Methotrexate Vial Dosage and Administration

2 DOSAGE AND ADMINISTRATION

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/m2 or greater (e.g., high-dose).
Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m2 to less than 500 mg/m2 (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.
o
Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy
o
Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output
o
Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher
o
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/m2 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/m2/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 to15 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/m2 to 8000 mg/m2 intravenously. When used as a single agent, recommended dosages include 8,000 mg/m2 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/m2 or 3,000 mg/m2 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/m2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m2 to 8,000 mg/m2 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/m2 (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/m2 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/m2 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/m2 to 200 mg/m2 or 0.4 mg/kg to1 mg/kg intravenously or intramuscularly.

For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m2 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/m2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/ m2 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

With Preservative (multiple-dose vial)

Methotrexate Injection formulation containing benzyl alcohol as a preservative may be administered by intramuscular, intravenous, or subcutaneous injection [see Dosage and Administration (2.1)]. Methotrexate Injection with preservative may be further diluted with 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 under refrigeration (2°C to 8°C).
Visually inspect product for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

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 immediately before use with preservative-free 0.9% Sodium Chloride Injection, USP. For the treatment or prophylaxis of meningeal leukemia, dilute the solution to a concentration of 1 mg/mL in 0.9% Sodium Chloride Injection, USP. Discard unused portion.
Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

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Dosage and Administration

2 DOSAGE AND ADMINISTRATION

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/m2 or greater (e.g., high-dose).
Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m2 to less than 500 mg/m2 (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.
o
Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy
o
Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output
o
Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher
o
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/m2 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/m2/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 to15 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/m2 to 8000 mg/m2 intravenously. When used as a single agent, recommended dosages include 8,000 mg/m2 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/m2 or 3,000 mg/m2 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/m2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m2 to 8,000 mg/m2 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/m2 (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/m2 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/m2 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/m2 to 200 mg/m2 or 0.4 mg/kg to1 mg/kg intravenously or intramuscularly.

For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m2 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/m2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/ m2 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

With Preservative (multiple-dose vial)

Methotrexate Injection formulation containing benzyl alcohol as a preservative may be administered by intramuscular, intravenous, or subcutaneous injection [see Dosage and Administration (2.1)]. Methotrexate Injection with preservative may be further diluted with 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 under refrigeration (2°C to 8°C).
Visually inspect product for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

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 immediately before use with preservative-free 0.9% Sodium Chloride Injection, USP. For the treatment or prophylaxis of meningeal leukemia, dilute the solution to a concentration of 1 mg/mL in 0.9% Sodium Chloride Injection, USP. Discard unused portion.
Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.
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