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

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Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].

•

Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection [see Contraindications (4) and Warnings and Precautions (5.1)].

•

For patients switching between a methotrexate product administered orally and Methotrexate Injection, consider potential differences in bioavailability.

2.2 Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens

To decrease the risk of severe adverse reactions [see Warnings and Precautions (5)]:

•

Administer leucovorin rescue in patients receiving Methotrexate Injection doses of 500 mg/m2 or greater (e.g., high-dose).

•

Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m2 to less than 500 mg/m2 (e.g., intermediate-dose).

Refer to the leucovorin Prescribing Information for additional information.

•

For high-dose Methotrexate Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate Injection regimens.

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Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy

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Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output

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Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher

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Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed

•

Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase Prescribing Information for additional information)

2.3 Recommended Dosage for Acute Lymphoblastic Leukemia

Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m2 intravenously. For high dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)]. Lower doses (e.g., 20 to 30 mg/m2/week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment.

2.4 Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment

Use only preservative-free Methotrexate Injection for intrathecal use.

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

The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on age:

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less than 1 year: 6 mg

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1 to less than 2 years: 8 mg

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2 to less than 3 years: 10 mg

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3 to less than 9 years: 12 mg

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greater than or equal to 9 years: 12 to15 mg

For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 or more days up to twice weekly; however, administration at intervals of less than 1 week may result in increased subacute toxicity. For meningeal leukemia prophylaxis, Methotrexate Injection is administered no more than once weekly.

For patients with Down Syndrome, administer leucovorin rescue with intrathecal Methotrexate Injection.

2.5 Recommended Dosage for Non-Hodgkin Lymphoma

The recommended dosage of Methotrexate Injection varies. When used in combination, recommended dosages range from 10 mg/m2 to 8000 mg/m2 intravenously. When used as a single agent, recommended dosages include 8,000 mg/m2 intravenously for central nervous system-directed therapy or 5 to 75 mg intravenously for cutaneous forms of Non-Hodgkin lymphoma.

As part of a combination chemotherapy regimen, a recommended dosage of Methotrexate Injection is 1,000 mg/m2 or 3,000 mg/m2 as an intravenous infusion over 24 hours followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)].

For central nervous system-directed therapy, a recommended dosage of Methotrexate Injection is 8,000 mg/m2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m2 to 8,000 mg/m2 followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)].

For intrathecal Methotrexate Injection (preservative-free), the recommended dose is based on age [see Dosage and Administration (2.4)]. The frequency of administration varies based on whether it is being used for treatment or prophylaxis, and other factors.

2.6 Recommended Dosage for Osteosarcoma

The recommended dosage of Methotrexate Injection is typically 12 g/m2 (maximum 20 g/dose) as an intravenous infusion over 4 hours administered as a component of a combination chemotherapy regimen. Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)]. Subsequent doses may need to be adjusted based on observed peak serum methotrexate concentrations. Dosage and schedule may vary based upon factors such as patient comorbidities, disease state, and prior treatments.

2.7 Recommended Dosage for Breast Cancer

A recommended dosage of Methotrexate Injection is 40 mg/m2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen.

2.8 Recommended Dosage for Squamous Cell Carcinoma of Head and Neck

The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m2 intravenously once weekly.

2.9 Recommended Dosage for Gestational Trophoblastic Neoplasia

For patients with low-risk gestational trophoblastic neoplasia (GTN) a recommended dosage for Methotrexate Injection is 30 mg/m2 to 200 mg/m2 or 0.4 mg/kg to1 mg/kg intravenously or intramuscularly.

For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m2 over 12 hours as an intravenous infusion as a component of a multi-drug regimen.

2.10 Recommended Dosage for Rheumatoid Arthritis

The recommended starting dosage of Methotrexate Injection is 7.5 mg once weekly, administered intramuscularly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression.

When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12)].

2.11 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis

The recommended starting dosage of Methotrexate Injection is 10 mg/m2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/ m2 per week may result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12)].

2.12 Recommended Dosage for Psoriasis

The recommended dosage of Methotrexate Injection is 10 mg to 25 mg intramuscularly or intravenously once weekly until adequate response is achieved.

Adjust the dose gradually to achieve optimal clinical response; do not exceed 25 mg per week. Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen.

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12)].

2.13 Dosage Modifications for Adverse Reactions

Discontinue Methotrexate Injection for:

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Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.2)]

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Lymphoproliferative disease [see Warnings and Precautions (5.13)]

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

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Myelosuppression [see Warnings and Precautions (5.4)]

Withhold or discontinue Methotrexate Injection as appropriate for:

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Serious infections [see Warnings and Precautions (5.5)]

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Renal toxicity [see Warnings and Precautions (5.6)]

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Hepatotoxicity [see Warnings and Precautions (5.7)]

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Neurotoxicity [see Warnings and Precautions (5.8)]

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Gastrointestinal toxicity [see Warnings and Precautions (5.9)]

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Pulmonary toxicity [see Warnings and Precautions (5.10)]

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Dermatologic reactions [see Warnings and Precautions (5.11)]

2.14 Administration and Handling Information

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

With preservative (multiple-dose vial)

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50 mg/2 mL (25 mg/mL)

Preservative-free (single-dose vial)

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1 g/40 mL (25 mg/mL)

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 [see Use in Specific Populations (8.1)].

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.

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.

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.

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.

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

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.

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

General disorders and administration site conditions: Injection site necrosis, injection site reaction

7.1 Effects of Other Drugs on Methotrexate

7.2 Effects of Methotrexate on Other Drugs

8.1 Pregnancy

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)].

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.

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)].

Manifestations

Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5.19)].

Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported.

Manifestations of intrathecal overdosage include CNS symptoms (e.g., headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy). In some cases, no symptoms were reported; however, cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported.

Management

Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin prescribing information). Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure.

Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information). If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.

Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

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

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 with preservative (multiple-dose vials) and preservative-free (single-dose vials) as follows:

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light.

After first puncture, store multiple-dose vials at 2°C to 8°C, and use within 30 days.

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

Embryo-Fetal Toxicity

•

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)].

•

Advise females of reproductive potential to use effective contraception during methotrexate therapy and for 6 months after the final dose [see Use in Specific Populations (8.3)].

•

Advise males of reproductive potential to use effective contraception during methotrexate therapy and for 3 months after the final dose [see Use in Specific Populations (8.3)].

Hypersensitivity Reactions

Advise patients of the potential risk of hypersensitivity and that Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity to methotrexate. Advise patients to seek immediate medical attention if signs or symptoms of a hypersensitivity reaction occur [see Warnings and Precautions (5.2)].

Myelosuppression and Serious Infections

Advise patient to contact their healthcare provider immediately for new onset fever, symptoms of infection, easy bruising or persistent bleeding [see Warnings and Precautions (5.4, 5.5)].

Renal Toxicity

Advise patients that methotrexate can cause renal toxicity. Advise patients to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions (5.6)].

Hepatotoxicity

Advise patients to report signs or symptoms of hepatic toxicity and avoidance of alcohol during methotrexate treatment [see Warnings and Precautions (5.7)].

Neurotoxicity

Advise patient to contact their healthcare provider immediately if they develop new neurological symptoms [see Warnings and Precautions (5.8)].

Gastrointestinal Toxicity

Advise patients to contact their healthcare provider if they develop diarrhea, vomiting, or stomatitis. Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see Warnings and Precautions (5.9)].

Pulmonary Toxicity

Advise patients to contact their healthcare provider for symptoms of cough, fever, and dyspnea [see Warnings and Precautions (5.10)].

Dermatologic Toxicity

Advise patients that Methotrexate Injection can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash. Advise patients to avoid excessive sun exposure and to use sun protection measures [see Warnings and Precautions (5.11)].

Secondary Malignancies

Advise patients on the risk of second primary malignancies during treatment with Methotrexate Injection [see Warnings and Precautions (5.13)].

Lactation

Advise women not to breastfeed during treatment with methotrexate and for 1 week after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential that methotrexate may cause impairment of fertility [see Use in Specific Populations (8.3)].

Drug Interactions

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Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

•

Instruct patients being treated for neoplastic indication to not take products containing folic acid or folinic acid unless directed to do so by their healthcare provider [see Warnings and Precautions (5.12)].