1.1 Acute Lymphoblastic Leukemia

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

1.2 Non-Hodgkin Lymphoma

Methotrexate Injection is indicated for the treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a combination chemotherapy regimen.

1.3 Burkitt Lymphoma

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

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 Limitations of Use

Methotrexate Injection is not indicated for non-oncology diseases.

2.1 Important Administration Information

For intravenous use only. Methotrexate Injection is available as a preservative-free solution at a concentration of 100 mg/mL. Verify the concentration prior to preparation and administration to avoid overdosage.

2.2 Recommended Monitoring and Concomitant Therapies to Promote Methotrexate Elimination and Decrease Toxicity for Intermediate- and High-Dose Regimens

• Consider leucovorin rescue for patients who will receive Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (e.g., intermediate-dose). Administer leucovorin rescue in patients who will receive Methotrexate Injection doses of 500 mg/m 2 or greater (e.g., high-dose). Refer to the leucovorin prescribing information for additional information.
• Consider the following for patients who will receive Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2. Complete the following for patients who will receive Methotrexate Injection doses of 500 mg/m 2 or greater [see Warnings and Precautions (5.3)]
  - Monitor serum creatinine and electrolytes at baseline and at least daily throughout treatment.
  - 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 urine pH of greater than 7.
  - Monitor serum methotrexate concentrations and adjust hydration and leucovorin dosage as appropriate.
  - 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

The recommended dosage of Methotrexate Injection varies from 30 mg/m 2 to 5,000 mg/m 2 intravenously as part of a combination chemotherapy regimen. Individualize the dose and schedule of Methotrexate Injection based on disease site, patient risk category, concurrent drugs, treatment phase and treatment response.

2.4 Recommended Dosage for Non-Hodgkin Lymphoma

The recommended dosage of Methotrexate Injection varies from 1,000 mg/m 2 to 3,000 mg/m 2 intravenously as part of a combination chemotherapy regimen. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs, treatment phase and treatment response.

2.5 Recommended Dosage for Burkitt Lymphoma

The recommended dosage of Methotrexate Injection varies from 1,000 mg/m 2 to 3,000 mg/m 2 intravenously as part of a combination chemotherapy regimen. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs, treatment phase and treatment response.

2.6 Recommended Dosage for Osteosarcoma

The recommended dosage of Methotrexate Injection is typically 12 grams/m 2 (maximum: 20 grams per dose) as an intravenous infusion over 4 hours followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)] . Adjust subsequent doses based on observed peak serum methotrexate concentrations as appropriate.

2.7 Dosage Modifications for Adverse Reactions

Discontinue Methotrexate Injection for

• Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.1)]
• Lymphoproliferative disease [see Warnings and Precautions (5.11)]

Withhold, dose reduce or discontinue Methotrexate Injection as appropriate for:

• Myelosuppression [see Warnings and Precautions (5.5)]

Withhold or discontinue Methotrexate Injection as appropriate for:

• Neurotoxicity [see Warnings and Precautions (5.2)]
• Severe renal toxicity [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]
• Severe gastrointestinal toxicity [see Warnings and Precautions (5.6)]
• Pulmonary toxicity [see Warnings and Precautions (5.7)]
• Severe dermatologic reactions [see Warnings and Precautions (5.8)]
• Serious infections [see Warnings and Precautions (5.9)]

2.8 Preparation

• Methotrexate Injection is available as a solution at a concentration of a 100 mg/mL. Verify the concentration prior to preparation and administration to avoid overdosage.
• Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures. 1
• Methotrexate Injection may be further diluted immediately before use with an appropriate sterile, preservative-free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate. Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity to methotrexate [see Contraindications (4), Adverse Reactions (6)] .

If anaphylaxis or another severe hypersensitivity reaction occurs, discontinue Methotrexate Injection [see Dosage and Administration (2.7)] .

5.2 Neurotoxicity

Methotrexate can cause severe acute and chronic neurotoxicity, which can be progressive, irreversible, and fatal [see Adverse Reactions (6)] .

Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with ALL who were treated with methotrexate at intravenous doses of 1,000 mg/m 2[see Use in Specific Populations (8.4)] .

Leukoencephalopathy can occur with intermediate- and high-dose regimens. The risk of leukoencephalopathy is increased with prior cranial radiation.

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

Monitor patients for neurotoxicity. Withhold or discontinue Methotrexate Injection as appropriate [see Dosage and Administration (2.7)] .

5.3 Renal Toxicity

Methotrexate can cause renal toxicity, including irreversible acute renal failure [see Adverse Reactions (6)] .

Monitor renal function at baseline, periodically during treatment, and as clinically indicated. Withhold or discontinue Methotrexate Injection for severe renal toxicity as appropriate [see Dosage and Administration (2.7)] . 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 (2.1)] .

5.4 Hepatotoxicity

Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions (6)] . The safety of Methotrexate Injection in patients with hepatic disease is unknown.

The risk of hepatotoxicity is increased with heavy alcohol consumption.

Monitor liver tests at baseline, periodically during treatment, and as clinically indicated. Withhold or discontinue Methotrexate Injection as appropriate [see Dosage and Administration (2.7)] .

5.5 Myelosuppression

Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse Reactions (6)] .

Obtain complete blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression. Withhold, dose reduce, or discontinue Methotrexate Injection as appropriate [see Dosage and Administration (2.7)] .

5.6 Gastrointestinal Toxicity

Methotrexate can cause diarrhea, vomiting, stomatitis, hemorrhagic enteritis and fatal intestinal perforation [see Adverse Reactions (6)] . Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions [see Drug Interactions (7.1)] .

Withhold or discontinue Methotrexate Injection for severe gastrointestinal toxicity as appropriate [see Dosage and Administration (2.7)] .

5.7 Pulmonary Toxicity

Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases, can occur with methotrexate [see Adverse Reactions (6)] .

Monitor patients for signs of pulmonary toxicity. Withhold or discontinue Methotrexate Injection for pulmonary toxicity as appropriate [see Dosage and Administration (2.7)] .

5.8 Dermatologic Toxicity

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)] .

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

Monitor patients for signs of dermatologic toxicity. Withhold or discontinue Methotrexate Injection for severe dermatologic reactions as appropriate [see Dosage and Administration (2.7)] . Advise patients to avoid excessive sun exposure and use sun protection measures.

5.9 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 [see Adverse Reactions (6)] .

Monitor patients for infection during and after treatment with Methotrexate Injection. Withhold or discontinue Methotrexate Injection for serious infections as appropriate [see Dosage and Administration (2.7)] .

5.10 Embryo-Fetal Toxicity

Based on published reports and its mechanism of action, Methotrexate Injection can cause fetal harm when administered to a pregnant woman.

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

5.11 Secondary Malignancies

Secondary malignancies can occur with methotrexate [see Adverse Reactions (6)] .

In some cases, lymphoproliferative disease that occurred during therapy with methotrexate regressed completely following withdrawal of methotrexate. If lymphoproliferative disease occurs, discontinue Methotrexate Injection [see Dosage and Administration (2.7)] .

5.12 Tumor Lysis Syndrome

Methotrexate can induce tumor lysis syndrome in patients with rapidly growing tumors. Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of Methotrexate Injection.

5.13 Immunization and Risks Associated with Live Vaccines

Disseminated infections following administration of live vaccines have been reported.

Administer immunizations according to current best practice guidelines prior to initiating Methotrexate Injection and then follow these guidelines for administering immunizations during treatment with Methotrexate Injection. Immunization with live vaccines is not recommended during treatment with Methotrexate Injection. The interval between live vaccines and initiation of Methotrexate Injection should be in accordance with the current best practice guidelines for patients on immunosuppressive therapies.

5.14 Increased Risk of Adverse Reactions Due to Third-Space Accumulation

Methotrexate accumulates in third-spaces (e.g., pleural effusions or ascites), which results in a prolonged elimination and increases the risk of adverse reactions. Evacuate significant third-space accumulations prior to Methotrexate Injection administration as appropriate.

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

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

5.16 Risk of Decreased Clinical Effectiveness with Folic Acid Supplementation

Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. Instruct patients not to take products containing folic acid or folinic acid unless directed to do so by their healthcare provider.

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 severe methotrexate adverse reactions. In some cases, the coadministration of methotrexate with these products may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products.

If coadministration cannot be avoided, closely monitor for methotrexate adverse reactions when coadministered with:

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 Injection. Consider alternative therapies in patients who have recently received nitrous oxide anesthesia.

Folic Acid

Coadministration of methotrexate with folic acid or its derivatives may decrease the clinical effectiveness of methotrexate. 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 (5.16)] .

8.1 Pregnancy

Risk Summary

Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)] , Methotrexate Injection can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman (see Data). There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women of the potential risk to a fetus.

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

Data

Human Data

Published data from cases, 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, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Methotrexate exposure during the second and third trimesters of pregnancy is associated with 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 per week after conception. The rate of miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with non-autoimmune disease (17%; 95% CI: 13, 23). 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, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2 Lactation

Risk Summary

Limited published literature report the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the final dose.

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 Use in Specific Populations (8.1)] .

Contraception

Females

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

Males

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

Infertility

Females

Based on published reports of female infertility after treatment 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 treatment with methotrexate, advise males of reproductive potential 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 have been established in pediatric patients for the treatment of ALL, Burkitt lymphoma and osteosarcoma [see Indications and Usage (1), Dosage and Administration (2)] . No new safety signals have been observed in pediatric patients [see Adverse Reactions (6)] .

Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with ALL who received methotrexate at intravenous doses of 1,000 mg/m 2[see Warnings and Precautions (5.2)] .

The safety and effectiveness of Methotrexate Injection have not been established in pediatric patients for non-Hodgkin lymphoma.

8.5 Geriatric Use

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

8.6 Renal Impairment

Methotrexate elimination is reduced in patients with renal impairment [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)] . 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 reactions based on the elimination characteristics of methotrexate [see Clinical Pharmacology (12.3)] . Consider reducing the dose or discontinuing Methotrexate Injection in patients with hepatic impairment as appropriate.

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.

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/kg 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 does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given intravenously.

Elimination

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 which 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 at the 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 at doses between 7.5 mg and 30 mg.

Specific Populations

Pediatric Patients

In pediatric patients receiving high-dose methotrexate for ALL (5,000 mg/m 2 administered intravenously over 24 hours), serum methotrexate level decreased from a median level of 66 µmol/L during the first 12 hours post infusion, with a median half-life of 1.8 hours (range: 1.7 h to 2.3 h).

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.