Methotrexate

• •
  Methotrexate can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception

  [see Contraindications (

  4 CONTRAINDICATIONS

  Methotrexate for Injection is contraindicated in:

  • •Patients with history of severe hypersensitivity to methotrexate
    [see Warnings and Precautions ]
    .
  • •Pregnancy in patients with non-neoplastic diseases
    [see Warnings and Precautions and Use in Specific Populations ]
    .

  • •History of severe hypersensitivity to methotrexate.
  • •Pregnancy: in patients with non-neoplastic diseases.

  ), Warnings and Precautions (

  5.1 Embryo-Fetal Toxicity

  Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity, including fetal death when administered to a pregnant woman.

  Methotrexate for Injection is contraindicated for use in pregnant women with non-neoplastic diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate for Injection is needed during pregnancy to treat a neoplastic disease

  [see Warnings and Precautions ]

  .

  Advise females of reproductive potential to use effective contraception during Methotrexate for Injection treatment and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate for Injection treatment and for 3 months after the final dose

  [see Contraindications and Use in Specific Populations ]

  .

  ), and Use in Specific Populations (

  8.1 Pregnancy

  Risk Summary

  Methotrexate for Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman

  [see Dataand Clinical Pharmacology ].

  There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate for Injection is needed during pregnancy to treat a neoplastic disease

  [see Warnings and Precautions and Use in Specific Populations ]

  .

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

  Data

  Human Data

  Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.

  A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2–58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8–29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13–22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6–5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03–9.5]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

  ,

  8.3 Females and Males of Reproductive Potential

  Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses

  [see Use in Specific Populations ]

  .

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate for Injection

  [see Contraindications and Use in Specific Populations ].

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of Methotrexate for Injection therapy.

  Males

  Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months after the final dose of Methotrexate for Injection therapy.

  Infertility

  Females

  Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that Methotrexate for Injection can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.

  Males

  Based on published reports of male infertility after therapy with methotrexate, advise males that Methotrexate for Injection can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.

  )]

  .
• •
  Methotrexate is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis

  [see Contraindications (

  4 CONTRAINDICATIONS

  Methotrexate for Injection is contraindicated in:

  • •Patients with history of severe hypersensitivity to methotrexate
    [see Warnings and Precautions ]
    .
  • •Pregnancy in patients with non-neoplastic diseases
    [see Warnings and Precautions and Use in Specific Populations ]
    .

  • •History of severe hypersensitivity to methotrexate.
  • •Pregnancy: in patients with non-neoplastic diseases.

  ) and Warnings and Precautions (

  5.2 Hypersensitivity Reactions

  Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate

  [see Adverse Reactions ].

  If signs or symptoms of anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Methotrexate for Injection and institute appropriate therapy

  [see Contraindications ]

  .

  )].
• •
  Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate 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 Dosage and Administration (

  2.1 Important Dosage and Safety Information

  • •
    Use only preservative-free Methotrexate for 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 and Use in Specific Populations ].
  • •Verify pregnancy status in females of reproductive potential before starting Methotrexate for Injection
    [see Contraindications and Warnings and Precautions ].
  • •For patients switching between a methotrexate product administered orally and Methotrexate for Injection, consider potential differences in bioavailability
    .

  ) and Warnings and Precautions (

  5.3 Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative

  Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis, if used in neonates or low-birth weight infants, intrathecally, or in high-dose regimens. Use only preservative-free Methotrexate for 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. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate for Injection is needed during pregnancy to treat a neoplastic disease

  [see Use in Specific Populations ]

  .

  Serious and Fatal Adverse Reactions Including Gasping Syndrome in Neonates and Low-Birth Weight Infants

  Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with drugs containing benzyl alcohol, including Methotrexate for Injection with preservative. The “gasping syndrome” is characterized by central nervous system (CNS) depression, metabolic acidosis, and gasping respirations.

  When prescribing in infants (non-neonate, non-low-birth weight), if a preservative-free formulation of Methotrexate for Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate for Injection (Methotrexate for Injection contains 9.4 mg of benzyl alcohol/per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known

  [see Use in Specific Populations ].

  Neurotoxicity Due to Intrathecal Administration

  Serious neurotoxicity can occur following the intrathecal administration of Methotrexate for Injection containing the preservative benzyl alcohol.

  Metabolic Acidosis with High-Dose Therapy

  Severe metabolic acidosis can occur with Methotrexate for Injection that contains the preservative benzyl alcohol.

  )].
• •
  Other serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate as appropriate

  [see Warnings and Precautions (

  5.4 Myelosuppression

  Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia

  [see Adverse Reactions ].

  Obtain blood counts at baseline and periodically during treatment. Monitor patients for possible clinical complications of myelosuppression. Provide supportive care and withhold, reduce dose, or discontinue Methotrexate for Injection as needed.

  ,

  5.5 Serious Infections

  Patients treated with methotrexate are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as

  Pneumocystis jiroveci

  pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminated

  Herpes zoster

  and cytomegalovirus infections.

  Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Methotrexate for Injection. Withhold or discontinue Methotrexate for Injection in patients who develop serious infections

  .

  ,

  5.6 Renal Toxicity

  Methotrexate can cause renal toxicity including irreversible acute renal failure. Monitor renal function and withhold or discontinue methotrexate as needed for severe renal toxicity.

  For patients receiving high-dose regimens, follow recommendations to decrease the risk of renal injury and mitigate renal toxicity

  [see Dosage and Administration ].

  Patients with impaired renal function are at increased risk for methotrexate toxicity

  [see Use in Specific Populations ].

  Consider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed clearance due to impaired renal function.

  [see Dosage and Administration (2.2)]

  .

  ,

  5.7 Hepatotoxicity

  Methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure

  [see Adverse Reactions ].

  In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver function tests. In patients with psoriasis, 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.

  The safety of Methotrexate for Injection in patients with liver disease is unknown. Avoid use of Methotrexate for Injection in patients with chronic liver disease, unless benefits clearly outweigh the risks. The risk of hepatotoxicity is increased with heavy alcohol consumption.

  Assess liver function prior to initiating Methotrexate for Injection and monitor liver function tests during treatment. Withhold or discontinue Methotrexate for Injection as appropriate.

  ,

  5.8 Neurotoxicity

  Methotrexate can cause severe acute and chronic neurotoxicity which can be progressive, irreversible, and fatal. Serious neurotoxicity, including generalized and focal seizures, have occurred in pediatric patients

  [see Use in Specific Populations ]

  . Monitor patients for signs of neurotoxicity and withhold or discontinue Methotrexate for Injection when appropriate.

  Leukoencephalopathy

  Leukoencephalopathy can occur with intermediate and high-dose intravenous regimens, intrathecal methotrexate, and low-dose methotrexate therapy. The risk of leukoencephalopathy is increased with prior cranial radiation.

  Transient Acute Neurologic Syndrome

  A transient acute stroke-like syndrome can occur with high-dose methotrexate. Clinical manifestations include confusion, hemiparesis, transient blindness, seizures, and coma.

  Neurologic Adverse Reactions Associated with Intrathecal Administration

  Intrathecal methotrexate can cause the following additional neurologic adverse reactions:

  • •Acute chemical arachnoiditis manifested by symptoms such as headache, back pain, nuchal rigidity, and fever.
  • •Subacute myelopathy characterized by paraparesis or paraplegia.

  Avoid the intrathecal use of Methotrexate for Injection that contains the preservative benzyl alcohol because of the risk of serious neurotoxicity

  [see Warnings and Precautions ].

  ,

  5.9 Gastrointestinal Toxicity

  Methotrexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis and fatal intestinal perforation

  [see Adverse Reactions ]

  . Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions.

  Withhold or discontinue Methotrexate for Injection for severe gastrointestinal toxicity, and institute appropriate supportive care as needed.

  ,

  5.10 Pulmonary Toxicity

  Methotrexate-induced pulmonary toxicity including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels. Monitor patients for signs of pulmonary toxicity and withhold or discontinue Methotrexate for Injection as appropriate.

  ,

  5.11 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 ].

  Psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.

  Methotrexate can also cause radiation recall dermatitis and photodermatitis (sunburn) reactivation.

  Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue Methotrexate for Injection for severe dermatologic adverse reactions. Counsel patients to avoid excessive sun exposure and use sun protection measures.

  )].

Methotrexate for Injection is a folate analog metabolic inhibitor indicated for:

• •The following neoplastic diseases for the:
  • oTreatment of adult and pediatric patients with acute lymphoblastic leukemia as part of a combination chemotherapy regimen (
    1.1 Acute Lymphoblastic Leukemia

    Methotrexate for Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen.
    )
  • oProphylaxis and treatment of adult and pediatric patients with meningeal leukemia (
    1.2 Meningeal Leukemia: Prophylaxis and Treatment

    Methotrexate for Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients.
    )
  • oTreatment of adult and pediatric patients with non-Hodgkin lymphoma (
    1.3 Non-Hodgkin Lymphoma

    Methotrexate for Injection is indicated for the treatment of adults and pediatric patients with Non-Hodgkin lymphoma.
    )
  • oTreatment of adult and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen (
    1.4 Osteosarcoma

    Methotrexate for Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen.
    )
  • oTreatment of adults with breast cancer as part of a combination chemotherapy regimen (
    1.5 Breast Cancer

    Methotrexate for Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen.
    )
  • oTreatment of adults with squamous cell carcinoma of the head and neck as single-agent (
    1.6 Squamous Cell Carcinoma of the Head and Neck

    Methotrexate for Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single-agent.
    )
  • oTreatment of adults with gestational trophoblastic neoplasia as part of a combination chemotherapy regimen (
    1.7 Gestational Trophoblastic Neoplasia

    Methotrexate for Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen.
    )
• •Treatment of adults with rheumatoid arthritis (RA). (
  1.8 Rheumatoid Arthritis

  Methotrexate for Injection is indicated for the treatment of adults with rheumatoid arthritis (RA).
  )
• •Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). (
  1.9 Polyarticular Juvenile Idiopathic Arthritis

  Methotrexate for Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).
  )
• •Treatment of adults with severe psoriasis. (
  1.10 Psoriasis

  Methotrexate for Injection is indicated for the treatment of adults with severe psoriasis.
  )

• •Verify pregnancy status in females of reproductive potential before starting Methotrexate for Injection. (
  2.1 Important Dosage and Safety Information

  • •
    Use only preservative-free Methotrexate for 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 and Use in Specific Populations ].
  • •Verify pregnancy status in females of reproductive potential before starting Methotrexate for Injection
    [see Contraindications and Warnings and Precautions ].
  • •For patients switching between a methotrexate product administered orally and Methotrexate for Injection, consider potential differences in bioavailability
    .
  ,
  4 CONTRAINDICATIONS

  Methotrexate for Injection is contraindicated in:

  • •Patients with history of severe hypersensitivity to methotrexate
    [see Warnings and Precautions ]
    .
  • •Pregnancy in patients with non-neoplastic diseases
    [see Warnings and Precautions and Use in Specific Populations ]
    .

  • •History of severe hypersensitivity to methotrexate.
  • •Pregnancy: in patients with non-neoplastic diseases.
  ,
  5.1 Embryo-Fetal Toxicity

  Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity, including fetal death when administered to a pregnant woman.

  Methotrexate for Injection is contraindicated for use in pregnant women with non-neoplastic diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate for Injection is needed during pregnancy to treat a neoplastic disease

  [see Warnings and Precautions ]

  .

  Advise females of reproductive potential to use effective contraception during Methotrexate for Injection treatment and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate for Injection treatment and for 3 months after the final dose

  [see Contraindications and Use in Specific Populations ]

  .
  )
• •Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens. (
  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 ]

  :

  • •Administer leucovorin rescue in patients receiving Methotrexate for Injection doses of 500 mg/m²or greater (e.g., high-dose)
    .
  • •Consider leucovorin rescue for patients receiving Methotrexate for Injection doses between 100 mg/m²to less than 500 mg/m²(e.g., intermediate-dose).

  Refer to the leucovorin Prescribing Information for additional information.

  • •For high-dose Methotrexate for Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate for 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 for Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m²intravenously. For high dose Methotrexate for Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

  [see Dosage and Administration ]

  . Lower doses (e.g., 20 to 30 mg/m²/week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate for 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 for Injection for intrathecal use.

  Prior to administration, dilute preservative-free Methotrexate for Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP.

  The recommended intrathecal dose of Methotrexate for 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 for Injection is administered no more than once weekly.

  For patients with Down Syndrome, administer leucovorin rescue with intrathecal Methotrexate for Injection.
  ,
  2.5 Recommended Dosage for Non-Hodgkin Lymphoma

  The recommended dosage of Methotrexate for Injection varies. When used in combination, recommended dosages range from 10 mg/m²to 8000 mg/m²intravenously. When used as a single agent, recommended dosages include 8,000 mg/m²intravenously 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 for Injection is 1,000 mg/m²or 3,000 mg/m²as an intravenous infusion over 24 hours followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

  [see Dosage and Administration ]

  .

  For central nervous system-directed therapy, a recommended dosage of Methotrexate for Injection is 8,000 mg/m²as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m²to 8,000 mg/m²followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

  [see Dosage and Administration ]

  .

  For intrathecal Methotrexate for Injection (preservative-free), the recommended dose is based on age

  [see Dosage and Administration ]

  . 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 for 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 ].

  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 for Injection is 40 mg/m²intravenously 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 for Injection ranges from 40 to 60 mg/m²intravenously once weekly.
  ,
  2.9 Recommended Dosage for Gestational Trophoblastic Neoplasia

  For patients with low-risk gestational trophoblastic neoplasia (GTN) a recommended dosage for Methotrexate for Injection is 30 mg/m²to 200 mg/m²or 0.4 mg/kg to1 mg/kg intravenously or intramuscularly.

  For patients with high-risk GTN, a recommended dosage for Methotrexate for Injection is 300 mg/m²over 12 hours as an intravenous infusion as a component of a multi-drug regimen.
  )
• •RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly; adjust dose to achieve an optimal response. (
  2.10 Recommended Dosage for Rheumatoid Arthritis

  The recommended starting dosage of Methotrexate for 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 ].
  )
• •pJIA: Recommended starting dosage of 10 mg/m² once weekly subcutaneously or intramuscularly; adjust dose to achieve an optimal response. (
  2.11 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis

  The recommended starting dosage of Methotrexate for Injection is 10 mg/m²once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/ m²per 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 ].
  )
• •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 Recommended Dosage for Psoriasis

  The recommended dosage of Methotrexate for 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 ].
  )

Injection: Methotrexate for Injection is a lyophilized powder and is supplied in single-dose vials (preservative‑ free) in the following strength:

• •1 gram

• •Lactation: Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate for Injection and for 1 week after the final dose.
  )
• •Pediatric use: Intermediate-dose methotrexate can cause serious neurotoxicity in patients with acute lymphoblastic leukemia. (
  8.4 Pediatric Use

  The safety and effectiveness of Methotrexate for Injection in pediatric patients have been established for ALL, meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the use of methotrexate in pediatric patients with pJIA demonstrated safety comparable to that observed in adults with RA

  [see Adverse Reactions ].

  The safety and effectiveness of Methotrexate for Injection have not been established in pediatric patients for the treatment of breast cancer, squamous cell carcinoma of the head and neck, gestational trophoblastic neoplasia, rheumatoid arthritis, and psoriasis. Additional risk information is described below.

  Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative

  Due to the risk of serious adverse reactions and fatal gasping syndrome following administration of intravenous solutions containing the preservative benzyl alcohol in neonates, use only preservative-free Methotrexate for Injection in neonates and low-birth weight infants. The “gasping syndrome” is characterized by CNS depression, metabolic acidosis, and gasping respirations.

  Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

  When prescribing in infants (non-neonate, non-low-birth weight), if a preservative-free formulation of Methotrexate for Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate for Injection (Methotrexate for Injection contains 9.4 mg of benzyl alcohol/per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known

  .

  Do not administer methotrexate formulations containing benzyl alcohol intrathecally due to the risk of severe neurotoxicity

  [see Warnings and Precautions ].

  Leukemia/Lymphoma

  Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 g/m²)

  [see Warnings and Precautions ].
  )