Methotrexate: uses, appearance and warnings

TREXALL is a 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 TREXALL is 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 TREXALL is indicated for the treatment of adults with rheumatoid arthritis. 1.3 Polyarticular Juvenile Idiopathic Arthritis TREXALL is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA). 1.4 Psoriasis TREXALL is indicated for the treatment of adults with severe psoriasis.

Tablets: 5 mg: Green, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 927/5 on the other side. 7.5 mg: Blue, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 928/7½ on the other side. 10 mg: Pink, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 929/10 on the other side. 15 mg: Purple, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 945/15 on the other side. Tablets: 5 mg, 7.5 mg, 10 mg and 15 mg ( 3 )

TREXALL ® (methotrexate tablets, USP) are supplied as follows: 5 mg: Green, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 927/5 on the other side. They are available in bottles of 30 tablets (NDC 51285-366-01). 7.5 mg: Blue, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 928/7 1 / 2 on the other side. They are available in bottles of 30 tablets (NDC 51285-367-01). 10 mg: Pink, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 929/10 on the other side. They are available in bottles of 30 tablets (NDC 51285-368-01). 15 mg: Purple, oval-shaped, film-coated, scored, biconvex tablet. Debossed with stylized b on one side and 945/15 on the other side. They are available in bottles of 30 tablets (NDC 51285-369-01). Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light. Keep this and all medications out of the reach of children. Methotrexate is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

TREXALL is contraindicated in: Pregnant women receiving TREXALL 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 TREXALL [see Warnings and Precautions ( 5.2 )]. In pregnancy for non-neoplastic diseases ( 4 ) History of severe hypersensitivity to TREXALL ( 4 )

Serious Infections : Monitor patients for infection during and after treatment with TREXALL. Withhold or discontinue TREXALL for serious infections as appropriate. ( 5.11 ) Neurotoxicity : Monitor patients for neurotoxicity and withhold or discontinue TREXALL 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 TREXALL. ( 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 TREXALL 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 TREXALL and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during TREXALL 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 TREXALL [see Contraindications ( 4 ), Adverse Reactions ( 6.1 )] . If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue TREXALL [see Dosage and Administration ( 2.6 )]. 5.3 Myelosuppression TREXALL 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 TREXALL 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 TREXALL 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 TREXALL for severe gastrointestinal toxicity taking into account the importance of TREXALL 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 TREXALL can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions ( 6.1 )] . The safety of TREXALL 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 TREXALL taking into account the importance of TREXALL 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 TREXALL [see Adverse Reactions ( 6.1 , 6.2 )] . Monitor patients for pulmonary toxicity and withhold or discontinue methotrexate tablets taking into account the importance of TREXALL 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 TREXALL [see Adverse Reactions ( 6.1 , 6.2 )] . Exposure to ultraviolet radiation while taking methotrexate may aggravate psoriasis. TREXALL can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation. Monitor patients for dermatologic toxicity and withhold or permanently discontinue TREXALL for severe dermatologic reactions taking into account the importance of TREXALL 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 TREXALL 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. …

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 …

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. …