METHOTREXATE

Methotrexate, USP (formerly Amethopterin) is a folate analog metabolic inhibitor used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Chemically methotrexate, USP 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. 454.44 Preservative-free Methotrexate Injection, USP is supplied in sterile single-dose vials for intravenous, intramuscular, subcutaneous, or intrathecal use. Methotrexate Injection, USP, Isotonic Liquid, Preservative Free is available in 50 mg/2 mL, 250 mg/10 mL, and 1 gram/40 mL single-dose vials. Each 25 mg/mL, 2 mL vial contains 50 mg methotrexate, USP equivalent to 54.8 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 9.8 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. Each 25 mg/mL, 10 mL vial contains 250 mg methotrexate, USP equivalent to 274.2 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 49 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. Each 25 mg/mL, 40 mL vial contains 1,000 mg methotrexate, USP equivalent to 1,096.7 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 196 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. structural formula

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

Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection. ( 2.1 , 4 , 5.1 ) Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly; adjust dose to achieve an optimal response. ( 2.10 ) pJIA: Recommended starting dosage of 10 mg/m 2 once weekly subcutaneously or intramuscularly; adjust dose to achieve an optimal response. ( 2.11 ) Psoriasis: Recommended dosage of 10 mg to 25 mg once weekly intramuscularly or intravenously; adjust dose to achieve optimal response. Once achieved, reduce to lowest possible dosage. ( 2.12 ) 2.1 Important Dosage and Safety Information Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.4 )] . Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . For patients switching between a methotrexate product administered orally and Methotrexate Injection, consider potential differences in bioavailability. 2.2 Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens To decrease the risk of severe adverse reactions [see Warnings and Precautions ( 5 )] : Administer leucovorin rescue in patients receiving Methotrexate Injection doses of 500 mg/m 2 or greater (e.g., high-dose). Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (e.g., intermediate-dose). Refer to the leucovorin prescribing information for additional information. For high-dose Methotrexate Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate Injection regimens. - Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy - Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output - Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher - Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information for additional information). 2.3 Recommended Dosage for Acute Lymphoblastic Leukemia Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m 2 intravenously. For high-dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration ( 2.2 )] . Lower doses (e.g., 20 to 30 mg/m 2 per week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. 2.4 Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment Use only preservative-free Methotrexate Injection for intrathecal use. Prior to administration, dilute preservative-free Methotrexate Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP. The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on age: less than 1 year: 6 mg 1 to less than 2 years: 8 mg 2 to less than 3 years: 10 mg 3 to less than 9 years: 12 mg greater than or equal to 9 years: 12 to 15 mg For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 or more days up to twice weekly; however, administration at intervals of less than 1 week may result in increased subacute toxicity. For meningeal leukemia prophylaxis, Methotrexate Injection is administered no more than once weekly. For patients with Down Syndrome, administer leucovorin rescue with intrathecal Methotrexate Injection. 2.5 Recommended Dosage for Non-Hodgkin Lymphoma The recommended dosage of Methotrexate Injection varies. When used in combination, recommended dosages range from 10 mg/m 2 to 8,000 mg/m 2 intravenously. When used as a single agent, recommended dosages include 8,000 mg/m 2 intravenously for central nervous system-directed therapy or 5 to 75 mg intravenously for cutaneous forms of non-Hodgkin lymphoma. As part of a combination chemotherapy regimen, a recommended dosage of Methotrexate Injection is 1,000 mg/m 2 or 3,000 mg/m 2 as an intravenous infusion over 24 hours followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration ( 2.2 )] . For central nervous system-directed therapy, a recommended dosage of Methotrexate Injection is 8,000 mg/m 2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m 2 to 8,000 mg/m 2 followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration ( 2.2 )] . For intrathecal Methotrexate Injection (preservative-free), the recommended dose is based on age [see Dosage and Administration ( 2.4 )] . The frequency of administration varies based on whether it is being used for treatment or prophylaxis, and other factors. 2.6 Recommended Dosage for Osteosarcoma The recommended dosage of Methotrexate Injection is typically 12 g/m 2 (maximum 20 g/dose) as an intravenous infusion over 4 hours administered as a component of a combination chemotherapy regimen. Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration ( 2.2 )] . Subsequent doses may need to be adjusted based on observed peak serum methotrexate concentrations. Dosage and schedule may vary based upon factors such as patient comorbidities, disease state, and prior treatments. 2.7 Recommended Dosage for Breast Cancer A recommended dosage of Methotrexate Injection is 40 mg/m 2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen. 2.8 Recommended Dosage for Squamous Cell Carcinoma of Head and Neck The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m 2 intravenously once weekly. 2.9 Recommended Dosage for Gestational Trophoblastic Neoplasia For patients with low-risk gestational trophoblastic neoplasia (GTN) a recommended dosage for Methotrexate Injection is 30 mg/m 2 to 200 mg/m 2 or 0.4 mg/kg to 1 mg/kg intravenously or intramuscularly. For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m 2 over 12 hours as an intravenous infusion as a component of a multi-drug regimen. 2.10 Recommended Dosage for Rheumatoid Arthritis The recommended starting dosage of Methotrexate Injection is 7.5 mg once weekly, administered intramuscularly 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 ( 5.12 )] . 2.11 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dosage of Methotrexate Injection is 10 mg/m 2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/m 2 per week may 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 ( 5.12 )] . 2.12 Recommended Dosage for Psoriasis The recommended dosage of Methotrexate Injection is 10 mg to 25 mg intramuscularly or intravenously once weekly until adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed 25 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 to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions ( 5.12 )] . 2.13 Dosage Modifications for Adverse Reactions Discontinue Methotrexate Injection 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 Injection as appropriate for: Myelosuppression [see Warnings and Precautions ( 5.4 )] Withhold or discontinue Methotrexate Injection as appropriate for: Serious infections [see Warnings and Precautions ( 5.5 )] Renal toxicity [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Neurotoxicity [see Warnings and Precautions ( 5.8 )] Gastrointestinal toxicity [see Warnings and Precautions ( 5.9 )] Pulmonary toxicity [see Warnings and Precautions ( 5.10 )] Dermatologic reactions [see Warnings and Precautions ( 5.11 )] 2.14 Administration and Handling Information Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1 Preservative-Free (Single-Dose Vial) Methotrexate Injection preservative-free may be administered by intramuscular, intravenous, subcutaneous, or intrathecal injection. Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use [see Warning and Precautions ( 5.3 ) and Use in Specific Populations ( 8.4 )] . Use preservative-free Methotrexate Injection for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available [see Warning and Precautions ( 5.3 ) and Use in Specific Populations ( 8.4 )] . Preservative-free Methotrexate Injection may be further diluted before use with preservative-free 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours when stored under refrigeration (2°C to 8°C). Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

Methotrexate Injection is contraindicated in: Patients with history of severe hypersensitivity to methotrexate [see Warnings and Precautions ( 5.2 )] . Pregnancy in patients with non-neoplastic diseases [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . History of severe hypersensitivity to methotrexate. ( 4 ) Pregnancy: in patients with non-neoplastic diseases. ( 4 )

The following adverse reactions are described, or described in greater detail, in other sections: Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Myelosuppression [see Warnings and Precautions ( 5.4 )] Serious Infections [see Warnings and Precautions ( 5.5 )] Renal Toxicity [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Neurotoxicity [see Warnings and Precautions ( 5.8 )] Gastrointestinal Toxicity [see Warnings and Precautions ( 5.9 )] Pulmonary Toxicity [see Warnings and Precautions ( 5.10 )] Dermatologic Reactions [see Warnings and Precautions ( 5.11 )] 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, and abdominal distress. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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. Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness. Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n=128) with RA treated with low-dose oral (7.5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence ≥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 (white blood cell count less than 3000/mm 3 ), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with RA on 7.5 mg per week to 15 mg per week oral doses showed the following adverse reactions: Incidence 1%: Interstitial pneumonitis. Other less common adverse reactions: Decreased hematocrit, 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 approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m 2 per week to 20 mg/m 2 per week or 0.1 mg/kg per week to 0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received 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%; rash, 0.2%. Psoriasis In two published series of adult psoriasis patients (n=204, 248) treated with methotrexate doses up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with RA, except for alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%). 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. Blood and lymphatic system disorders: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia Cardiovascular disorders: 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 disorders: Optic neuropathy, blurred vision, ocular irritation, conjunctivitis, xerophthalmia Gastrointestinal disorders: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration and bleeding Hepatobiliary disorders: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis, liver failure Immune system disorders: Anaphylaxis, anaphylactoid reactions, vasculitis Metabolism: Hyperglycemia Musculoskeletal disorders: Stress fracture, soft tissue necrosis, arthralgia, myalgia, osteoporosis Nervous system disorders: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, leukoencephalopathy, and convulsions. Also, spinal radiculopathy with intrathecal use Renal disorders: Severe renal toxicity including renal failure, azotemia, hematuria, proteinuria, cystitis Reproductive disorders: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction Respiratory disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis Skin disorders: 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 General disorders and administration site conditions: Injection site necrosis, injection site reaction

Refer to full prescribing information for drug interactions with Methotrexate Injection. ( 7 ) 7.1 Effects of Other Drugs on Methotrexate Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: Penicillin or sulfonamide antibiotics Highly protein bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Probenecid Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs). Mercaptopurine Hepatotoxic products Weak acids (e.g., salicylates) Nephrotoxic products Hematotoxic agents Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions ( 5.12 )] . 7.2 Effects of Methotrexate on Other Drugs Theophylline Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.