Methotrexate injection
Other products: Methotrexate
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Boxed warning
WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS • Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ] . • Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.2) ].
• Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Dosage and Administration (2.1) and Warnings and Precautions (5.3) ]. • Other serious adverse reactions, including death, have been reported with methotrexate.
Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate [see Warnings and Precautions (5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 , 5.11) ]. WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS See full prescribing information for complete boxed warning . • Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. Use in non-neoplastic diseases is contraindicated during pregnancy.
Advise females and males of reproductive potential to use effective contraception during and after treatment with Methotrexate Injection. ( 4 , 5.1 , 8.1 , 8.3 ) • Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis. ( 4 , 5.2 ) • Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants, and for intrathecal use.
Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available. ( 2.1 ,…
Handling and access
NIOSH hazardous drug
Table 1NIOSH lists methotrexate as a hazardous drug. AHFS class: 10:00 antineoplastic agents; 92:20 immunomodulatory agents; 92:36 disease-modifying antirheumatic drugs; 92:44 immunosuppressive agents.
- The package insert includes manufacturer's special handling information (MSHI). Follow it when preparing, administering, and disposing of this drug.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Dosing in kidney impairment
Renal Impairment Methotrexate elimination is reduced in patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology ] . Patients with renal impairment are at increased risk for methotrexate adverse reactions. Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration and Warnings and Precautions ] .
Consider reducing the dose or discontinuing Methotrexate Injection in patients with renal impairment as appropriate.
Dosing in liver impairment
Hepatic Impairment The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown. Patients with hepatic impairment may be at increased risk for methotrexate adverse reaction based on elimination characteristics of methotrexate [see Clinical Pharmacology ]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with hepatic impairment as appropriate [see Warnings and Precautions ].
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Preparation and administration
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Administration and Handling Information Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1 With Preservative (Multiple-Dose Vial)
Methotrexate Injection formulation containing benzyl alcohol as a preservative may be administered by intramuscular, intravenous, or subcutaneous injection [see Dosage and Administration ] . Methotrexate Injection with preservative may be further diluted with 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours under refrigeration (2°C to 8°C).
Visually inspect product for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed. Preservative-Free (Single-Dose Vial) Methotrexate Injection preservative-free may be administered by intramuscular, intravenous, subcutaneous, or intrathecal injection.
Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use [see Warning and Precautions and Use in Specific Populations ] .
Use preservative-free Methotrexate Injection for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available [see Warning and Precautions and Use in Specific Populations] .
Preservative-free Methotrexate Injection may be further diluted before use with preservative‑free 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours when stored under refrigeration (2°C to 8°C).
Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.
Drug interactions
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- Methotrexate injection
Label text (6 paragraphs)
Refer to full prescribing information for drug interactions with Methotrexate Injection. ( 7 )
7.1 Effects of Other Drugs on Methotrexate Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products.
If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: • Penicillin or sulfonamide antibiotics • Highly protein bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) • Proton pump inhibitors • Probenecid • Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) • Aspirin and other nonsteroidal anti-inflammatory drugs Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high-dose) and nonsteroidal anti-inflammatory drugs (NSAIDs).
• Mercaptopurine • Hepatotoxic products • Weak acids (e.g., salicylates) • Nephrotoxic products • Hematotoxic agents Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases.
Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions (5.12) ].
7.2 Effects of Methotrexate on Other Drugs Theophylline Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.
Supplement interactions
Dietary supplement interactions
1 noted- Methotrexate (Rheumatrex, Trexall), used to treat cancer and autoimmune diseases, is a folate antagonist. Patients taking methotrexate for cancer should consult their oncologist before taking folate supplements because the supplements could interfere with methotrexate’s anticancer effects.
Contraindications
Methotrexate Injection is contraindicated in: • Patients with history of severe hypersensitivity to methotrexate [see Warnings and Precautions (5.2) ] . • Pregnancy in patients with non-neoplastic diseases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . • History of severe hypersensitivity to methotrexate. ( 4 ) • Pregnancy: in patients with non-neoplastic diseases. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
ALikelihood score A: Well known cause of chronic, clinically significant liver injury, portal hypertension and cirrhosis.
Methotrexate is an antineoplastic and immunosuppressive agent widely used in the therapy of leukemia, lymphoma, solid tumors, psoriasis and rheumatoid arthritis. When given in high intravenous doses, methotrexate can cause acute elevations in serum enzymes, and long term methotrexate therapy has been associated with frequent but mild elevations in serum liver enzymes and, more importantly, with development of chronic liver injury, progressive fibrosis, cirrhosis and portal hypertension.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ]. 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.
The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, 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, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.
A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg per week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2–58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8–29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13–22.8).
Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6–5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03–9.5]) (2.9%).…
Breastfeeding (LactMed)
Maternal doses of methotrexate up to 92 mg (1.12 mg/kg) produce low levels in milk. Pharmacokinetic modeling predicts infant exposure to be less than 1% of the mothers with weekly doses of 25 mg or less. Recent guidelines state that low single or weekly doses, such as those used for ectopic pregnancy or rheumatoid arthritis (25 mg per week or less), are an acceptable alternative during breastfeeding, although some older expert opinion warns against this use. Withholding breastfeeding for 24 hours after a weekly low dose of methotrexate may decrease the infant's dose by 40%.- If breastfeeding during long-term, low-dose methotrexate use is undertaken, monitoring of the infant's complete blood count and differential and liver enzymes can be considered. Most sources consider breastfeeding to be contraindicated during maternal high-dose antineoplastic drug therapy with methotrexate.
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