Methotrexate Prescribing Information
- 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[seeContraindications (4),., Use in Specific Populations (8.1, 8.3)]
5.1 Embryo-Fetal
ToxicityBased on published reports and its mechanism of action, methotrexate tablets can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate tablets are contraindicated for use in pregnant women receiving methotrexate tablets 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 tablets and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate tablets treatment and for 3 months after the final dose
[seeContraindications (4), 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),.]
5.2 Hypersensitivity ReactionsHypersensitivity reactions, including anaphylaxis, can occur with methotrexate
[seeContraindications (4), Adverse Reactions (6.1)].If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue methotrexate tablets
[seeDosage and Administration (2.6)]. - 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[.,
5.3 MyelosuppressionMethotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia
[seeAdverse Reactions (6.1)].Obtain blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression. Withhold, dose reduce, or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)].,5.4 Gastrointestinal ToxicityDiarrhea, vomiting, nausea, and stomatitis occurred in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported
[seeAdverse Reactions (6.1, 6.2)]. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions[seeDrug Interactions (7.1)].Withhold or discontinue methotrexate tablets for severe gastrointestinal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)].,5.5 HepatotoxicityMethotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure
[seeAdverse Reactions (6.1)]. The safety of methotrexate tablets in patients with hepatic disease is unknown.The risk of hepatotoxicity is increased with heavy alcohol consumption. In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver tests; the risk of hepatotoxicity appears to increase with total cumulative dose and generally occurs after receipt of a total cumulative dose of 1.5 g or more.
Monitor liver tests at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)].,5.6 Pulmonary ToxicityPulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate
[seeAdverse Reactions (6.1, 6.2)].Monitor patients for pulmonary toxicity and withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)].,5.7 Dermatologic ReactionsSevere, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with methotrexate
[seeAdverse Reactions (6.1, 6.2)].Exposure to ultraviolet radiation while taking methotrexate may aggravate psoriasis.
Methotrexate can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation.
Monitor patients for dermatologic toxicity and withhold or permanently discontinue methotrexate tablets for severe dermatologic reactions taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. Advise patients to avoid excessive sun exposure and use sun protection measures.)]5.8 Renal ToxicityMethotrexate can cause renal toxicity, including irreversible acute renal failure
[seeAdverse Reactions (6.2)].Monitor renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets for severe renal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)].Administer glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional information.
Tablets: 2.5 mg methotrexate, USP: round, biconvex, yellow tablets, scored in half on one side, engraved with “A” above the score and “1” below.
Methotrexate tablets are contraindicated in:
- Pregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [seeand,
5.1 Embryo-Fetal
ToxicityBased on published reports and its mechanism of action, methotrexate tablets can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate tablets are contraindicated for use in pregnant women receiving methotrexate tablets 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 tablets and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate tablets treatment and for 3 months after the final dose
[seeContraindications (4), Use in Specific Populations (8.1, 8.3)].Use in Specific Populations (8.1, 8.3)]. - Patients with a history of a severe hypersensitivity reactions, including anaphylaxis, to methotrexate [see.]
5.2 Hypersensitivity ReactionsHypersensitivity reactions, including anaphylaxis, can occur with methotrexate
[seeContraindications (4), Adverse Reactions (6.1)].If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue methotrexate tablets
[seeDosage and Administration (2.6)].
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hypersensitivity Reactions [see]
5.2 Hypersensitivity ReactionsHypersensitivity reactions, including anaphylaxis, can occur with methotrexate
[seeContraindications (4), Adverse Reactions (6.1)].If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue methotrexate tablets
[seeDosage and Administration (2.6)]. - Myelosuppression [see]
5.3 MyelosuppressionMethotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia
[seeAdverse Reactions (6.1)].Obtain blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression. Withhold, dose reduce, or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. - Gastrointestinal Toxicity [see]
5.4 Gastrointestinal ToxicityDiarrhea, vomiting, nausea, and stomatitis occurred in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported
[seeAdverse Reactions (6.1, 6.2)]. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions[seeDrug Interactions (7.1)].Withhold or discontinue methotrexate tablets for severe gastrointestinal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. - Hepatotoxicity [see]
5.5 HepatotoxicityMethotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure
[seeAdverse Reactions (6.1)]. The safety of methotrexate tablets in patients with hepatic disease is unknown.The risk of hepatotoxicity is increased with heavy alcohol consumption. In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver tests; the risk of hepatotoxicity appears to increase with total cumulative dose and generally occurs after receipt of a total cumulative dose of 1.5 g or more.
Monitor liver tests at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. - Pulmonary Toxicity [see]
5.6 Pulmonary ToxicityPulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate
[seeAdverse Reactions (6.1, 6.2)].Monitor patients for pulmonary toxicity and withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. - Dermatologic Reactions [see]
5.7 Dermatologic ReactionsSevere, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with methotrexate
[seeAdverse Reactions (6.1, 6.2)].Exposure to ultraviolet radiation while taking methotrexate may aggravate psoriasis.
Methotrexate can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation.
Monitor patients for dermatologic toxicity and withhold or permanently discontinue methotrexate tablets for severe dermatologic reactions taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. Advise patients to avoid excessive sun exposure and use sun protection measures. - Renal Toxicity [see]
5.8 Renal ToxicityMethotrexate can cause renal toxicity, including irreversible acute renal failure
[seeAdverse Reactions (6.2)].Monitor renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets for severe renal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)].Administer glucarpidase in patients with toxic plasma methotrexate concentrations (> 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional information.
- Serious Infections [see]
5.11 Serious InfectionsPatients treated with methotrexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections, including opportunistic infections such as
Pneumocystis jirovecipneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminatedHerpes zosterand cytomegalovirus infections[seeAdverse Reactions (6.2)].Monitor patients for infection during and after treatment with methotrexate tablets. Withhold or discontinue methotrexate tablets for serious infections taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. - Neurotoxicity [see]
5.12 NeurotoxicityMethotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal
[seeAdverse Reactions (6.2)]. The risk of leukoencephalopathy is increased in patients who received prior cranial radiation.Monitor patients for neurotoxicity and withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy
[seeDosage and Administration (2.6)]. - Secondary Malignancies [see]
5.13 Secondary MalignanciesSecondary malignancies can occur with methotrexate
[seeAdverse Reactions (6.2)]. The risk of cutaneous malignancies is further increased when cyclosporine is administered to patients with psoriasis who received prior methotrexate.In some cases, lymphoproliferative disease occurring during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue methotrexate tablets
[seeDosage and Administration (2.6)]. - Tumor Lysis Syndrome [see]
5.14 Tumor Lysis SyndromeMethotrexate can induce tumor lysis syndrome in patients with rapidly growing tumors. Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate tablets.
- Increased Risk of Adverse Reactions Due to Third-Space Accumulation [see]
5.17 Increased Risk of Adverse Reactions Due to Third-Space
AccumulationMethotrexate accumulates in third-spaces (e.g., pleural effusions or ascites), which results in prolonged elimination and increases the risk of adverse reactions. Evacuate significant third-space accumulations prior to methotrexate tablets administration taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy.
Methotrexate, USP is dihydrofolate reductase inhibitor with the chemical name of N-[4-[[(2,4 diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L glutamic acid. The molecular formula is C20H22N8O5 and the molecular weight is 454.4 g/mol. The structural formula is:
Methotrexate tablets, USP for oral use are available in bottles of 36 and 100 tablets. Each methotrexate tablet, USP contains 2.5 mg methotrexate, USP equivalent to 2.74 mg methotrexate disodium and the following inactive ingredients: lactose monohydrate, magnesium stearate and maize starch.
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. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.
The mechanism of action in rheumatoid arthritis and in psoriasis is unknown.