC 61703-408-41)Active
    Sponsor: Hospira, Inc., a Pfizer Company
    Updated
  • Methotrexate Sodium, Injection, 50 mg/2 mL (25 mg/mL) (NDC 61703-350-10)Active
    Sponsor: Hospira, Inc., a Pfizer Company
    Updated
  • Methotrexate Sodium, Injection, 50 mg/2 mL (25 mg/mL) (NDC 61703-350-38)Active
    Sponsor: Hospira, Inc., a Pfizer Company
    Updated
  • Methotrexate, Preservative Free, Injection, 1 g (NDC 0143-9830-01)Active
    Sponsor: Hikma Pharmaceuticals USA, Inc.
    Updated
  • Methotrexate, Preservative Free, Injection, 25 mg/1 mL (NDC 0143-9519-10)Active
    Sponsor: Hikma Pharmaceuticals USA, Inc.
    Updated
  • Otrexup, Injection, 10 mg/.4 mL (NDC 82497-010-04)To be discontinued
    Sponsor: Assertio Specialty Pharmaceuticals, LLC
    Updated
  • Otrexup, Injection, 12.5 mg/.4 mL (NDC 82497-012-04)To be discontinued
    Sponsor: Assertio Specialty Pharmaceuticals, LLC
    Updated
  • Otrexup, Injection, 15 mg/.4 mL (NDC 82497-015-04)To be discontinued
    Sponsor: Assertio Specialty Pharmaceuticals, LLC
    Updated
  • Otrexup, Injection, 17.5 mg/.4 mL (NDC 82497-017-04)To be discontinued
    Sponsor: Assertio Specialty Pharmaceuticals, LLC
    Updated
  • Otrexup, Injection, 20 mg/.4 mL (NDC 82497-020-04)To be discontinued
    Sponsor: Assertio Specialty Pharmaceuticals, LLC
    Updated
  • Otrexup, Injection, 22.5 mg/.4 mL (NDC 82497-022-04)To be discontinued
    Sponsor: Assertio Specialty Pharmaceuticals, LLC
    Updated
  • Otrexup, Injection, 25 mg/.4 mL (NDC 82497-025-04)To be discontinued
    Sponsor: Assertio Specialty Pharmaceuticals, 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.
484,881 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 Ineffective92,61819%
  2. 2Rheumatoid Arthritis42,4458.8%
  3. 3Arthralgia40,4538.3%
  4. 4Pain39,3888.1%
  5. 5Off Label Use39,3878.1%
  6. 6Fatigue32,7226.7%
  7. 7Nausea28,6975.9%
  8. 8Joint Swelling24,8265.1%
  9. 9Drug Intolerance24,1935.0%
  10. 10Condition Aggravated23,5474.9%
  11. 11Headache23,1824.8%
  12. 12Rash22,1904.6%
  13. 13Diarrhoea20,6284.3%
  14. 14Pain In Extremity19,9294.1%
  15. 15Drug Hypersensitivity19,5264.0%

Literature

View JSON

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

Clinical trials

View JSON

The 10 most recently updated of 2,333 ClinicalTrials.gov registrations naming Methotrexate as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

Pharmacogenomics

View JSON

CPIC-curated drug–gene pairs for Methotrexate. Levels describe the strength of curated evidence and guideline status — never a recommendation to test or to adjust therapy.

  • ABCB1CPIC C (provisional)ClinPGx 3
  • ATICCPIC D (provisional)ClinPGx 2B
  • MTHFRCPIC C (provisional)ClinPGx 2A
  • MTRRCPIC D (provisional)ClinPGx 3
  • SLCO1B1CPIC C (provisional)ClinPGx 3

Structural analogs

View JSON

Ranked by 2D fingerprint (Tanimoto) similarity over PubChem structures. Structural proximity only — not a claim of therapeutic equivalence.

Frequently asked questions

How does Methotrexate work?
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.
What is Methotrexate used for?
According to FDA labeling, Methotrexate carries indications including: Methotrexate tablets are a diydrofolate 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 with rheumatoid arthritis (1.2) • Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) (1.3) • Treatment of adults with severe psoriasis (1.4) 1.1 Neoplastic Diseases Methotrexate tablets are indicated for the: • treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen • treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent or as part of a combination chemotherapy regimen • treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of a metronomic combination chemotherapy regimen 1.2 Rheumatoid Arthritis Methotrexate tablets are indicated for the treatment of adults with rheumatoid arthritis.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.
What class of drug is Methotrexate?
Methotrexate is classified as Folic acid analogues, Other immunosuppressants, Folate Analog Metabolic Inhibitor, Dihydrofolate Reductase Inhibitors, Folic Acid Metabolism Inhibitors, Thymidylate Synthetase Inhibitors, Decreased DNA Integrity, Decreased Epithelial Proliferation, Decreased Immunologic Activity.
What are the brand names for Methotrexate?
Methotrexate is marketed under brand names including Jylamvo, Otrexup, Rasuvo, Reditrex, Trexall, Xatmep.
What are the contraindications for Methotrexate?
Methotrexate labeling lists contraindications including: Methotrexate tablets are contraindicated in: • Pregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]. • Patients with a history of severe hypersensitivity reactions, including anaphylaxis, to methotrexate.. Always consult the full prescribing information and a clinician.
Note. Data for methotrexate 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