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Methotrexate Vial Warnings and Precautions

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

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

Methotrexate 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)].

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.

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.

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.

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.

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.

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.

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