1.1 Acute Lymphoblastic Leukemia

Methotrexate Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen.

1.2 Meningeal Leukemia: Prophylaxis and Treatment

Methotrexate Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients.

1.3 Non-Hodgkin Lymphoma

Methotrexate Injection is indicated for the treatment of adults and pediatric patients with Non-Hodgkin lymphoma.

1.4 Osteosarcoma

Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen.

1.5 Breast Cancer

Methotrexate Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen.

1.6 Squamous Cell Carcinoma of the Head and Neck

Methotrexate Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single-agent.

1.7 Gestational Trophoblastic Neoplasia

Methotrexate Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen.

1.8 Rheumatoid Arthritis

Methotrexate Injection is indicated for the treatment of adults with rheumatoid arthritis (RA).

1.9 Polyarticular Juvenile Idiopathic Arthritis

Methotrexate Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).

1.10 Psoriasis

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

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)]. 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)]. 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.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/m 2 or greater (e.g., high-dose).

• Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (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.

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 Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m 2 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/m 2/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 mgless than 1 year: 6 mg
• 1 to less than 2 years: 8 mg1 to less than 2 years: 8 mg
• 2 to less than 3 years: 10 mg2 to less than 3 years: 10 mg
• 3 to less than 9 years: 12 mg3 to less than 9 years: 12 mg
• greater than or equal to 9 years: 12 to15 mggreater 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/m 2 to 8000 mg/m 2 intravenously. When used as a single agent, recommended dosages include 8,000 mg/m 2 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/m 2 or 3,000 mg/m 2 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/m 2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m 2 to 8,000 mg/m 2 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/m 2 (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/m 2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen.

2.8 Recommended Dosage for Squamous Cell Carcinoma of the Head and Neck

The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m 2 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/m 2 to 200 mg/m 2 or 0.4 mg/kg to 1 mg/kg intravenously or intramuscularly.

For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m over 12 hours as an intravenous infusion as a component of a multi-drug regimen. For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m 2 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/m 2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/m 2 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.

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.

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 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 Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions ( 5.3)].

Advise females of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 3 months after the final dose [see Contraindications ( 4) and Use in Specific Populations ( 8.1, 8.3, 8.4)].

5.2 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Adverse Reactions ( 6.1)] . If signs or symptoms of anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Methotrexate Injection and institute appropriate therapy [see Contraindications ( 4)] .

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 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 Injection is needed during pregnancy to treat a neoplastic disease . 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 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 Injection is needed during pregnancy to treat a neoplastic disease [see Use in Specific Populations ( 8.1)] .

. 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 Injection with preservative. The “gasping syndrome” is characterized by central nervous system (CNS) depression, metabolic acidosis, and gasping respirations.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 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 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 Injection (Methotrexate 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 ( 8.4)] .

. Neurotoxicity Due to Intrathecal Administration.

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

. Metabolic Acidosis with High-Dose Therapy.

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

5.4 Myelosuppression

Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse Reactions ( 6.1)] .

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 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 Injection. Withhold or discontinue Methotrexate Injection in patients who develop serious infections.Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Methotrexate Injection. Withhold or discontinue Methotrexate 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 ( 2.2)].

Patients with impaired renal function are at increased risk for methotrexate toxicity [see Use in Specific Populations ( 8.6)].

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 ( 6.1, 6.2)].

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 Injection in patients with liver disease is unknown. Avoid use of Methotrexate 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 Injection and monitor liver function tests during treatment. Withhold or discontinue Methotrexate Injection as appropriate.Assess liver function prior to initiating Methotrexate Injection and monitor liver function tests during treatment. Withhold or discontinue Methotrexate 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 ( 8.4)]. Monitor patients for signs of neurotoxicity and withhold or discontinue Methotrexate 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 Injection that contains the preservative benzyl alcohol because of the risk of serious neurotoxicity [see Warnings and Precautions ( 5.3)].

5.9 Gastrointestinal Toxicity

Methotrexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis and fatal intestinal perforation [see Adverse Reactions ( 6.1)]. Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions.

Withhold or discontinue Methotrexate Injection for severe gastrointestinal toxicity, and institute appropriate supportive care as needed.Withhold or discontinue Methotrexate 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 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 ( 6.1, 6.2)].

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 Injection for severe dermatologic adverse reactions. Counsel patients to avoid excessive sun exposure and use sun protection measures.

5.12 Folic Acid Supplementation

Neoplastic Diseases

Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Avoid use of products containing folic acid or folinic acid unless clinically indicated [see Drug Interactions ( 7.1)].

Non-neoplastic Diseases

Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid to patients with rheumatoid arthritis, pJIA, and psoriasis [see Dosage and Administration ( 2.10, 2.11, 2.12)].

5.13 Secondary Malignancies

Secondary malignancies can occur at all dose levels of methotrexate. In some cases, lymphoproliferative disease that occurred during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue Methotrexate Injection and institute appropriate treatment if lymphoma does not regress.

5.14 Tumor Lysis Syndrome

Methotrexate can induce tumor lysis syndrome in patients with rapidly growing tumors. Institute appropriate treatment for prevention and management of tumor lysis syndrome.

5.15 Immunization and Risks Associated with Live Vaccines

Immunization during Methotrexate Injection treatment may be ineffective.

Disseminated infections following administration of live vaccines have been reported.

Update immunizations according to immunization guidelines prior to initiating Methotrexate Injection. Immunization with live vaccines is not recommended during treatment. The interval between live vaccinations and initiation of Methotrexate Injection should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

5.16 Infertility

Based on published reports, methotrexate can cause impairment of fertility, oligospermia, and menstrual dysfunction. It is not known if the infertility may be reversible in affected patients. Discuss the risk of effects on reproduction with female and male patients of reproductive potential [see Use in Specific Populations ( 8.3)].

5.17 Increased Risk of Adverse Reactions Due to Third Space Accumulation

Methotrexate can exit slowly from third space accumulations resulting in prolonged terminal plasma half-life and toxicity. Evacuate significant third-space accumulations prior to Methotrexate Injection administration [see Clinical Pharmacology ( 12.3)].

5.18 Increased Risk of Soft Tissue and Bone Toxicity with Concomitant Radiotherapy

Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate.

5.19 Risk of Serious Adverse Reactions with Medication Errors

Serious adverse reactions, including death, have occurred due to medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed. Ensure that patients receive the recommended dosage, because medication errors have led to death.

6.1 Clinical Trials Experience

Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness.

Rheumatoid Arthritis

The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n=128) with RA treated with low-dose oral (7.5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies.

Incidence ≥10%: Elevated liver function tests 15%, nausea/vomiting 10%.

Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm 3).

Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count less than 3000/mm 3), pancytopenia, dizziness.

Two other controlled trials of patients (n=680) with RA on 7.5 mg per week to 15 mg per week oral doses showed the following adverse reactions:

Incidence 1%: Interstitial pneumonitis.

Other less common adverse reactions: Decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge.

Polyarticular Juvenile Idiopathic Arthritis (pJIA)
The approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m 2 per week to 20 mg/m 2 per week or 0.1 mg/kg per week to 0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; rash, 0.2%.

Psoriasis
In two published series of adult psoriasis patients (n=204, 248) treated with methotrexate doses up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with RA, except for alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%). Painful plaque erosions have been reported.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of methotrexate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia

Cardiovascular disorders: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death

Endocrine: Diabetes

Eye disorders: Optic neuropathy, blurred vision, ocular irritation, conjunctivitis, xerophthalmia

Gastrointestinal disorders: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration and bleeding

Hepatobiliary disorders: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis, liver failure

Immune system disorders: Anaphylaxis, anaphylactoid reactions, vasculitis

Metabolism: Hyperglycemia

Musculoskeletal disorders: Stress fracture, soft tissue necrosis, arthralgia, myalgia, osteoporosis

Nervous system disorders: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, leukoencephalopathy, and convulsions. Also, spinal radiculopathy with intrathecal use

Renal disorders: Severe renal toxicity including renal failure, azotemia, hematuria, proteinuria, cystitis

Reproductive disorders: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction

Respiratory disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis

Skin disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis

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.

Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with:

• Penicillin or sulfonamide antibiotics
• Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines)
• Proton pump inhibitors
• Probenecid
• Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides)
• Aspirin and other nonsteroidal anti-inflammatory drugs
  Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs)
• Mercaptopurine
• Hepatotoxic products
• Weak acids (e.g., salicylates)
• Nephrotoxic products

Nitrous Oxide

Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia.

Folic Acid

Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions ( 5.12)] .

7.2 Effects of Methotrexate on Other Drugs

Theophylline

Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.

8.1 Pregnancy

Risk Summary

Methotrexate 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 Data and Clinical Pharmacology ( 12.1)] . 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 Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.4)] .

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.

8.2 Lactation

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 ( 8.1)] .

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications ( 4) and Use in Specific Populations ( 8.1)] .

Contraception

Females

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

Infertility

Females

Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that Methotrexate 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 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.

8.4 Pediatric Use

The safety and effectiveness of Methotrexate 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 ( 6.1)] . The safety and effectiveness of Methotrexate 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 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 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 Injection (Methotrexate 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 ( 5.3)] .

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/m 2) [see Warnings and Precautions ( 5.8)] .

8.5 Geriatric Use

Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal Impairment

Methotrexate elimination is reduced in patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology ( 12.3)]. Patients with renal impairment are at increased risk for methotrexate adverse reactions.

Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration ( 2.2) and Warnings and Precautions ( 5.6)]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with renal impairment as appropriate.

8.7 Hepatic Impairment

The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown Patients with hepatic impairment may be at increased risk for methotrexate adverse reaction based on elimination characteristics of methotrexate [see Clinical Pharmacology ( 12.3)]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with hepatic impairment as appropriate [see Warnings and Precautions ( 5.7)].

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

Distribution

After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 L/to 0.8 L/kg (40% to 80% of body weight).

Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved.

Methotrexate in serum is approximately 50% protein bound.

Methotrexate may be displaced from plasma albumin by various compounds, including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin.

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given intravenously, intramuscularly, or subcutaneously.

Elimination

The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2).

Following intravenous administration of high-dose methotrexate, the terminal half-life is 8 hours to 15 hours.

Metabolism

Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Methotrexate undergoes minor metabolism to 7-hydroxymethotrexate, and accumulation may become significant following high dosages. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the solubility of methotrexate.

Excretion

Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With intravenous administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose.

Enterohepatic recirculation of methotrexate has been proposed.

Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg.

Specific Populations

Pediatric Patients

In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2), or for JIA (3.75 mg/m 2 to 26.2 mg/m 2), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively [see Use in Specific Populations ( 8.4)].

Patients with Renal impairment

The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations ( 8.6)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells [see Use in Specific Populations ( 8.1, 8.2, 8.3)].

How Supplied

Methotrexate Injection is a clear, yellow, sterile solution available as preservative-free (single-dose vials) as follows.

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from light.

Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1