Methotrexate

RECENT MAJOR CHANGES Warnings and Precautions (5.11) 05/2025

1 INDICATIONS AND USAGE Methotrexate for Injection is a folate analog metabolic inhibitor indicated for: • The following neoplastic diseases for the: o Treatment of adult and pediatric patients with acute lymphoblastic leukemia as part of a combination chemotherapy regimen ( 1.1 ) o Prophylaxis and treatment of adult and pediatric patients with meningeal leukemia ( 1.2 ) o Treatment of adult and pediatric patients with non-Hodgkin lymphoma ( 1.3 ) o Treatment of adult and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen ( 1.4 ) o Treatment of adults with breast cancer as part of a combination chemotherapy regimen ( 1.5 ) o Treatment of adults with squamous cell carcinoma of the head and neck as single-agent ( 1.6 ) o Treatment of adults with gestational trophoblastic neoplasia as part of a combination chemotherapy regimen ( 1.7 ) • Treatment of adults with rheumatoid arthritis (RA). ( 1.8 ) • Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). ( 1.9 ) • Treatment of adults with severe psoriasis. ( 1.10 ) 1.1 Acute Lymphoblastic Leukemia Methotrexate for Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen. 1.2 Meningeal Leukemia: Prophylaxis and Treatment Methotrexate for Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients. 1.3 Non-Hodgkin Lymphoma Methotrexate for Injection is indicated for the treatment of adults and pediatric patients with Non-Hodgkin lymphoma. 1.4 Osteosarcoma Methotrexate for Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. 1.5 Breast Cancer Methotrexate for Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen. 1.6 Squamous Cell Carcinoma of the Head and Neck Methotrexate for Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single-agent. 1.7 Gestational Trophoblastic Neoplasia Methotrexate for Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen. 1.8 Rheumatoid Arthritis Methotrexate for Injection is indicated for the treatment of adults with rheumatoid arthritis (RA). 1.9 Polyarticular Juvenile Idiopathic Arthritis Methotrexate for Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). 1.10 Psoriasis Methotrexate for Injection is indicated for the treatment of adults with severe psoriasis.

2 DOSAGE AND ADMINISTRATION • Verify pregnancy status in females of reproductive potential before starting Methotrexate for Injection. ( 2.1 , 4 , 5.1 ) • Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) • RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly; adjust dose to achieve an optimal response. ( 2.10 ) • pJIA: Recommended starting dosage of 10 mg/m 2 once weekly subcutaneously or intramuscularly; adjust dose to achieve an optimal response. ( 2.11 ) • Psoriasis: Recommended dosage of 10 mg to 25 mg once weekly intramuscularly or intravenously; adjust dose to achieve optimal response. Once achieved, reduce to lowest possible dosage. ( 2.12 ) 2.1 Important Dosage and Safety Information • Use only preservative-free Methotrexate for 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 Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.4 )]. • Verify pregnancy status in females of reproductive potential before starting Methotrexate for Injection [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. • For patients switching between a methotrexate product administered orally and Methotrexate for Injection, consider potential differences in bioavailability . 2.2 Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens To decrease the risk of severe adverse reactions [see Warnings and Precautions ( 5 )] : • Administer leucovorin rescue in patients receiving Methotrexate for Injection doses of 500 mg/m 2 or greater (e.g., high-dose) . • Consider leucovorin rescue for patients receiving Methotrexate for Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (e.g., intermediate-dose). Refer to the leucovorin Prescribing Information for additional information. • For high-dose Methotrexate for Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate for Injection regimens. - Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy - Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output - Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher - Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed • Administer glucarpidase in patients who have 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) 2.3 Recommended Dosage for Acute Lymphoblastic Leukemia Methotrexate for Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m 2 intravenously. For high dose Methotrexate for Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration ( 2.2 )] . Lower doses (e.g., 20 to 30 mg/m 2 /week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate for Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. 2.4 Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment Use only preservative-free Methotrexate for Injection for intrathecal use. Prior to administration, dilute preservative-free Methotrexate for Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP. The recomme …

3 DOSAGE FORMS AND STRENGTHS Injection: Methotrexate for Injection, USP is a yellow cake, lyophilized powder and is supplied in single-dose vials (preservative-free) in the following strength: Preservative-free (single-dose vial) 1 g Injection: (3) Preservative-free (single-dose vials): 1g

CONTRAINDICATIONS Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (see PRECAUTIONS ) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. (see Boxed WARNINGS ). Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers. Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate. Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia, should not receive methotrexate. Patients with a known hypersensitivity to methotrexate should not receive the drug.

ADVERSE REACTIONS IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTIONS SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult. Alimentary System - gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis. Blood and Lymphatic System Disorders - suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely. Cardiovascular - pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus). Central Nervous System - headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders - hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations. Infection - There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex . Musculoskeletal System - stress fracture. Ophthalmic - conjunctivitis, serious visual changes of unknown etiology. Pulmonary System – respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. Skin - erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis. Urogenital System - severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects. Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis, and osteonecrosis. Anaphylactoid reactions have been reported. Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies The approximate incidences of methotrexate-attributed (i.e., placebo rate s …

Drug Interactions Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin). Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment. Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, resulting in the potential for increased toxicity such as stomatitis, myelosuppression, and neurotoxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate. Use caution when administering methotrexate after a rece …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) Pediatric use: Intermediate-dose methotrexate can cause serious neurotoxicity in patients with acute lymphoblastic leukemia. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling 8.1 Pregnancy Risk Summary Methotrexate for 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 for 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/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%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes. 8.2 Lactation Risk Summary Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate for Injection and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate for Injection [see Contraindications (4) and Use in Specific Populations (8.1) ]. Contraception Fem …

12.1 Mechanism of Action 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, pJIA, and in psoriasis is unknown.

DESCRIPTION Methotrexate is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Chemically methotrexate is L-(+)- N -[ p -[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-benzoyl]glutamic acid. The structural formula is: Structural Formula C 20 H 22 N 8 O 5 M.W.=454.44 Methotrexate for injection (Preservative Free) is sterile and non-pyrogenic and may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. (See DOSAGE AND ADMINISTRATION .) Methotrexate for Injection, USP, Lyophilized, Preservative Free , for single use only , is available in 1 gram vials. Each 1 gram vial of lyophilized powder contains methotrexate sodium equivalent to 1 gram methotrexate. Contains no preservative. Sodium hydroxide and, if necessary, hydrochloric acid are added during manufacture to adjust the pH. The 1 gram vial contains approximately 7 mEq sodium. Structural Formula

OVERDOSAGE Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28(6): 846-854, 1996). Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within two hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. There are published case reports of intravenous and intrathecal glucarpidase treatment to hasten clearance of methotrexate in cases of overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methotrexate for Injection, USP, Lyophilized, Preservative Free, for Single Dose Only. Product No. NDC No. 102250 63323-122-50 1 gram per vial Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. Discard unused portion. The container closure is not made with natural rubber latex. Methotrexate for Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1