FDA label 2b480a86-eecd-c37e-e063-6394a90ae54b

WARNINGS: HYPERSENSITIVITY REACTIONS and SERIOUS ADVERSE REACTIONS Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [ Contraindications (4) , Warnings and Precautions (5.1) ] . Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the nervous system, kidneys, liver, bone marrow, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate [ Warnings and Precautions (5.2 , 5.3 , 5.4 , 5.5 , 5.6 , 5.7 , 5.8 )] . WARNING: HYPERSENSITIVITY REACTIONS and SERIOUS ADVERSE REACTIONS See full prescribing information for complete boxed warning. Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis ( 4 , 5.1 ). Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the nervous system, kidneys, liver, bone marrow, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate ( 5.2 , 5.3 , 5.4 , 5.5 , 5.6 , 5.7 , 5.8 ).

5 WARNINGS AND PRECAUTIONS Serious Infections : Monitor patients for infection during and after treatment with Methotrexate Injection. Withhold or discontinue Methotrexate Injection for serious infections as appropriate ( 5.9 ). Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.10 , 8.1 , 8.3 ). Secondary Malignancies : Can occur with methotrexate ( 5.11 ). Tumor Lysis Syndrome : Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of Methotrexate Injection ( 5.12 ). Immunizations and Risks Associated with Live Vaccines : Administer immunizations according to best practice guidelines prior to and during treatment with Methotrexate Injection. Immunizations with live vaccines is not recommended ( 5.13 ). 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate. Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity to methotrexate [see Contraindications (4) , Adverse Reactions (6) ] . If anaphylaxis or another severe hypersensitivity reaction occurs, discontinue Methotrexate Injection [see Dosage and Administration (2.7) ] . 5.2 Neurotoxicity Methotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal [see Adverse Reactions (6) ] . Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with ALL who were treated with methotrexate at intravenous doses of 1,000 mg/m 2 [see Use in Specific Populations (8.4) ] . Leukoencephalopathy can occur with intermediate- and high-dose regimens. The risk of leukoencephalopathy is increased with prior cranial radiation. A transient acute stroke-like syndrome can occur with high-dose methotrexate. Clinical manifestations include confusion, hemiparesis, transient blindness, seizures, and coma. Monitor patients for neurotoxicity. Withhold or discontinue Methotrexate Injection as appropriate [see Dosage and Administration (2.7) ] . 5.3 Renal Toxicity Methotrexate can cause renal toxicity, including irreversible acute renal failure [see Adverse Reactions (6) ] . Monitor renal function at baseline, periodically during treatment, and as clinically indicated. Withhold or discontinue Methotrexate Injection for severe renal toxicity as appropriate [see Dosage and Administration (2.7) ] . 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 (2.1) ] . 5.4 Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions (6) ] . The safety of Methotrexate Injection in patients with hepatic disease is unknown. The risk of hepatotoxicity is increased with heavy alcohol consumption. Monitor liver tests at baseline, periodically during treatment, and as clinically indicated. Withhold or discontinue Methotrexate Injection as appropriate [see Dosage and Administration (2.7) ] . 5.5 Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse Reactions (6) ] . Obtain complete blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression. Withhold, dose reduce, or discontinue Methotrexate Injection as appropriate [see Dosage and Administration (2.7) ] . 5.6 Gastrointestinal Toxicity Methotrexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis and fatal intestinal perforation [see Adverse Reactions (6) ] . Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions [see Drug Interactions (7.1) ] . Withhold or discontinue Methotrexate Injection for severe gastrointestinal toxicity as appropriate [see Dosage and Administration (2.7) ] . 5.7 Pulmonary Toxicity Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate [see Adverse Reactions (6) ] . Monitor patients for signs of pulmonary toxicity. Withhold or discontinue Methotrexate Injection for pulmonary toxicity as appropriate [see Dosage and Administration (2.7) ] . 5.8 Dermatologic Toxicity Severe, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens- Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, can occur with methotrexate [see Adverse Reactions (6) ] . Methotrexate can also cause radiation recall dermatitis and photodermatitis (sunburn) reactivation. Monitor patients for signs of dermatologic toxicity. Withhold or discontinue Methotrexate Injection for severe dermatologic reactions as appropriate [see Dosage and Administration (2.7) ] . Advise patients to avoid excessive sun exposure and use sun protection measures. 5.9 Serious Infections Patients treated with methotrexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated Herpes zoster and cytomegalovirus infections [see Adverse Reactions (6) ] . Monitor patients for infection during and after treatment with Methotrexate Injection. Withhold or discontinue Methotrexate Injection for serious infections as appropriate [see Dosage and Administration (2.7) ] . 5.10 Embryo-Fetal Toxicity Based on published reports and its mechanism of action, Methotrexate Injection can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Methotrexate Injection and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Methotrexate Injection and for 3 months after the final dose [see Use in Specific Populations (8.1 , 8.3) ] . 5.11 Secondary Malignancies Secondary malignancies can occur with methotrexate [see Adverse Reactions (6) ] . In some cases, lymphoproliferative disease that occurred during therapy with methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue Methotrexate Injection [see Dosage and Administration (2.7) ] . 5.12 Tumor Lysis Syndrome Methotrexate 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 Injection. 5.13 Immunization and Risks Associated with Live Vaccines Disseminated infections following administration of live vaccines have been reported. Administer immunizations according to current best practice guidelines prior to initiating Methotrexate Injection and then follow these guidelines for administering immunizations during treatment with Methotrexate Injection. Immunization with live vaccines is not recommended during treatment with Methotrexate Injection. The interval between live vaccines and initiation of Methotrexate Injection should be in accordance with the current best practice guidelines for patients on immunosuppressive therapies. 5.14 Increased Risk of Adverse Reactions Due to Third-Space Accumulation Methotrexate accumulates in third-spaces (e.g., pleural effusions or ascites), which results in a prolonged elimination and increases the risk of adverse reactions. Evacuate significant third-space accumulations prior to Methotrexate Injection administration as appropriate. 5.15 Increased Risk of Soft Tissue and Bone Toxicity with Concomitant Radiotherapy Concomitant radiotherapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate. 5.16 Risk of Decreased Clinical Effectiveness with Folic Acid Supplementation Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Instruct patients not to take products containing folic acid or folinic acid unless directed to do so by their healthcare provider.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Neurotoxicity [see Warnings and Precautions (5.2) ] Renal Toxicity [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Myelosuppression [see Warnings and Precautions (5.5) ] Gastrointestinal Toxicity [see Warnings and Precautions (5.6) ] Pulmonary toxicity [see Warnings and Precautions (5.7) ] Dermatologic Toxicity [see Warnings and Precautions (5.8) ] Serious infections [see Warnings and Precautions (5.9) ] Secondary Malignancies [see Warnings and Precautions (5.11) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.12) ] The following adverse reactions associated with the use of methotrexate were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions were: infection, malaise, fatigue, chills, fever, and dizziness. Blood and lymphatic system disorders: aplastic anemia, lymphadenopathy, hypogammaglobulinemia Cardiac disorders: thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolus pericarditis, pericardial effusion, hypotension, and sudden death) Endocrine disorders: diabetes Eye disorders: optic neuropathy, blurred vision, ocular irritation, conjunctivitis, xerophthalmia Gastrointestinal disorders: hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration and bleeding Hepatobiliary disorders: acute hepatitis, fibrosis, cirrhosis, decreased serum albumin Immune system disorders: anaphylaxis, vasculitis Metabolism and nutrition disorders: hyperglycemia Nervous system disorders: headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, convulsions Renal and urinary disorders: azotemia, hematuria, proteinuria, cystitis Reproductive system and breast disorders: defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction Respiratory, thoracic and mediastinal disorders: pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis Skin and subcutaneous disorders: toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis Common adverse reactions are: ulcerative stomatitis, leukopenia, nausea and abdominal distress ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .