Browse the corpus

WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, SEVERE ADVERSE REACTIONS, and RISK OF MEDICATION ERRORS 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 [see Contraindications (4), Warnings and Precautions (5.1), 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), Warnings and Precautions (5.2)] . Methotrexate tablets when inadvertently administered once daily have resulted in death (5.9). 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 [Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7, 5.8)] . WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, SEVERE ADVERSE REACTIONS, and RISK OF MEDICATION ERRORS See full prescribing information for complete boxed warning. Methotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception (4, 5.1, 8.1, 8.3). Methotrexate tablets are contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis (4, 5.2). Methotrexate tablets when inadvertently administered once daily have resulted in death (5.9). 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, 5.4, 5.5, 5.6, 5.7, 5.8).

1 INDICATIONS AND USAGE Methotrexate tablets are dihydrofolate reductase inhibitor indicated for the: Treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen (1.1) Treatment of adults with mycosis fungoides (1.1) Treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a metronomic combination regimen (1.1) Treatment of adults with rheumatoid arthritis (1.2) Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) (1.3) Treatment of adults with severe psoriasis (1.4) 1.1 Neoplastic Diseases Methotrexate tablets are indicated for the: treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent or as part of a combination chemotherapy regimen. treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of a metronomic combination chemotherapy regimen 1.2 Rheumatoid Arthritis Methotrexate tablets are indicated for the treatment of adults with rheumatoid arthritis. 1.3 Polyarticular Juvenile Idiopathic Arthritis Methotrexate tablets are indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). 1.4 Psoriasis Methotrexate tablets are indicated for the treatment of adults with severe psoriasis.

2 DOSAGE AND ADMINISTRATION Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. (2.1, 5.9) Verify pregnancy status in females of reproductive potential before starting methotrexate tablets (4, 5.1). ALL: The recommended dosage is 20 mg/m 2 orally once weekly as a part of a combination chemotherapy maintenance regimen. (2.2) Mycosis fungoides: The recommended dosage is 25 mg to 75 mg orally once weekly as monotherapy; 10 mg/m 2 orally twice weekly as part of combination chemotherapy. (2.2) Relapsed or refractory non-Hodgkin lymphoma: The recommended dosage is 2.5 mg orally two to four times per week as part of metronomic combination chemotherapy. (2.2) Rheumatoid Arthritis: The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response (2.3) pJIA: The recommended starting dosage is 10 mg/m 2 orally once weekly; adjust dose to achieve an optimal response (2.4) Psoriasis: The recommended dosage is 10 mg to 25 mg orally once weekly until adequate response is achieved. (2.5) 2.1 Important Dosage and Safety Information Verify pregnancy status in females of reproductive potential before starting methotrexate tablets [see Contraindications (4), Warnings and Precautions (5.1)]. Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths [see Warnings and Precautions (5.9)]. When switching the dosing regimen from oral administration to intravenous, intramuscular, or subcutaneous administration, an alternative dosing regimen may be necessary. Do not administer to patients who are unable to swallow a tablet. Methotrexate tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 2.2 Recommended Dosage for Neoplastic Diseases Acute Lymphoblastic Leukemia The recommended starting dosage of methotrexate tablets is 20 mg/m 2 orally once weekly, as part of a combination chemotherapy maintenance regimen. After initiating methotrexate tablets, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dose to maintain ANC at a desirable level and for excessive myelosuppression. Mycosis Fungoides The recommended dosage of methotrexate tablets is 25 mg to 75 mg orally once weekly when administered as a single agent or 10 mg/m 2 orally twice weekly as part of a combination chemotherapy regimen. Relapsed or Refractory Non-Hodgkin Lymphomas The recommended dosage of methotrexate tablets is 2.5 mg orally 2 to 4 times per week (maximum 10 mg per week) as part of a metronomic combination chemotherapy regimen. 2.3 Recommended Dosage for Rheumatoid Arthritis The recommended starting dosage of methotrexate tablets is 7.5 mg orally once weekly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10)]. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dosage of methotrexate tablets is 10 mg/m 2 orally once weekly with escalation to achieve optimal response.

lic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10)]. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dosage of methotrexate tablets is 10 mg/m 2 orally once weekly with escalation to achieve optimal response. Dosages of more than 30 mg/m 2 once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation. Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10)]. 2.5 Recommended Dosage for Psoriasis The recommended dosage of methotrexate tablets is 10 mg to 25 mg orally once weekly until an adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed a dose of 30 mg per week. Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen. Administer folic acid or folinic acid supplementation to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10)] . 2.6 Dosage Modifications for Adverse Reactions Discontinue methotrexate tablets for: Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.2)] Lymphoproliferative disease [see Warnings and Precautions (5.13)] Withhold, dose reduce or discontinue methotrexate tablets as appropriate for: Myelosuppression [see Warnings and Precautions (5.3)] Withhold or discontinue methotrexate tablets as appropriate for: Severe gastrointestinal toxicity [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Pulmonary toxicity [see Warnings and Precautions (5.6)] Severe dermatologic reactions [see Warnings and Precautions (5.7)] Severe renal toxicity [see Warnings and Precautions (5.8)] Serious infections [see Warnings and Precautions (5.11)] Neurotoxicity [see Warnings and Precautions (5.12)]

4 CONTRAINDICATIONS Methotrexate tablets are contraindicated in: Pregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]. Patients with a history of a severe hypersensitivity reactions, including anaphylaxis, to methotrexate. [see Warnings and Precautions (5.2)]. In pregnancy for non-neoplastic diseases (4) History of severe hypersensitivity to methotrexate (4)

5 WARNINGS AND PRECAUTIONS Serious Infections : Monitor patients for infection during and after treatment with methotrexate tablets. Withhold or discontinue methotrexate tablets for serious infections as appropriate. (5.11) Neurotoxicity : Monitor patients for neurotoxicity and withhold or discontinue methotrexate tablets as appropriate. (5.12) Secondary Malignancies : Can occur with methotrexate. (5.13) Tumor Lysis Syndrome : Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate tablets. (5.14) Immunizations and Risk Live Vaccines : Immunizations with live vaccines is not recommended. Follow current vaccination practice guidelines. (5.15) Infertility : Can cause impairment of fertility, oligospermia, and menstrual dysfunction. (5.16, 8.3) 5.1 Embryo-Fetal Toxicity Based 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 [see Contraindications (4), Use in Specific Populations (8.1, 8.3)] . 5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Contraindications (4), Adverse Reactions (6.1)]. If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue methotrexate tablets [see Dosage and Administration (2.6)]. 5.3 Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse 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 [see Dosage and Administration (2.6)]. 5.4 Gastrointestinal Toxicity Diarrhea, 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 [see Adverse Reactions (6.1, 6.2)]. 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 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 [see Dosage and Administration (2.6)] .

iscontinue 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 [see Dosage and Administration (2.6)] . 5.5 Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see Adverse 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 [see Dosage and Administration (2.6)] . 5.6 Pulmonary Toxicity Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate [see Adverse 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 [see Dosage and Administration (2.6)] . 5.7 Dermatologic Reactions 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 (6.1, 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 [see Dosage and Administration (2.6)] . Advise patients to avoid excessive sun exposure and use sun protection measures. 5.8 Renal Toxicity Methotrexate can cause renal toxicity, including irreversible acute renal failure [see Adverse 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 [see Dosage 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. 5.9 Risk of Fatal Adverse Reactions with Medication Error Deaths occurred in patients as a result of medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed.

to the glucarpidase prescribing information for additional information. 5.9 Risk of Fatal Adverse Reactions with Medication Error Deaths occurred in patients as a result of medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed. For patients prescribed a once weekly dosing regimen, instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to death. 5.10 Folic Acid Supplementation Neoplastic Diseases Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Therefore, instruct patients not to take products containing folic acid or folinic acid unless directed to do so by their healthcare provider. Non-neoplastic Diseases Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid for patients with rheumatoid arthritis, pJIA, and psoriasis [see Dosage and Administration (2.3, 2.4, 2.5)] . 5.11 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 (6.2)] . 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 [see Dosage and Administration (2.6)] . 5.12 Neurotoxicity Methotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal [see Adverse 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 [see Dosage and Administration (2.6)] . 5.13 Secondary Malignancies Secondary malignancies can occur with methotrexate [see Adverse 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 [see Dosage and Administration (2.6)] . 5.14 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 tablets. 5.15 Immunization and Risks Associated with Live Vaccines Disseminated infections following administration of live vaccines have been reported. Immunization with live vaccines is not recommended during treatment. Follow current vaccination practice guidelines for administration of immunizations in patients receiving methotrexate tablets. Update immunizations according to immunization guidelines prior to initiating methotrexate tablets.

ines have been reported. Immunization with live vaccines is not recommended during treatment. Follow current vaccination practice guidelines for administration of immunizations in patients receiving methotrexate tablets. Update immunizations according to immunization guidelines prior to initiating methotrexate tablets. The interval between live vaccinations and initiation of methotrexate should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 5.16 Infertility Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility may be reversible. Discuss the risk of infertility with females and males of reproductive potential [see Use in Specific Populations (8.3)] . 5.17 Increased Risk of Adverse Reactions Due to Third-Space Accumulation Methotrexate 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Myelosuppression [see Warnings and Precautions (5.3)] Gastrointestinal Toxicity [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Pulmonary Toxicity [see Warnings and Precautions (5.6)] Dermatologic Reactions [see Warnings and Precautions (5.7)] Renal Toxicity [see Warnings and Precautions (5.8)] Serious Infections [see Warnings and Precautions (5.11)] Neurotoxicity [see Warnings and Precautions (5.12)] Secondary Malignancies [see Warnings and Precautions (5.13)] Tumor Lysis Syndrome [see Warnings and Precautions (5.14)] Increased Risk of Adverse Reactions Due to Third-Space Accumulation [see Warnings and Precautions (5.17)] Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, abdominal distress. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness. Rheumatoid Arthritis The most common adverse reactions of methotrexate that exceeded the rate of placebo in 12- to 18-week double-blind studies in patients (n=128) with rheumatoid arthritis are listed below. Patients received methotrexate 7.5 to 15 mg orally once weekly. Most patients received concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and some also received corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence ≥10%: Elevated liver tests 15%, nausea/vomiting 10% Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count < 100,000/mm 3 ) Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count <3,000/mm 3 ), pancytopenia, dizziness Two other controlled trials of patients (n=680) with rheumatoid arthritis who received methotrexate 7.5 mg to 15 mg orally once weekly showed the following serious adverse reaction: Incidence 1%: Interstitial pneumonitis Other less common adverse reactions were: anemia, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge. Polyarticular Juvenile Idiopathic Arthritis (pJIA) The most common adverse reactions reported in patients 2 to 18 years of age with pJIA treated with methotrexate 5 mg/m 2 to 20 mg/m 2 orally once weekly or 0.1 to 0.65 mg/kg orally once weekly were as follows: elevated liver tests 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea) 11%; stomatitis 2%; leukopenia 2%; headache 1.2%; alopecia 0.5%; dizziness 0.2%; rash 0.2%. Most patients received concomitant NSAIDs and some also received corticosteroids.

y or 0.1 to 0.65 mg/kg orally once weekly were as follows: elevated liver tests 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea) 11%; stomatitis 2%; leukopenia 2%; headache 1.2%; alopecia 0.5%; dizziness 0.2%; rash 0.2%. Most patients received concomitant NSAIDs and some also received corticosteroids. Psoriasis In two published series of adults with psoriasis (n=204, 248) who received methotrexate up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with rheumatoid arthritis, except for alopecia, photosensitivity, and “burning of skin lesions” (3% to 10% each). Painful plaque erosions have been reported. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of methotrexate. Because these reactions are 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 Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death Endocrine: Diabetes Eye: Optic neuropathy, blurred vision, ocular pain, conjunctivitis, xerophthalmia Gastrointestinal: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration Hematology: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia Hepatobiliary: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis Immune system: Anaphylaxis, anaphylactoid reactions, vasculitis Metabolism: Hyperglycemia Musculoskeletal: Stress fracture, soft tissue and bone necrosis, arthralgia, myalgia, osteoporosis Nervous system: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, and convulsions. Renal: Azotemia, hematuria, proteinuria, cystitis Reproductive: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction Respiratory: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis

7 DRUG INTERACTIONS Refer to the full prescribing information for drug interactions with methotrexate. (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. In some cases, the coadministration of methotrexate with these products may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. 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: Oral antibiotics (including neomycin) Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Oral or intravenous penicillin or sulfonamide antibiotics Aspirin and other nonsteroidal anti-inflammatory drugs Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Hepatotoxic products Proton pump inhibitors Weak acids (e.g., salicylates) Nephrotoxic products Probenecid 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 (5.10)].

8 USE IN SPECIFIC POPULATIONS Lactation: Instruct not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4)] . Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)] , methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 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, central nervous system 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 and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with non-autoimmune disease (17%; 95% CI: 13, 23). 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, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (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 report the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final 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 [Use in Specific Populations (8.1)].

child, instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final 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 [Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating methotrexate tablets [see Contraindications (4), Use in Specific Populations (8.1)]. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose. Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 3 months after the final dose. Infertility Females Based on published reports of female infertility after methotrexate, advise females of reproductive potential that methotrexate can cause impairment of fertility and menstrual dysfunction during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected females. Males Based on published reports of male infertility after methotrexate, advise males that methotrexate can cause oligospermia or infertility during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected males. 8.4 Pediatric Use The safety and effectiveness of methotrexate tablets in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see Indications and Usage (1), Dosage and Administration (2)]. No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions (6.1)]. The safety and effectiveness of methotrexate tablets have not been established in pediatric patients for the other indications [see Indications and Usage (1)]. 8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Renal Impairment Methotrexate elimination is reduced in patients with renal impairment [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk for methotrexate adverse reactions. Closely monitor patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, Cockcroft-Gault] for adverse reactions. Reduce the dosage or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.8)]. 8.7 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 reactions based on the elimination characteristics of methotrexate [see Clinical Pharmacology (12.3)]. Closely monitor patients with hepatic impairment for adverse reactions. Reduce the dosage or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.5)].

8.1 Pregnancy Risk Summary Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4)] . Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)] , methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 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, central nervous system 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 and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with non-autoimmune disease (17%; 95% CI: 13, 23). 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, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.4 Pediatric Use The safety and effectiveness of methotrexate tablets in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see Indications and Usage (1), Dosage and Administration (2)]. No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions (6.1)]. The safety and effectiveness of methotrexate tablets have not been established in pediatric patients for the other indications [see Indications and Usage (1)].

10 OVERDOSAGE Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5. 9)]. Manifestations Manifestations of methotrexate overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported. Management Leucovorin and levoleucovorin are indicated for diminishing the methotrexate adverse reactions of methotrexate overdosage. Administer leucovorin or levoleucovorin as soon as possible after methotrexate overdosage). Monitor serum creatinine and methotrexate levels to guide leucovorin or levoleucovorin therapy. Refer to the leucovorin or levoleucovorin prescribing information for additional dosage information. Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional dosage information. Administer concomitant hydration and urinary alkalinization. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, methotrexate has been effectively cleared with acute, intermittent hemodialysis using a high-flux dialyzer.

11 DESCRIPTION Methotrexate 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 C 20 H 22 N 8 O 5 and the molecular weight is 454.4 g/mol. The structural formula is: Methotrexate Tablets, USP for oral use is available in bottles of 36 and 100 tablets. Each methotrexate tablet contains 2.5 mg methotrexate equivalent to 2.74 mg methotrexate sodium and the following inactive ingredients: lactose monohydrate, magnesium stearate and microcrystalline cellulose. spl-structure

12 CLINICAL PHARMACOLOGY 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 and in psoriasis is unknown. 12.3 Pharmacokinetics Absorption At doses of 30 mg/m 2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to 6 hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized. Effect of Food Food has been shown to delay absorption and reduce peak concentration. Distribution Methotrexate in serum is approximately 50% protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages. Elimination The elimination half-life of methotrexate is approximately 3 to 10 hours. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg. Metabolism Methotrexate is partially metabolized by intestinal flora after oral administration. Methotrexate primarily undergoes hepatic and intracellular metabolism to active polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. Methotrexate also undergoes minor metabolism to active 7-hydroxymethotrexate. Excretion Methotrexate primarily undergoes renal excretion by glomerular filtration and active tubular secretion that is dependent upon dosage and route of administration. Biliary excretion accounts for ≤10% of the methotrexate dose. Specific Populations The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown. Pediatric Patients In pediatric patients with leukemia, oral absorption (23% to 95%) of methotrexate is variable and dose-dependent. The difference between highest and lowest peak methotrexate concentrations (C max 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) was 20-fold. The time to peak concentration (T max 0.67 to 4 hours after a 15 mg/m 2 dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m 2 is significantly less than that of lower doses. In pediatric patients with pJIA, plasma concentrations of methotrexate are variable. Following oral administration of methotrexate 6.4 mg/m 2 /week to 11.2 mg/m 2 /week, mean serum concentrations were 0.59 micromolar (0.03 to 1.40) at 1 hour, 0.44 micromolar (0.01 to 1.00) at 2 hours, and 0.29 micromolar (0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ) or for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively.

0) at 2 hours, and 0.29 micromolar (0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ) or for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively. Patients with Renal impairment The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.

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 and in psoriasis is unknown.

12.3 Pharmacokinetics Absorption At doses of 30 mg/m 2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to 6 hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized. Effect of Food Food has been shown to delay absorption and reduce peak concentration. Distribution Methotrexate in serum is approximately 50% protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages. Elimination The elimination half-life of methotrexate is approximately 3 to 10 hours. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg. Metabolism Methotrexate is partially metabolized by intestinal flora after oral administration. Methotrexate primarily undergoes hepatic and intracellular metabolism to active polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. Methotrexate also undergoes minor metabolism to active 7-hydroxymethotrexate. Excretion Methotrexate primarily undergoes renal excretion by glomerular filtration and active tubular secretion that is dependent upon dosage and route of administration. Biliary excretion accounts for ≤10% of the methotrexate dose. Specific Populations The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown. Pediatric Patients In pediatric patients with leukemia, oral absorption (23% to 95%) of methotrexate is variable and dose-dependent. The difference between highest and lowest peak methotrexate concentrations (C max 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) was 20-fold. The time to peak concentration (T max 0.67 to 4 hours after a 15 mg/m 2 dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m 2 is significantly less than that of lower doses. In pediatric patients with pJIA, plasma concentrations of methotrexate are variable. Following oral administration of methotrexate 6.4 mg/m 2 /week to 11.2 mg/m 2 /week, mean serum concentrations were 0.59 micromolar (0.03 to 1.40) at 1 hour, 0.44 micromolar (0.01 to 1.00) at 2 hours, and 0.29 micromolar (0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ) or for JIA (3.75 mg/m 2 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively. Patients with Renal impairment The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells.

16 HOW SUPPLIED/STORAGE AND HANDLING Methotrexate Tablets, USP are supplied as 2.5 mg yellow, round, uncoated, scored, flat tablets with a diameter of 6 mm and embossed with code "ORN57” on one side available in: NDC 47335-235-96 (Bottle of 36) NDC 47335-235-83 (Bottle of 100) 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]. Methotrexate Tablets, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose [see Use in Specific Populations (8.3)]. Advise males of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 3 months after the final dose [see Use in Specific Populations (8.3)]. Hypersensitivity Reactions Advise patients and their caregivers of the potential risk of hypersensitivity and that methotrexate tablets are contraindicated in patients with a history of hypersensitivity reactions to methotrexate. Instruct patients to seek immediate medical attention for signs of a hypersensitivity reaction [see Warnings and Precautions (5.2)]. Myelosuppression and Serious Infections Inform patients and their caregivers that methotrexate tablets can cause myelosuppression and the need for frequent monitoring of blood cell counts. Advise patients and their caregivers to immediately report new onset fever, symptoms of infection, easy bruising or persistent bleeding to their healthcare provider [see Warnings and Precautions (5.3, 5.11)]. Gastrointestinal Toxicity Advise patients and their caregivers to report new or worsening diarrhea, vomiting, or stomatitis to their healthcare provider. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see Warnings and Precautions (5.4)]. Hepatotoxicity Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.5)]. Pulmonary Toxicity Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider [see Warnings and Precautions (5.6)]. Dermatologic Reactions Advise patients and their caregivers that methotrexate tablets can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients and their caregivers to avoid excessive sun exposure and use sun protection measures [see Warnings and Precautions (5.7)]. Renal Toxicity Advise patients and their caregivers to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions (5.8)]. Risk of Fatal Adverse Reactions with Medication Error For patients who are prescribed a once weekly dosing regimen, advise patients and caregivers that the recommended dosage is to be taken once weekly as a single dose and that mistakenly taking the recommended weekly dosage once daily has led to fatal adverse reactions [see Warnings and Precautions (5.9)]. Neurotoxicity Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see Warnings and Precautions (5.12)]. Secondary Malignancies Advise patients on the risk of second primary malignancies during treatment with methotrexate tablets [see Warnings and Precautions (5.13)].

xicity Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see Warnings and Precautions (5.12)]. Secondary Malignancies Advise patients on the risk of second primary malignancies during treatment with methotrexate tablets [see Warnings and Precautions (5.13)]. Lactation Instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final dose [see Use in Specific Populations (8.2)]. Infertility Advise females and males of reproductive potential that methotrexate may impair fertility [see Warnings and Precautions (5.16), Use in Specific Populations (8.3)]. Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

Patient Information Methotrexate (meth oh trex ate) Tablets USP What is the most important information I should know about methotrexate tablets? Methotrexate can cause serious side effects that may be severe and lead to death, including: Harm to an unborn baby, including birth defects or death of an unborn baby. Females who can become pregnant: Your healthcare provider should do a pregnancy test before you start taking methotrexate tablets to see if you are pregnant. o If you are being treated for a medical condition other than cancer, do not take methotrexate tablets if you are pregnant. See “Who should not take methotrexate tablets?” o If you are taking methotrexate to treat your cancer, you and your healthcare provider will decide if you will take methotrexate if you are pregnant. o Use effective birth control (contraception) during treatment and for 6 months after your final dose of methotrexate tablet. Ask your healthcare provider what forms of birth control you can use during this time. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with methotrexate tablets. Males with female partners who are able to become pregnant: o Use effective birth control during treatment and for 3 months after your final dose of methotrexate tablet. Tell your healthcare provider right away if your female partner becomes pregnant during treatment with methotrexate tablets. Severe allergic reactions. Severe allergic reactions can happen with methotrexate tablets. Signs and symptoms of a severe allergic reaction may include: • skin rash, itching and hives • swelling of the face, lips, tongue, or throat • dizziness • trouble breathing • wheezing • fast heart rate • feeling faint • stomach-area pain • vomiting or diarrhea Do not take methotrexate tablets if you have had a severe allergic reaction to methotrexate tablets in the past. Get medical help right away if you develop any of the signs or symptoms of a severe allergic reaction listed above. Decreased blood cell counts. Methotrexate can affect your bone marrow and cause decreases in red blood counts, white blood cell counts, and platelets that can be severe and life-threatening. Your healthcare provider will check your blood cell counts when you start and during treatment with methotrexate tablets. Call your healthcare provider right away if you develop any of the following: • a new fever • symptoms of infection • easy bruising or bleeding that will not stop (persistent bleeding) Severe stomach and intestine problems (gastrointestinal) problems. Diarrhea, vomiting, nausea, and mouth sores can happen in people who take methotrexate tablets. Inflammation of the intestine with severe bleeding and a tear in the intestinal wall (perforation) have happened with methotrexate tablets and cause death. People who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have a greater risk of developing severe stomach or intestine problems with methotrexate tablets. Tell your healthcare provider if you develop new or worsening diarrhea, vomiting, or mouth sores during treatment with methotrexate tablets. Tell your healthcare provider right away if you develop high fever, shaking chills (rigors), pain in your stomach-area (abdomen) that will not go away or is severe, severe constipation, if you are vomiting blood or have blood in your stools. Liver problems.

ng, or mouth sores during treatment with methotrexate tablets. Tell your healthcare provider right away if you develop high fever, shaking chills (rigors), pain in your stomach-area (abdomen) that will not go away or is severe, severe constipation, if you are vomiting blood or have blood in your stools. Liver problems. Methotrexate can cause severe liver problems including liver scarring (fibrosis), cirrhosis, and liver failure that may not get better (possibly irreversible) and can cause death. In people with psoriasis who take methotrexate tablets, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases as with the amount of methotrexate tablets that you take over time. Your healthcare provider will do tests to monitor your liver function before you start and during treatment with methotrexate tablets. Tell your healthcare provider if you get any signs or symptoms of liver problems during treatment with methotrexate tablets, including: tiredness easy bleeding or bruising loss of appetite nausea difficulty thinking clearly swelling in your legs, feet or ankles weight loss itchy skin yellowing of your skin or the white part of your eyes weakness Lung problems. Lung problems can happen suddenly (acute) with methotrexate tablets or they can develop over a long period- of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death. Tell your healthcare provider if you have any new or worsening symptoms including: cough (especially a dry cough), fever, or trouble breathing. Severe skin reactions. Severe skin reactions can happen with Methotrexate and can lead to death. In people with psoriasis: Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light. Methotrexate tablets can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall dermatitis) and cause sunburn to come back (photodermatitis). Limit sunlight exposure during treatment with methotrexate tablets. Use sunscreen and wear protective clothing when you will be exposed to sunlight during treatment with methotrexate tablets. Tell your healthcare provider right away about any new or worsening skin rash during treatment with methotrexate tablets. Kidney problems. Kidney problems can happen with methotrexate tablets, including kidney failure which can happen suddenly (acute) and may not go away (irreversible). Your healthcare provider will check your kidney function before you start and during treatment with methotrexate tablets. Tell your healthcare provider right away if you develop any signs or symptoms of kidney problems, including: a big change (either increase or decrease) in the of urine you produce swelling in your legs, ankles or feet shortness of breath tiredness weight gain Risk of death from taking Methotrexate the wrong way . Methotrexate is taken 1 time each week for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (pJIA), and severe psoriasis. Deaths have happened when Methotrexate was taken every day instead of 1 time weekly. See “How should I take Methotrexate?” for instructions on taking this medicine correctly. See “What are the possible side effects of methotrexate tablets” for more information about side effects. What are methotrexate tablets?

oriasis. Deaths have happened when Methotrexate was taken every day instead of 1 time weekly. See “How should I take Methotrexate?” for instructions on taking this medicine correctly. See “What are the possible side effects of methotrexate tablets” for more information about side effects. What are methotrexate tablets? Methotrexate tablets are prescription medicine used: in combination with other chemotherapy medicines in adults and children, for maintenance treatment of acute lymphoblastic leukemia (ALL) to treat adults with mycosis fungoides (cutaneous T-cell lymphoma) in combination with other therapies to treat adults with non-Hodgkin lymphoma that has come back (relapsed) or did not respond to previous treatment (refractory) to treat adults with rheumatoid arthritis to treat children with polyarticular juvenile idiopathic arthritis (pJIA) to treat adults with severe psoriasis It is not known if methotrexate tablets are safe and effective in treating children with any disease other than ALL as part of a combination regimen used for maintenance therapy of their cancer, and for the treatment of pJIA. It is not known if methotrexate tablets are safe in people with liver problems. Do not take methotrexate tablets if you : are pregnant and are being treated or will be treated with methotrexate tablets for rheumatoid arithritis, pJIA, or severe psoriasis or for any disease other than cancer. methotrexate tablets can cause harm to an unborn baby, including birth defects or death of an unborn baby. See “Wha t is the most important information I should know about methotrexate tablets?” have or had a severe allergic reaction to methotrexate tablets in the past. See “ What is the most important information I should know about methotrexate tablets?” See the end of this leaflet for a complete list of ingredients in methotrexate tablets. Before taking Methotrexate tell your healthcare provider about all of your medical conditions, including if you: have problems swallowing tablets have kidney problems or are receiving dialysis treatments have liver problems drink alcohol-containing beverages and, during treatment with methotrexate tablets, if there are any changes in the amount of alcoholic beverages you drink have fluid in your stomach-area (ascites) have lung problems or fluid in your lungs (pleural effusion) plan to have any surgeries with general anesthesia, including dental surgery have stomach ulcers (peptic ulcer disease) have ulcerative colitis have recently received or are scheduled to receive a vaccine. You should not receive live vaccines during treatment with methotrexate tablets. are breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for 1 week after your final dose of methotrexate tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Methotrexate tablets and certain other medicines can affect each other and cause serious side effects. Do not start or change any medicines unless you have talked to your healthcare provider and your healthcare provider has told you it is safe. Know all the medicines that you take and keep a list of them with you at all times to show your healthcare provider and pharmacist. How should I take methotrexate tablets? Take Methotrexate exactly as prescribed by your healthcare provider. Your dose of methotrexate tablets and when you take it will depend on the condition that is being treated. o Do not take more methotrexate tablets than prescribed. Do not change your dose of methotrexate tablets unless your healthcare provider tells you to.

ethotrexate exactly as prescribed by your healthcare provider. Your dose of methotrexate tablets and when you take it will depend on the condition that is being treated. o Do not take more methotrexate tablets than prescribed. Do not change your dose of methotrexate tablets unless your healthcare provider tells you to. o Taking more methotrexate tablets than prescribed or taking methotrexate tablets more often than prescribed, can lead to severe side effects and cause death. If you are not sure how often to take Methotrexate, ask your healthcare provider or pharmacist. o If you take too much methotrexate tablets call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive a medicine as soon as possible to help reduce side effects that could be severe and could cause death. o If you miss taking a dose of methotrexate tablets, call your healthcare provider for instructions about when to take your next dose of methotrexate tablets. If you are taking methotrexate tablets for treatment of severe psoriasis, rheumatoid arthritis, or polyarticular juvenile idiopathic arthritis: Take your methotrexate tablets dose 1 time each week (on same day of the week). o Do not take Methotrexate every day. Severe side effects and death have happened in people who have mistakenly taken Methotrexate every day instead of 1 time each week. Take a folic acid or folinic acid supplement every day during treatment with methotrexate tablets, as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores. If you are taking methotrexate tablets to treat your cancer: Follow your healthcare provider’s instructions about how much methotrexate tablets to take and when to take it. Do not take folic acid or folinic acid during treatment with methotrexate tablets unless your healthcare provider tells you to. Taking folic acid or folinic acid with methotrexate tablets may make your methotrexate tablets treatment less effective. What are the possible side effects of methotrexate tablets? Methotrexate tablets can cause serious side effects that may be severe and lead to death including: See “ What is the most important information I should know about methotrexate tablets?” Serious infections. People who take methotrexate tablets have an increased risk of developing infections that can be life-threatening or cause death. These infections may include: bacterial, fungal, or viral infections, including Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B infection that comes back (reactivation), turberculosis infection that may be new or reactivation, and Herpes zoster or cytomegalovirus (CMV) that spreads throughout the body (disseminated). Tell your healthcare provider right away if you develop a new fever or if you have any symptoms of infection during treatment with methotrexate tablets. Brain and spinal cord (nervous system) problems. Methotrexate tablets can cause nervous system problems that can be severe and last for a short time or last for a long time. These nervous system problems can get progressively worse, may not get better (irreversible), and can cause death. The risk for a certain nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head (cranial radiation) in the past. Tell your healthcare provider about any new nervous system symptoms that you develop during treatment with methotrexate tablets. Secondary cancers. Secondary (new) cancers can happen in people who take methotrexate tablets.

reased in people who have had radiation treatment to their head (cranial radiation) in the past. Tell your healthcare provider about any new nervous system symptoms that you develop during treatment with methotrexate tablets. Secondary cancers. Secondary (new) cancers can happen in people who take methotrexate tablets. o In people with psoriasis, the risk of new skin cancers is increased with methotrexate tablets and further increased if you take the medicine cyclosporine after receiving treatment with methotrexate tablets. o Certain blood cancers can happen during treatment with methotrexate tablets. In some cases, these blood cancers may completely go away (regress completely) after methotrexate tablets are stopped. Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving methotrexate tablets as a cancer treatment. Possible fertility problems (infertility) in males and females. Methotrexate tablets can cause fertility problems in males and females, and can cause sperm production to stop in males, and menstrual problems in females. Males may not be able to father a child. Females may not be able to become pregnant. It is not known if your fertility may return. Talk with your healthcare provider about your risk for infertility if this is a concern for you. The most common side effects of methotrexate tablets include: mouth sores low white blood cells. See “What is the most important information I should know about methotrexate tablets?” nausea upset stomach These are not all the side effects of methotrexate tablets. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088. How should I store methotrexate tablets? Store methotrexate tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep methotrexate tablets away from light. Keep methotrexate tablets and all medicines out of the reach of children. General information about the safe and effective use of methotrexate tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use methotrexate tablets for a condition for which it was not prescribed. Do not give methotrexate tablets to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about methotrexate tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about methotrexate tablets that is written for healthcare professionals. W hat are the ingredients in methotrexate tablets? Active Ingredient : methotrexate Inactive Ingredients : lactose monohydrate, magnesium stearate and microcrystalline cellulose. Manufactured by: Orion Corporation, Orion Pharma Turku, Finland Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 For additional information, please contact Sun Pharmaceutical Industries, Inc. at toll free number: 1-800-818-4555.

<table border="1" cellspacing="0" cellpadding="0"><tbody><tr><td colspan="10" valign="top"><paragraph><content styleCode="bold">Patient Information</content></paragraph><paragraph>Methotrexate (meth oh trex ate)</paragraph><paragraph>Tablets USP<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about methotrexate tablets?</content></paragraph><paragraph><content styleCode="bold">Methotrexate can cause serious side effects that may be severe and lead to death, </content>including:<content styleCode="bold"/></paragraph><list listType="unordered"><item><content styleCode="bold">Harm to an unborn baby, including birth defects or death of an unborn baby. </content></item></list><paragraph><content styleCode="bold">Females who can become pregnant:</content></paragraph><list listType="unordered"><item>Your healthcare provider should do a pregnancy test before you start taking methotrexate tablets to see if you are pregnant.<content styleCode="bold"/></item></list><paragraph> o <content styleCode="bold">If you are being treated for a medical condition other than cancer, do not take methotrexate tablets if you are pregnant. See &#x201C;Who should not take methotrexate</content><content styleCode="bold">tablets?&#x201D;</content></paragraph><paragraph> o If you are taking methotrexate to treat your cancer, you and your healthcare provider will decide if you will take methotrexate if you are pregnant.</paragraph><paragraph> o Use effective birth control (contraception) during treatment and for <content styleCode="bold">6</content> months after your final dose of methotrexate tablet. Ask your healthcare provider what forms of birth control you can use during this time.</paragraph><paragraph><content styleCode="bold">Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with methotrexate tablets.</content></paragraph><paragraph><content styleCode="bold">Males with female partners who are able to become pregnant:</content></paragraph><paragraph> o Use effective birth control during treatment and for <content styleCode="bold">3</content> months after your final dose of methotrexate tablet.</paragraph><paragraph><content styleCode="bold">Tell your healthcare provider right away if your female partner becomes pregnant during treatment with methotrexate tablets.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Severe allergic reactions. </content>Severe allergic reactions can happen with methotrexate tablets.

yleCode="bold">Tell your healthcare provider right away if your female partner becomes pregnant during treatment with methotrexate tablets.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Severe allergic reactions. </content>Severe allergic reactions can happen with methotrexate tablets. Signs and symptoms of a severe allergic reaction may include:</item></list><paragraph><content styleCode="bold"/></paragraph></td></tr><tr><td colspan="5" valign="top"><paragraph/><paragraph><content styleCode="bold"/></paragraph></td><td colspan="3" valign="top"><paragraph>&#x2022; skin rash, itching and hives </paragraph><paragraph>&#x2022; swelling of the face, lips, tongue, or throat</paragraph><paragraph>&#x2022; dizziness </paragraph><paragraph>&#x2022; trouble breathing</paragraph><paragraph>&#x2022; wheezing</paragraph></td><td colspan="2" valign="top"><paragraph>&#x2022; fast heart rate</paragraph><paragraph>&#x2022; feeling faint</paragraph><paragraph>&#x2022; stomach-area pain</paragraph><paragraph>&#x2022; vomiting or diarrhea<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph><content styleCode="bold">Do not </content>take methotrexate tablets if you have had a severe allergic reaction to methotrexate tablets in the past.<content styleCode="bold"/></paragraph><paragraph><content styleCode="bold">Get medical help right away </content>if you develop any of the signs or symptoms of a severe allergic reaction listed above.</paragraph><paragraph><content styleCode="bold">Decreased blood cell counts.

ction to methotrexate tablets in the past.<content styleCode="bold"/></paragraph><paragraph><content styleCode="bold">Get medical help right away </content>if you develop any of the signs or symptoms of a severe allergic reaction listed above.</paragraph><paragraph><content styleCode="bold">Decreased blood cell counts. </content>Methotrexate can affect your bone marrow and cause decreases in red blood counts, white blood cell counts, and platelets that can be severe and life-threatening.</paragraph><list listType="unordered"><item>Your healthcare provider will check your blood cell counts when you start and during treatment with methotrexate tablets.<content styleCode="bold"/></item></list><paragraph><content styleCode="bold">Call your healthcare provider right away if you develop any of the following:</content></paragraph></td></tr><tr><td colspan="4" valign="top"><paragraph><content styleCode="bold"/></paragraph></td><td colspan="2" valign="top"><paragraph>&#x2022; a new fever<content styleCode="bold"/></paragraph></td><td colspan="2" valign="top"><paragraph>&#x2022; symptoms of infection<content styleCode="bold"/></paragraph></td><td colspan="2" valign="top"><paragraph>&#x2022; easy bruising or bleeding that will not stop (persistent bleeding)<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><list listType="unordered"><item><content styleCode="bold">Severe stomach and intestine problems (gastrointestinal) problems.</content><list listType="unordered"><item>Diarrhea, vomiting, nausea, and mouth sores can happen in people who take methotrexate tablets.</item><item><content styleCode="bold">Inflammation of the intestine with severe bleeding and a tear in the intestinal wall (perforation) have happened with methotrexate tablets</content><content styleCode="bold">and cause death.</content></item><item>People who have stomach ulcers (peptic ulcer disease) or ulcerative colitis (UC) have a greater risk of developing severe stomach or intestine problems with methotrexate tablets.</item></list></item></list><paragraph>Tell your healthcare provider if you develop new or worsening diarrhea, vomiting, or mouth sores during treatment with methotrexate tablets.</paragraph><paragraph><content styleCode="bold">Tell your healthcare provider right away if you develop high fever, shaking chills (rigors), pain in your stomach-area (abdomen) that will not go away or is severe, severe constipation, if you are vomiting blood or have blood in your stools.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Liver problems. </content>Methotrexate can cause severe liver problems including liver scarring (fibrosis), cirrhosis,<content styleCode="bold"/>and<content styleCode="bold"/>liver failure that may not get better (possibly irreversible) and can cause death.<content styleCode="bold"/><list listType="unordered"><item><content styleCode="bold">In people with psoriasis </content>who take methotrexate tablets, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests.

/>liver failure that may not get better (possibly irreversible) and can cause death.<content styleCode="bold"/><list listType="unordered"><item><content styleCode="bold">In people with psoriasis </content>who take methotrexate tablets, liver fibrosis or cirrhosis may happen without any symptoms or abnormal liver tests. The risk for liver problems in people with psoriasis increases as with the amount of methotrexate tablets that you take over time.</item><item>Your healthcare provider will do tests to monitor your liver function before you start and during treatment with methotrexate tablets.<content styleCode="bold"/></item></list></item></list><paragraph><content styleCode="bold">Tell your healthcare provider if you get any signs or symptoms of liver problems </content>during treatment with methotrexate tablets, including:<content styleCode="bold"/></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold"/></paragraph></td><td valign="top"><list listType="unordered"><item>tiredness </item><item>easy bleeding or bruising</item><item>loss of appetite </item><item>nausea </item><item>difficulty thinking clearly</item></list></td><td valign="top" colspan="8"><list listType="unordered"><item>swelling in your legs, feet or ankles</item><item>weight loss</item><item>itchy skin</item><item>yellowing of your skin or the white part of your eyes</item><item>weakness</item></list></td></tr><tr><td colspan="10" valign="top"><list listType="unordered"><item><content styleCode="bold">Lung problems. </content>Lung problems can happen suddenly (acute) with methotrexate tablets or they can develop over a long period- of-time (chronic). Lung problems may not get better (possibly irreversible) and can cause death.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider if you have any new or worsening symptoms including: cough (especially a dry cough), fever, or trouble breathing.</content></paragraph><paragraph><content styleCode="bold">Severe skin reactions. </content>Severe skin reactions can happen with Methotrexate and can lead to death.</paragraph><list listType="unordered"><item><content styleCode="bold">In people with psoriasis: </content>Your psoriasis may get worse if you are exposed to sunlight or other types of ultraviolet light.</item><item>Methotrexate tablets can cause reactivation of skin reactions that can happen after radiation therapy (radiation recall dermatitis) and cause sunburn to come back (photodermatitis).</item></list><paragraph>Limit sunlight exposure during treatment with methotrexate tablets. Use sunscreen and wear protective clothing when you will be exposed to sunlight during treatment with methotrexate tablets.</paragraph><paragraph><content styleCode="bold">Tell your healthcare provider right away about any new or worsening skin rash during treatment with methotrexate tablets.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Kidney problems.

sunlight during treatment with methotrexate tablets.</paragraph><paragraph><content styleCode="bold">Tell your healthcare provider right away about any new or worsening skin rash during treatment with methotrexate tablets.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Kidney problems. Kidney problems can happen with methotrexate tablets, including kidney failure which can happen suddenly (acute) and may not go away (irreversible).</content></item></list><paragraph>Your healthcare provider will check your kidney function before you start and during treatment with methotrexate tablets.</paragraph><paragraph><content styleCode="bold">Tell your healthcare provider right away </content>if you develop any signs or symptoms of kidney problems, including:</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold"/></paragraph></td><td colspan="8" valign="top"><list listType="unordered"><item>a big change (either increase or decrease) in the of urine you produce</item><item>swelling in your legs, ankles or feet</item></list></td><td valign="top"><list listType="unordered"><item>shortness of breath</item><item>tiredness</item><item>weight gain</item></list></td></tr><tr><td colspan="10" valign="top"><paragraph><content styleCode="bold">Risk of death from taking Methotrexate the wrong way</content>. Methotrexate is taken 1 time each week for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (pJIA), and severe psoriasis. Deaths have happened when Methotrexate was taken every day instead of 1 time weekly. See &#x201C;How should I take Methotrexate?&#x201D; for instructions on taking this medicine correctly.</paragraph><paragraph>See<content styleCode="bold"> &#x201C;What are the possible side effects of methotrexate tablets&#x201D; </content>for more information about side effects.<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">What are methotrexate </content><content styleCode="bold">tablets?</content></paragraph><paragraph styleCode="TableParagraph">Methotrexate tablets are prescription medicine used:</paragraph><list listType="unordered"><item>in combination with other chemotherapy medicines in adults and children, for maintenance treatment of acute lymphoblastic leukemia (ALL)</item><item>to treat adults with mycosis fungoides (cutaneous T-cell lymphoma)</item><item>in combination with other therapies to treat adults with non-Hodgkin lymphoma that has come back (relapsed) or did not respond to previous treatment (refractory)</item><item>to treat adults with rheumatoid arthritis</item><item>to treat children with polyarticular juvenile idiopathic arthritis (pJIA)</item><item>to treat adults with severe psoriasis</item></list><paragraph styleCode="TableParagraph">It is not known if methotrexate tablets are safe and effective in treating children with any disease other than ALL as part of a combination regimen used for maintenance therapy of their cancer, and for the treatment of pJIA.</paragraph><paragraph>It is not known if methotrexate tablets are safe in people with liver problems.<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">Do not take methotrexate </content><content styleCode="bold">tablets if you</content>:</paragraph><list listType="unordered"><item>are pregnant and are being treated or will be treated with methotrexate tablets for rheumatoid arithritis, pJIA, or severe psoriasis or for any disease other than cancer. methotrexate tablets can cause harm to an unborn baby, including birth defects or death of an unborn baby.

paragraph><list listType="unordered"><item>are pregnant and are being treated or will be treated with methotrexate tablets for rheumatoid arithritis, pJIA, or severe psoriasis or for any disease other than cancer. methotrexate tablets can cause harm to an unborn baby, including birth defects or death of an unborn baby. See <content styleCode="bold">&#x201C;Wha</content><content styleCode="bold">t is the most important information I should know about </content><content styleCode="bold">methotrexate tablets?&#x201D;</content></item><item>have or had a severe allergic reaction to methotrexate tablets in the past. See &#x201C;<content styleCode="bold">What is the most important information I should know about </content><content styleCode="bold">methotrexate tablets?&#x201D; </content>See the end of this leaflet for a complete list of ingredients in methotrexate tablets.<content styleCode="bold"/></item></list></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">Before taking Methotrexate tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item>have problems swallowing tablets</item><item>have kidney problems or are receiving dialysis treatments</item><item>have liver problems</item><item>drink alcohol-containing beverages and, during treatment with methotrexate tablets, if there are any changes in the amount of alcoholic beverages you drink</item><item>have fluid in your stomach-area (ascites)</item><item>have lung problems or fluid in your lungs (pleural effusion)</item><item>plan to have any surgeries with general anesthesia, including dental surgery</item><item>have stomach ulcers (peptic ulcer disease)</item><item>have ulcerative colitis</item><item>have recently received or are scheduled to receive a vaccine. You should not receive live vaccines during treatment with methotrexate tablets.</item><item>are breastfeeding or plan to breastfeed. Methotrexate may pass into your breast milk. Do not breastfeed during treatment and for 1 week after your final dose of methotrexate tablets.</item></list><paragraph styleCode="TableParagraph"><content styleCode="bold">Tell your healthcare provider about all the medicines you take, </content>including prescription and over-the-counter medicines, vitamins and herbal supplements. Methotrexate tablets and certain other medicines can affect each other and cause serious side effects. Do not start or change any medicines unless you have talked to your healthcare provider and your healthcare provider has told you it is safe. Know all the medicines that you take and keep a list of them with you at all times to show your healthcare provider and pharmacist.<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">How should I take </content><content styleCode="bold">methotrexate</content><content styleCode="bold">tablets?</content></paragraph><list listType="unordered"><item><content styleCode="bold">Take Methotrexate exactly as prescribed by your healthcare provider. </content>Your dose of methotrexate tablets and when you take it will depend on the condition that is being treated.</item></list><paragraph> o <content styleCode="bold">Do not </content>take more methotrexate tablets than prescribed. Do not change your dose of methotrexate tablets unless your healthcare provider tells you to.</paragraph><paragraph> o <content styleCode="bold">Taking more </content><content styleCode="bold">methotrexate tablets than prescribed or taking methotrexate tablets more often than prescribed, can lead to severe side effects and cause death.

r dose of methotrexate tablets unless your healthcare provider tells you to.</paragraph><paragraph> o <content styleCode="bold">Taking more </content><content styleCode="bold">methotrexate tablets than prescribed or taking methotrexate tablets more often than prescribed, can lead to severe side effects and cause death. If you are not sure how often to take Methotrexate, ask your healthcare provider or pharmacist.</content></paragraph><paragraph> o <content styleCode="bold">If you take too much </content><content styleCode="bold">methotrexate tablets call your healthcare provider or go to your nearest hospital emergency room right way. You will need to receive a medicine as soon as possible to help reduce side effects that could be severe and could cause death.</content></paragraph><paragraph> o <content styleCode="bold">If you miss taking a dose of </content><content styleCode="bold">methotrexate tablets, call your healthcare provider for instructions about when to take your next dose of methotrexate tablets.</content></paragraph><paragraph styleCode="TableParagraph"><content styleCode="bold">If you are taking </content><content styleCode="bold">methotrexate tablets for treatment of severe psoriasis, rheumatoid arthritis, or polyarticular juvenile idiopathic arthritis:</content></paragraph><list listType="unordered"><item><content styleCode="bold">Take your </content><content styleCode="bold">methotrexate tablets dose 1 time each week (on same day of the week).</content></item></list><paragraph> o <content styleCode="bold">Do not take Methotrexate every day. Severe side effects and death have happened in people who have mistakenly taken </content><content styleCode="bold">Methotrexate every day instead of 1 time each week.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Take a folic acid or folinic acid supplement every day during treatment with </content><content styleCode="bold">methotrexate tablets, </content>as instructed by your healthcare provider, to help reduce the chance of developing certain side effects, such as mouth sores.</item></list><paragraph styleCode="TableParagraph"><content styleCode="bold">If you are taking </content><content styleCode="bold">methotrexate tablets to treat your cancer:</content></paragraph><list listType="unordered"><item><content styleCode="bold">Follow your healthcare provider&#x2019;s instructions about how much </content><content styleCode="bold">methotrexate</content><content styleCode="bold">tablets to take and when to take it.</content></item><item><content styleCode="bold">Do not take folic acid or folinic acid </content>during treatment with methotrexate tablets unless your healthcare provider tells you to. Taking folic acid or folinic acid with methotrexate tablets may make your methotrexate tablets treatment less effective.<content styleCode="bold"/></item></list></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">What are the possible side effects of </content><content styleCode="bold">methotrexate</content><content styleCode="bold">tablets?</content></paragraph><paragraph styleCode="TableParagraph">Methotrexate tablets can cause serious side effects that may be severe and lead to death including:</paragraph><list listType="unordered"><item>See &#x201C;<content styleCode="bold">What is the most important information I should know about </content><content styleCode="bold">methotrexate tablets?&#x201D;</content></item><item><content styleCode="bold">Serious infections. </content>People who take methotrexate tablets have an increased risk of developing infections that can be life-threatening or cause death.

most important information I should know about </content><content styleCode="bold">methotrexate tablets?&#x201D;</content></item><item><content styleCode="bold">Serious infections. </content>People who take methotrexate tablets have an increased risk of developing infections that can be life-threatening or cause death. These infections may include: bacterial, fungal, or viral infections, including <content styleCode="italics">Pneumocystis jiroveci</content> pneumonia, invasive fungal infections, hepatitis B infection that comes back (reactivation), turberculosis infection that may be new or reactivation, and <content styleCode="italics">Herpes zoster or cytomegalovirus</content> (CMV) that spreads throughout the body (disseminated).</item></list><paragraph styleCode="TableParagraph"><content styleCode="bold">Tell your healthcare provider right away if you develop a new fever or if you have any symptoms of infection during treatment with </content><content styleCode="bold">methotrexate tablets.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Brain and spinal cord (nervous system) problems. </content>Methotrexate tablets can cause nervous system problems that can be severe and last for a short time or last for a long time. These nervous system problems can get progressively worse, may not get better (irreversible), and can cause death. The risk for a certain nervous system problem called leukoencephalopathy is increased in people who have had radiation treatment to their head (cranial radiation) in the past.</item></list><paragraph styleCode="TableParagraph">Tell your healthcare provider about any new nervous system symptoms that you develop during treatment with methotrexate tablets.</paragraph><list listType="unordered"><item><content styleCode="bold">Secondary cancers. </content>Secondary (new) cancers can happen in people who take methotrexate tablets.</item></list><paragraph> o In people with psoriasis, the risk of new skin cancers is increased with methotrexate tablets and further increased if you take the medicine cyclosporine after receiving treatment with methotrexate tablets.</paragraph><paragraph> o Certain blood cancers can happen during treatment with methotrexate tablets. In some cases, these blood cancers may completely go away (regress completely) after methotrexate tablets are stopped.</paragraph><list listType="unordered"><item><content styleCode="bold">Tumor lysis syndrome (TLS). </content>TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS if you are receiving methotrexate tablets as a cancer treatment.</item><item><content styleCode="bold">Possible fertility problems (infertility) in males and females. </content>Methotrexate tablets can cause fertility problems in males and females, and can cause sperm production to stop in males, and menstrual problems in females. Males may not be able to father a child. Females may not be able to become pregnant. It is not known if your fertility may return. Talk with your healthcare provider about your risk for infertility if this is a concern for you.</item></list><paragraph styleCode="TableParagraph">The most common side effects of methotrexate tablets include:</paragraph><list listType="unordered"><item>mouth sores</item><item>low white blood cells. <content styleCode="bold">See &#x201C;What is the most important information I should know about </content><content styleCode="bold">methotrexate tablets?&#x201D;</content></item><item>nausea</item><item>upset stomach</item></list><paragraph styleCode="TableParagraph">These are not all the side effects of methotrexate tablets.

styleCode="bold">See &#x201C;What is the most important information I should know about </content><content styleCode="bold">methotrexate tablets?&#x201D;</content></item><item>nausea</item><item>upset stomach</item></list><paragraph styleCode="TableParagraph">These are not all the side effects of methotrexate tablets. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">How should I store methotrexate tablets?</content></paragraph><list listType="unordered"><item>Store methotrexate tablets at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item>Keep methotrexate tablets away from light.</item></list><paragraph styleCode="TableParagraph"><content styleCode="bold">Keep methotrexate tablets and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">General information about the safe and effective use of </content><content styleCode="bold">methotrexate tablets.</content></paragraph><paragraph styleCode="TableParagraph">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use methotrexate tablets for a condition for which it was not prescribed. Do not give methotrexate tablets to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about methotrexate tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about methotrexate tablets that is written for healthcare professionals.<content styleCode="bold"/></paragraph></td></tr><tr><td colspan="10" valign="top"><paragraph styleCode="TableParagraph"><content styleCode="bold">W</content><content styleCode="bold">hat are the ingredients in methotrexate tablets? </content></paragraph><paragraph styleCode="TableParagraph"><content styleCode="bold">Active Ingredient</content>: methotrexate</paragraph><paragraph><content styleCode="bold">Inactive Ingredients</content>: lactose monohydrate, magnesium stearate and microcrystalline cellulose.</paragraph><paragraph/><paragraph>Manufactured by:</paragraph><paragraph><content styleCode="bold">Orion Corporation, </content></paragraph><paragraph>Orion Pharma</paragraph><paragraph>Turku, Finland</paragraph><paragraph/><paragraph>Distributed by:</paragraph><paragraph><content styleCode="bold">Sun Pharmaceutical Industries, Inc. </content></paragraph><paragraph>Cranbury, NJ 08512</paragraph></td></tr></tbody></table>

(Contains Preservative) Rx only WARNINGS: SEE BOXED WARNINGS . For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high dose therapy because it contains benzyl alcohol. Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high doses), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.

trexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE: 1. Administration of methotrexate should be delayed until recovery if: the WBC count is less than 1,500/microliter the neutrophil count is less than 200/microliter the platelet count is less than 75,000/microliter the serum bilirubin level is greater than 1.2 mg/dL the SGPT level is greater than 450 U mucositis is present, until there is evidence of healing persistent pleural effusion is present; this should be drained dry prior to infusion. 2. Adequate renal function must be documented. a. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. b. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). 3. Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. a. Administer 1,000 mL/m 2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m 2 /hr (3 liters/m 2 /day) during the methotrexate infusion, and for 2 days after the infusion has been completed. b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. 4. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5x10 -8 mol/L (0.05 micromolar). 5. The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below. ‡ ) Patients who experience delayed early methotrexate elimination are likely to develop non-reversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. 6. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY. Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis Recommended Starting Dosage Schedules 1. Single oral doses of 7.5 mg once weekly. † 2.

ays be reconsidered when laboratory abnormalities or clinical toxicities are observed. CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY. Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis Recommended Starting Dosage Schedules 1. Single oral doses of 7.5 mg once weekly. † 2. Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly. † † Methotrexate Sodium Tablets for oral administration are available. Polyarticular-Course Juvenile Rheumatoid Arthritis The recommended starting dose is 10 mg/m 2 given once weekly. For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m 2 /wk in children, there are too few published data to assess how doses over 20 mg/m 2 /wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m 2 /wk (0.65 to 1 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. The patient should be fully informed of the risks involved and should be under constant supervision of the physician (see Information for Patients under PRECAUTIONS ). Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy (see PRECAUTIONS ). Appropriate steps should be taken to avoid conception during methotrexate therapy (see PRECAUTIONS and CONTRAINDICATIONS ). All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (see ADVERSE REACTIONS ). Maximal myelosuppression usually occurs in seven to ten days. Psoriasis Recommended Starting Dose Schedule 1. Weekly single oral, intramuscular or intravenous dosage schedule: 10 to 25 mg per week until adequate response is achieved. † 2. Divided oral dose schedule: 2.5 mg at 12 hour intervals for three doses. † † Methotrexate Sodium Tablets for oral administration are available. Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged. HANDLING AND DISPOSAL: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. DILUTION INSTRUCTIONS FOR LIQUID METHOTREXATE INJECTION PRODUCT: Methotrexate Injection USP, Isotonic Liquid, Contains Preservative If desired, the solution may be further diluted with a compatible medium such as Sodium Chloride Injection, USP. Storage for 24 hours at a temperature of 21° to 25°C results in a product which is within 90% of label potency. ‡ LEUCOVORIN RESCUE SCHEDULES FOLLOWING TREATMENT WITH HIGHER DOSES OF METHOTREXATE Clinical Situation Laboratory Findings Leucovorin Dosage and Duration Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours 15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration, (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours, until methotrexate level is less than 0.05 micromolar. www.fresenius-kabi.com/us 451043F Revised: May 2020 logo

WARNINGS FOR INTRATHECAL AND HIGH-DOSE THERAPY, USE THE PRESERVATIVE-FREE FORMULATION OF METHOTREXATE. DO NOT USE THE PRESERVED FORMULATION FOR INTRATHECAL OR HIGH-DOSE THERAPY BECAUSE IT CONTAINS BENZYL ALCOHOL. METHOTREXATE SHOULD BE USED ONLY IN LIFE-THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY. DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS. PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES (see PRECAUTIONS ). PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY. THE USE OF METHOTREXATE HIGH-DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE (see DOSAGE AND ADMINISTRATION ). HIGH-DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED. Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate (see CONTRAINDICATIONS ). Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some non-steroidal anti-inflammatory drugs (NSAIDs) (see PRECAUTIONS , Drug Interactions ). Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population (see PRECAUTIONS , Organ System Toxicity , Hepatic ). Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.

reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy (see PRECAUTIONS , Organ System Toxicity , Skin ). Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

DESCRIPTION: Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Chemically, methotrexate is N -[4-[[(2,4-diamino-6-pteridinyl) methyl] methylamino]benzoyl]-L-glutamic acid. The structural formula is: C 20 H 22 N 8 O 5 M.W. 454.45 Methotrexate Injection, USP is sterile and non-pyrogenic and may be given by the intramuscular, intravenous or intra-arterial route (see DOSAGE AND ADMINISTRATION ). The preserved formulation contains benzyl alcohol; do not use for intrathecal or high-dose therapy. Methotrexate Injection, USP, Isotonic Liquid, Contains Preservative is available in 10 mL (25 mg/mL) vials. Each mL contains methotrexate sodium equivalent to 25 mg methotrexate, 0.9% w/v of benzyl alcohol as a preservative, and the following inactive ingredients: sodium chloride 0.26% w/v and water for injection, q.s. ad 100% v. Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH to approximately 8.5. structure

CLINICAL PHARMACOLOGY: 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. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies. In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosions and other radiologic changes which result in impaired joint use, functional disability, and deformity. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short-term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy. In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high-dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown.

e may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual mechanism of action is unknown. In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m 2 provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity). Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m 2 /wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-third were using low-dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m 2 was not significantly more effective than placebo in this trial. Two Pediatric Oncology Group studies (one randomized and one non-randomized) demonstrated a significant improvement in relapse-free survival in patients with non-metastatic osteosarcoma, when high-dose methotrexate with leucovorin rescue was used in combination with other chemotherapeutic agents following surgical resection of the primary tumor. These studies were not designed to demonstrate the specific contribution of high-dose methotrexate/leucovorin rescue therapy to the efficacy of the combination. However, a contribution can be inferred from the reports of objective responses to this therapy in patients with metastatic osteosarcoma, and from reports of extensive tumor necrosis following preoperative administration of this therapy to patients with non-metastatic osteosarcoma. Pharmacokinetics Absorption Oral absorption appears to be dose dependent. Peak plasma concentrations are reached within 0.75 to 6.0 hours following oral administration. At doses of 30 mg/m 2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m 2 is significantly less, possibly due to a saturation effect. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (C max : 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (T max : 0.67 to 4 hrs after a 15 mg/m 2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m 2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA.

e is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m 2 /week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.4) at 1 hour, 0.44 micromolar (range, 0.01 to 1) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m 2 ), or for JRA (3.75 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively. Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints. Metabolism After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Half-Life The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2 ). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion.

tion, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Non-linear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION . Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1.

Pharmacokinetics Absorption Oral absorption appears to be dose dependent. Peak plasma concentrations are reached within 0.75 to 6.0 hours following oral administration. At doses of 30 mg/m 2 or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/m 2 is significantly less, possibly due to a saturation effect. In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak levels (C max : 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) has been reported. Significant interindividual variability has also been noted in time to peak concentration (T max : 0.67 to 4 hrs after a 15 mg/m 2 dose) and fraction of dose absorbed. The absorption of doses greater than 40 mg/m 2 has been reported to be significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to 11.2 mg/m 2 /week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar (range, 0.03 to 1.4) at 1 hour, 0.44 micromolar (range, 0.01 to 1) at 2 hours, and 0.29 micromolar (range, 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m 2 ), or for JRA (3.75 to 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively. Distribution After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints. Metabolism After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase.

inflamed joints to the level of normal joints. Metabolism After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after oral administration. Half-Life The terminal half-life reported for methotrexate is approximately three to ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2 ). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed. Renal excretion occurs by glomerular filtration and active tubular secretion. Non-linear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustments of leucovorin dosing. Guidelines for monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION . Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1.

INDICATIONS AND USAGE: Neoplastic Diseases Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated for use in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas. Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor. Psoriasis Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses. Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Aspirin, (NSAIDs), and/or low-dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored (see PRECAUTIONS , Drug Interactions ). Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued.

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 pre-existing 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.

PRECAUTIONS: General Methotrexate has the potential for serious toxicity (see BOXED WARNINGS ). Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on methotrexate closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer (see OVERDOSAGE ). If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of toxicity. The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity. Some of the effects mentioned under ADVERSE REACTIONS , such as dizziness and fatigue, may affect the ability to drive or operate machinery. Information for Patients Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity. Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. Prescriptions should not be written or refilled on a PRN basis. Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate. Laboratory Tests Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray. During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated. Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation (see PRECAUTIONS , Organ System Toxicity , Hepatic ). A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.

, Organ System Toxicity , Hepatic ). A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available. Drug Interactions Non-steroidal 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.

stered 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 recent history of nitrous oxide administration. Carcinogenesis, Mutagenesis, Impairment of Fertility No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Benefits should be weighed against the potential risk before using methotrexate alone or in combination with other drugs, especially in pediatric patients or young adults. Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. Pregnancy Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X (see CONTRAINDICATIONS ). Nursing Mothers See CONTRAINDICATIONS . Pediatric Use Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis (see CLINICAL PHARMACOLOGY , ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION ). For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol. Use the preservative-free formulation of methotrexate in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.

onates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ) (see PRECAUTIONS , Organ System Toxicity , Neurologic ). Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population (see PRECAUTIONS , Drug Interactions ). Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age (see BOXED WARNINGS and ADVERSE REACTIONS ). Organ System Toxicity Gastrointestinal If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis. Hematologic Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with malignancy and preexisting hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm 3 ) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm 3 ) in 6 patients, and pancytopenia in 2 patients. In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy. Hepatic Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function.

tal cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low-grade portal inflammation, are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis). If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), methotrexate may be continued and the patient monitored as per recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV). Infection or Immunologic States Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.

ot recommended. There have been reports of disseminated vaccinia infections after smallpox immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered. Neurologic There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic syndrome has been observed in patients treated with high-dose regimens. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; subacute myelopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal. Pulmonary Pulmonary symptoms (especially a dry nonproductive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages. Renal Methotrexate may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration. Skin Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Other Precautions Methotrexate should be used with extreme caution in the presence of debility. Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity.

tients with neoplastic and non-neoplastic diseases. Other Precautions Methotrexate should be used with extreme caution in the presence of debility. Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate.

Pediatric Use Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis. Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis (see CLINICAL PHARMACOLOGY , ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION ). For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol. Use the preservative-free formulation of methotrexate in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m 2 ) (see PRECAUTIONS , Organ System Toxicity , Neurologic ).

Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population (see PRECAUTIONS , Drug Interactions ). Since decline in renal function may be associated with increases in adverse events and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age (see BOXED WARNINGS and ADVERSE REACTIONS ).

ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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.

lmonary 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 subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant non-steroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies (see PRECAUTIONS ). Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm 3 ). Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3,000/mm 3 ), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1% (see PRECAUTIONS ). Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge. Adverse Reactions in Psoriasis There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35 : 835-838, 1996). Adverse Reactions in JRA Studies The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m 2 /wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant non-steroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m 2 /wk in JRA, the published data for doses above 20 mg/m 2 /wk are too limited to provide reliable estimates of adverse reaction rates.

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 post-marketing 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.

DOSAGE AND ADMINISTRATION: Neoplastic Diseases For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol. Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate Injection may be given by the intramuscular, intravenous or intra-arterial route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Choriocarcinoma and Similar Trophoblastic Diseases Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful. Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma. Leukemia Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m 2 in combination with 60 mg/m 2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m 2 . It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.

in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy. Lymphomas In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily. Mycosis fungoides (cutaneous T cell lymphoma) Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease. Osteosarcoma An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m 2 . If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10 -3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m 2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given intravenously or intramuscularly at the same dose and schedule. Drug* Dose* Treatment Week After Surgery Methotrexate 12 g/m 2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15, 16,29,30,44,45 Leucovorin 15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion. _ _ _ Doxorubicin † as a single drug 30 mg/m 2 /day IV x 3 days 8,17 Doxorubicin † Cisplatin † 50 mg/m 2 IV 100 mg/m 2 IV 20,23,33,36 20,23,33,36 Bleomycin † Cyclophosphamide † Dactinomycin † 15 units/m 2 IV x 2 days 600 mg/m 2 IV x 2 days 0.6 mg/m 2 IV x 2 days 2,13,26,39,42 2,13,26,39,42 2,13,26,39,42 *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity. When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Clinical Situation </content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold"> Laboratory Findings </content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Leucovorin Dosage and Duration </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Normal Methotrexate Elimination </td><td styleCode="Rrule" valign="top">Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours </td><td styleCode="Rrule" valign="top">15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Delayed Late Methotrexate Elimination </td><td styleCode="Rrule" valign="top">Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. </td><td styleCode="Rrule" valign="top">Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar. </td></tr><tr><td styleCode="Lrule Rrule" valign="top">Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury </td><td styleCode="Rrule" valign="top">Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration, (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). </td><td styleCode="Rrule" valign="top">150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours, until methotrexate level is less than 0.05 micromolar. </td></tr></tbody></table>

HOW SUPPLIED: Parenteral Methotrexate Injection, USP, Isotonic Liquid, Contains Preservative . Each mL contains methotrexate sodium equivalent to 25 mg methotrexate. Product No. NDC No. Strength 102310 63323-123-10 250 mg per 10 mL (25 mg per mL) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. PROTECT FROM LIGHT. The container closure is not made with natural rubber latex.

<table width="50%"><col width="33.333%"/><col width="33.333%"/><col width="33.333%"/><tbody><tr><td align="left" valign="top" styleCode="Toprule Lrule Botrule Rrule"><content styleCode="bold">Product No. </content></td><td align="left" valign="top" styleCode="Toprule Lrule Botrule Rrule"><content styleCode="bold">NDC No. </content></td><td align="left" valign="top" styleCode="Toprule Lrule Botrule Rrule"><content styleCode="bold"> Strength </content></td></tr><tr><td align="left" valign="top" styleCode="Toprule Lrule Botrule Rrule">102310 </td><td align="left" valign="top" styleCode="Toprule Lrule Botrule Rrule">63323-123-10 </td><td align="left" valign="top" styleCode="Toprule Lrule Botrule Rrule">250 mg per 10 mL (25 mg per mL) </td></tr></tbody></table>

REFERENCES: Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health Syst Pharma 1996: 53:1669-1685. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA , 1985; 253 (11): 1590-1592. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. Ca- A Cancer Journal for Clinicians Sept/Oct 1983; 258-263. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033-1049.