Methotrexate

Methotrexate Injection is a folate analog metabolic inhibitor indicated for: • The following neoplastic diseases for the: o Treatment of adult and pediatric patients with acute lymphoblastic leukemia as part of a combination chemotherapy regimen. o Prophylaxis and treatment of adult and pediatric patients with meningeal leukemia. o Treatment of adult and pediatric patients with non-Hodgkin lymphoma. o Treatment of adult and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen. o Treatment of adults with breast cancer as part of a combination chemotherapy regimen. o Treatment of adults with squamous cell carcinoma of the head and neck as a single agent. o Treatment of adults with gestational trophoblastic neoplasia as part of a combination chemotherapy regimen. • Treatment of adults with rheumatoid arthritis (RA).

Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis, pJIA, and in psoriasis is unknown.

• Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection. • Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens. • RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly, adjust dose to achieve an optimal response. • pJIA: Recommended starting dosage of 10 mg/m 2 once weekly subcutaneously or intramuscularly, adjust dose to achieve an optimal response. • 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.

Methotrexate Injection is contraindicated in: • Patients with history of severe hypersensitivity to methotrexate. • Pregnancy in patients with non-neoplastic diseases. • History of severe hypersensitivity to methotrexate. • Pregnancy: in patients with non-neoplastic diseases.

Boxed warning: Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception. • Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis. • Secondary malignancies can occur. • Tumor lysis syndrome can occur in patients with rapidly growing tumors. • Immunizations and Risks associated with Live Vaccines: Immunizations may be ineffective. Live vaccines are not recommended due to risk of disseminated infection. • Infertility: Can cause impairment of fertility, oligospermia, and menstrual dysfunction.

The following adverse reactions are described, or described in greater detail, in other sections: • Hypersensitivity Reactions • Myelosuppression • Serious Infections • Renal Toxicity • Hepatotoxicity • Neurotoxicity • Gastrointestinal Toxicity • Pulmonary Toxicity • Dermatologic Reactions • Secondary Malignancies • Tumor Lysis Syndrome • Increased Risk of Adverse Reactions due to Third-Space Accumulation Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress.

Refer to full prescribing information for drug interactions with Methotrexate Injection. 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.

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). After first puncture, store multiple-dose vials at 2°C to 8°C, and use within 30 days. Protect from light.