Hazardous agent. Might cause renal damage leading to acute renal failure, especially with high-dose methotrexate. Use caution in osteosarcoma patients treated with high-dose methotrexate in combination with nephrotoxic chemotherapy. Bone marrow suppression might occur, resulting in anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia (use caution in pre-existing bone marrow suppression). Dermatologic reactions possible, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme. Diarrhea and ulcerative stomatitis may require interruption of therapy (use with caution in peptic ulcer disease, ulcerative colitis). May cause impairment of fertility, oligospermia, and menstrual dysfunction. Associated with acute (elevated transaminases) and potentially fatal chronic (fibrosis, cirrhosis) hepatotoxicity (use caution with pre-existing liver impairment, and when used with other hepatotoxic agents). Associated with development of malignant lymphomas. Might cause neurotoxicity, including seizures, leukoencephalopathy and stroke-like encephalopathy. Chemical arachnoiditis (headache, back pain, nuchal rigidity, fever), myelopathy and chronic leukoencephalopathy may result from intrathecal administration. Immune suppression might lead to potentially fatal opportunistic infections. Might cause potentially life-threatening pneumonitis. Tumor lysis syndrome might occur in high tumor burden. Elimination reduced in ascites and/or pleural fluid. Use with caution in pre-existing liver impairment, in peptic ulcer disease, and in ulcerative colitis (diarrhea and stomatitis might occur). Methotrexate elimination reduced in renal impairment. Use caution when used with other hepatotoxic agents (azathioprine, retinoids, sulfasalazine). Use caution in osteosarcoma patients treated with high-dose methotrexate in combination with nephrotoxic chemotherapy (e.g. cisplatin). Concurrent administration with NSAIDs might cause severe bone marrow suppression, aplastic anemia, and gastrointestinal toxicity. Use caution in the elderly (increased risk of toxicity). Might cause fetal death or congenital abnormalities. Concomitant methotrexate administration with radiotherapy may increase risk of soft tissue necrosis and osteonecrosis. Injection may contain benzyl alcohol («gasping syndrome» in neonates). Methotrexate formulations and/or diluents containing preservatives should not be used for intrathecal or high-dose therapy.