Methotrexate

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

  [see

  4 CONTRAINDICATIONS

  Methotrexate tablets

  are

  contraindicated in:

  • Pregnant women receiving methotrexate tablets for treatment
    of
    non-neoplastic diseases
    [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]
    .
  • Patients with a history of a severe hypersensitivity reactions, including anaphylaxis, to methotrexate.
    [see Warnings and Precautions (5.2)].

  • In pregnancy for non-neoplastic diseases
  • History of severe hypersensitivity to methotrexate

  ,

  5.1 Embryo-Fetal Toxicity

  Based on published reports and its mechanism of action, methotrexate tablets can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate tablets are contraindicated for use

  in

  pregnant women receiving methotrexate tablets for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate tablets treatment and for 3 months after the final dose

  [see Contraindications (4), Use in Specific Populations (8.1, 8.3)].

  ,

  8.1 Pregnancy

  Risk Summary

  
  
  

  Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases

  [see Contraindications (4)].

  
  
  

  Based on published reports and its mechanism of action

  [see Clinical Pharmacology (12.1)]

  , methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. 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.

  
  
  

  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, central nervous system 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 and 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 nonautoimmune 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]) (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

  [ Use in Specific Populations (8.1)].

  
  
  

  Pregnancy Testing

  
  
  

  Verify the pregnancy status of females of reproductive potential prior to initiating methotrexate tablets

  [see Contraindications (4), Use in Specific Populations (8.1)].

  
  
  

  Contraception

  
  
  

  Females

  
  
  

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

  
  
  

  Males

  
  
  

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

  
  
  

  Infertility

  
  
  

  Females

  
  
  

  Based on published reports of female infertility after methotrexate, advise females of reproductive potential that methotrexate can cause impairment of fertility and menstrual dysfunction during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected females.

  
  
  

  Males

  
  
  

  Based on published reports of male infertility after methotrexate, advise males that methotrexate can cause oligospermia or infertility during treatment with methotrexate tablets and after the final dose. It is not known if the infertility may be reversed in all affected males.

  ]

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

  [

  4 CONTRAINDICATIONS

  Methotrexate tablets

  are

  contraindicated in:

  • Pregnant women receiving methotrexate tablets for treatment
    of
    non-neoplastic diseases
    [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]
    .
  • Patients with a history of a severe hypersensitivity reactions, including anaphylaxis, to methotrexate.
    [see Warnings and Precautions (5.2)].

  • In pregnancy for non-neoplastic diseases
  • History of severe hypersensitivity to methotrexate

  ,

  5.2 Hypersensitivity Reactions

  Hypersensitivity reactions, including anaphylaxis,

  can

  occur with methotrexate

  [see Contraindications (4), Adverse Reactions (6.1)].

  If anaphylaxis or other serious hypersensitivity

  reaction

  occurs, immediately and permanently discontinue methotrexate tablets

  [see Dosage and Administration (2.6)].

  ]

  .
•  
  Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate

  [

  5.3 Myelosuppression

  Methotrexate suppresses hematopoiesis and can cause severe

  and

  life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia

  [see Adverse Reactions (6.1)]

  .

  
  
  

  Obtain blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression. Withhold, dose reduce, or discontinue methotrexate tablets taking into account

  the

  importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy

  [see Dosage and Administration (2.6)].

  ,

  5.4 Gastrointestinal Toxicity

  Diarrhea, vomiting,

  nausea

  , and stomatitis occurred in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported

  [see Adverse Reactions (6.1, 6.2)]

  . 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 tablets for severe gastrointestinal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity

  of

  the adverse drug reaction, and availability of alternative therapy

  [see Dosage and Administration (2.6)]

  .

  ,

  5.5 Hepatotoxicity

  Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure

  [see Adverse Reactions (6.1)]

  . The safety of methotrexate tablets in patients with hepatic disease is unknown.

  
  
  

  The risk of hepatotoxicity is increased with heavy alcohol consumption. In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver tests; 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.

  
  
  

  Monitor liver tests at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy

  [see Dosage and Administration (2.6)]

  .

  ,

  5.6 Pulmonary Toxicity

  Pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases,

  can

  occur with methotrexate

  [see Adverse Reactions (6.1, 6.2)]

  .

  
  
  

  Monitor patients for pulmonary toxicity and withhold or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity

  of

  the adverse drug reaction, and availability of alternative therapy

  [see Dosage and Administration (2.6)]

  .

  ,

  5.7 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)].

  
  
  

  Exposure

  to

  ultraviolet radiation while taking methotrexate may aggravate psoriasis.

  
  
  

  Methotrexate can cause radiation recall dermatitis

  and

  photodermatitis (sunburn) reactivation.

  Monitor patients for dermatologic toxicity and withhold or permanently discontinue methotrexate tablets for severe dermatologic reactions taking into account the importance of methotrexate tablet treatment in the context of the severity

  of

  the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy

  [see Dosage and Administration (2.6)]

  . Advise patients to avoid excessive sun exposure and use sun protection measures.

  ,

  5.8 Renal Toxicity

  Methotrexate

  can

  cause renal toxicity, including irreversible acute renal failure

  [see Adverse Reactions (6.2)].

  
  
  

  Monitor renal function at baseline, periodically during treatment and as clinically indicated. Withhold or discontinue methotrexate tablets for severe renal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity

  of

  the adverse drug reaction, and availability of alternative therapy

  [see Dosage and Administration (2.6)].

  
  
  

  Administer glucarpidase in patients with 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.

  ].

Boxed Warning                                                                          5/2020

Indications and Usage (

Dosage and Administration (

Contraindications (

Warnings and Precautions (

Methotrexate tablets are a dihydrofolate reductase inhibitor indicated for the:

• Treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen (
  1.1 Neoplastic Diseases

  Methotrexate tablets

  are

  indicated for the:

  • treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL)
    as
    part of a combination chemotherapy maintenance regimen
  • treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent
    or
    as part of a combination chemotherapy regimen.
  • treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part
    of
    a metronomic combination chemotherapy regimen
  )
• Treatment of adults with mycosis fungoides (
  1.1 Neoplastic Diseases

  Methotrexate tablets

  are

  indicated for the:

  • treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL)
    as
    part of a combination chemotherapy maintenance regimen
  • treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent
    or
    as part of a combination chemotherapy regimen.
  • treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part
    of
    a metronomic combination chemotherapy regimen
  )
• Treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a metronomic combination regimen (
  1.1 Neoplastic Diseases

  Methotrexate tablets

  are

  indicated for the:

  • treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL)
    as
    part of a combination chemotherapy maintenance regimen
  • treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent
    or
    as part of a combination chemotherapy regimen.
  • treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part
    of
    a metronomic combination chemotherapy regimen
  )
• Treatment of adults with rheumatoid arthritis (
  1.2 Rheumatoid Arthritis

  Methotrexate tablets are indicated for the treatment

  of

  adults with rheumatoid arthritis.
  )
• Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) (
  1.3 Polyarticular Juvenile Idiopathic Arthritis

  Methotrexate tablets are indicated for the treatment

  of

  pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).
  )
• Treatment of adults with severe psoriasis (
  1.4 Psoriasis

  Methotrexate tablets are indicated

  for

  the treatment of adults with severe psoriasis.
  )

• Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. (
  2.1 Important Dosage and Safety Information

  Verify pregnancy status in females

  of

  reproductive potential before starting methotrexate tablets

  [see Contraindications (4), Warnings and Precautions (5.1)].

  
  
  

  Instruct patients and caregivers

  to

  take the recommended dosage as directed, because medication errors have led to deaths

  [see Warnings and Precautions (5.9)].

  
  
  

  When switching the dosing regimen from oral administration

  to

  intravenous, intramuscular, or subcutaneous administration, an alternative dosing regimen may be necessary.

  
  
  

  Do not administer to patients who are unable

  to

  swallow a tablet.

  
  
  

  Methotrexate tablet

  is

  a cytotoxic drug. Follow applicable special handling and disposal procedures.¹
  ,
  5.9 Risk of Serious Adverse Reactions with Medication Error

  Deaths occurred in patients as a result of medication errors. Most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed.

  
  
  

  For patients prescribed a once weekly dosing regimen, instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to death.
  )
• Verify pregnancy status in females of reproductive potential before starting methotrexate tablets (
  4 CONTRAINDICATIONS

  Methotrexate tablets

  are

  contraindicated in:

  • Pregnant women receiving methotrexate tablets for treatment
    of
    non-neoplastic diseases
    [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]
    .
  • Patients with a history of a severe hypersensitivity reactions, including anaphylaxis, to methotrexate.
    [see Warnings and Precautions (5.2)].

  • In pregnancy for non-neoplastic diseases
  • History of severe hypersensitivity to methotrexate
  ,
  5.1 Embryo-Fetal Toxicity

  Based on published reports and its mechanism of action, methotrexate tablets can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate tablets are contraindicated for use

  in

  pregnant women receiving methotrexate tablets for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate tablets treatment and for 3 months after the final dose

  [see Contraindications (4), Use in Specific Populations (8.1, 8.3)].
  ).
• ALL
  : The recommended dosage is 20 mg/m² orally once weekly as a part of a combination chemotherapy maintenance regimen. (
  2.2 Recommended Dosage for Neoplastic Diseases

  Acute Lymphoblastic

  Leukemia

  
  
  

  The recommended starting dosage

  of

  methotrexate tablets is 20 mg/m²orally once weekly, as part of a combination chemotherapy maintenance regimen. After initiating methotrexate tablets, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dose to maintain ANC at a desirable level and for excessive myelosuppression.

  
  
  

  Mycosis

  Fungoides

  
  
  

  The recommended dosage of methotrexate tablets is 25 mg

  to

  75 mg orally once weekly when administered as a single agent or 10 mg/m²orally twice weekly as part of a combination chemotherapy regimen.

  
  
  

  Relapsed or Refractory

  Non

  -Hodgkin Lymphomas

  
  
  

  The recommended dosage of methotrexate tablets is 2.5 mg orally 2

  to

  4 times per week (maximum 10 mg per week) as part of a metronomic combination chemotherapy regimen.
  )
• Mycosis fungoides
  : The recommended dosage is 25 to 75 mg orally once weekly as monotherapy; 10 mg/m² orally twice weekly as part of combination chemotherapy. (
  2.2 Recommended Dosage for Neoplastic Diseases

  Acute Lymphoblastic

  Leukemia

  
  
  

  The recommended starting dosage

  of

  methotrexate tablets is 20 mg/m²orally once weekly, as part of a combination chemotherapy maintenance regimen. After initiating methotrexate tablets, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dose to maintain ANC at a desirable level and for excessive myelosuppression.

  
  
  

  Mycosis

  Fungoides

  
  
  

  The recommended dosage of methotrexate tablets is 25 mg

  to

  75 mg orally once weekly when administered as a single agent or 10 mg/m²orally twice weekly as part of a combination chemotherapy regimen.

  
  
  

  Relapsed or Refractory

  Non

  -Hodgkin Lymphomas

  
  
  

  The recommended dosage of methotrexate tablets is 2.5 mg orally 2

  to

  4 times per week (maximum 10 mg per week) as part of a metronomic combination chemotherapy regimen.
  )
• Relapsed or refractory non-Hodgkin lymphoma
  : The recommended dosage is 2.5 mg orally two to four times per week as part of metronomic combination chemotherapy. (
  2.2 Recommended Dosage for Neoplastic Diseases

  Acute Lymphoblastic

  Leukemia

  
  
  

  The recommended starting dosage

  of

  methotrexate tablets is 20 mg/m²orally once weekly, as part of a combination chemotherapy maintenance regimen. After initiating methotrexate tablets, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dose to maintain ANC at a desirable level and for excessive myelosuppression.

  
  
  

  Mycosis

  Fungoides

  
  
  

  The recommended dosage of methotrexate tablets is 25 mg

  to

  75 mg orally once weekly when administered as a single agent or 10 mg/m²orally twice weekly as part of a combination chemotherapy regimen.

  
  
  

  Relapsed or Refractory

  Non

  -Hodgkin Lymphomas

  
  
  

  The recommended dosage of methotrexate tablets is 2.5 mg orally 2

  to

  4 times per week (maximum 10 mg per week) as part of a metronomic combination chemotherapy regimen.
  )
• Rheumatoid Arthritis
  : The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response (
  2.3 Recommended Dosage for Rheumatoid Arthritis

  The recommended starting dosage of methotrexate tablets is 7.5 mg orally once weekly 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 (5.10)].
  )
• pJIA
  : The recommended starting dosage is 10 mg/m² orally once weekly; adjust dose to achieve an optimal response (
  2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis

  The recommended starting dosage of methotrexate tablets is 10 mg/m²orally once weekly with escalation to achieve optimal response. Dosages of more than 30 mg/m²once 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 (5.10)].
  )
• Psoriasis
  : The recommended dosage is 10 to 25 mg orally once weekly until adequate response is achieved. (
  2.5 Recommended Dosage for Psoriasis

  The recommended dosage of methotrexate tablets is 10 mg to 25 mg orally once weekly until an adequate response is achieved. Adjust the dose gradually to achieve optimal clinical response; do not exceed

  a

  dose of 30 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 supplementation to reduce the risk

  of

  methotrexate adverse reactions

  [see Warnings and Precautions (5.10)].
  )

Methotrexate tablets USP, 2.5 mg are round, convex, yellow