Methotrexate: Package Insert and Label Information

METHOTREXATE- methotrexate sodium tablet
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WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS AND SEVERE ADVERSE REACTIONS

1 INDICATIONS AND USAGE

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

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. 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 10 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:

Withhold, dose reduce or discontinue methotrexate tablets as appropriate for:

3 DOSAGE FORMS AND STRENGTHS

Tablets: 2.5 mg methotrexate, USP: round, biconvex, yellow tablets, scored in half on one side, engraved with “A” above the score and “1” below.

4 CONTRAINDICATIONS

Methotrexate tablets are contraindicated in:

5 WARNINGS AND PRECAUTIONS

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)] .

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.

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