Methotrexate

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

  [see

  4 CONTRAINDICATIONS

  Methotrexate Injection is contraindicated in:

  • Patients with history of severe hypersensitivity to methotrexate
    [see Warnings and Precautions (5.2)]
    .
  • Pregnancy in patients with non-neoplastic diseases
    [see Warnings and Precautions (5.1)and Use in Specific Populations (8.1)]
    .

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

  ,

  5.1 Embryo-Fetal Toxicity

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

  Methotrexate 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)]

  .

  , and

  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 Dataand 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 to 4% and 15 to 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 to 58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8 to 29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13 to 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 to 5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03 to 9.5]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

  ,

  8.3 Females and Males of Reproductive Potential

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

  [see Use in Specific Populations (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.

  ]

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

  [see

  4 CONTRAINDICATIONS

  Methotrexate Injection is contraindicated in:

  • Patients with history of severe hypersensitivity to methotrexate
    [see Warnings and Precautions (5.2)]
    .
  • Pregnancy in patients with non-neoplastic diseases
    [see Warnings and Precautions (5.1)and Use in Specific Populations (8.1)]
    .

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

  and

  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)]

  .

  ].
• Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. 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

  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)].
  • 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

    .

  and

  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.

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

  [see

  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.

  ].

The following adverse reactions are described, or described in greater detail, in other sections:

• Hypersensitivity Reactions
  [see

  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)]

  .

  ]
• Myelosuppression
  [see

  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.

  ]
• Serious Infections
  [see

  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

  .

  ]
• Renal Toxicity
  [see

  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)]

  .

  ]
• Hepatotoxicity
  [see

  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.

  ]
• Neurotoxicity
  [see

  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)].

  ]
• Gastrointestinal Toxicity
  [see

  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.

  ]
• Pulmonary Toxicity
  [see

  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.

  ]
• Dermatologic Reactions
  [see

  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.

  ]
• Secondary Malignancies
  [see

  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.

  ]
• Tumor Lysis Syndrome
  [see

  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.

  ]
• Increased Risk of Adverse Reactions due to Third Space Accumulation
  [see

  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)].

  ]

Methotrexate is a folate analog metabolic inhibitor with the chemical name of

Preservative-free Methotrexate Injection, USP is supplied in sterile single-dose vials for intravenous, intramuscular, subcutaneous, or intrathecal use.

• Each 25 mg/mL, 2 mL vial contains 50 mg methotrexate, USP equivalent to 54.8 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 9.8 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 2 mL solution contains approximately 0.43 mEq of sodium per vial and is an isotonic solution.
• Each 25 mg/mL, 4 mL vial contains 100 mg methotrexate, USP equivalent to 109.7 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 19.6 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 4 mL solution contains approximately 0.86 mEq of sodium per vial and is an isotonic solution.
• Each 25 mg/mL, 8 mL vial contains 200 mg methotrexate, USP equivalent to 219.3 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 39.2 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 8 mL solution contains approximately 1.72 mEq of sodium per vial and is an isotonic solution.
  
  
• Each 25 mg/mL, 10 mL vial contains 250 mg methotrexate, USP equivalent to 274.2 mg of methotrexate sodium, and the following inactive ingredients: sodium chloride 49 mg. May contain sodium hydroxide and/or hydrochloric acid to adjust the pH to 8.5. The 10 mL solution contains approximately 2.15 mEq of sodium per vial and is an isotonic solution.

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.