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  • CLASSES

    Antipsoriatic Monoclonal Antibodies and Others
    Folic Acid Analogs
    Other Immunosuppressants
    Other Specific Antirheumatics

    BOXED WARNING

    Serious rash

    Serious rash and occasionally fatal dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Recovery has been reported with methotrexate discontinuation. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue methotrexate depending on the severity of the reaction.

    Radiation therapy, sunburn, sunlight (UV) exposure

    Methotrexate is a radiation sensitizer. Methotrexate given concurrently with radiation therapy may increase the risk of soft tissue necrosis and osteonecrosis. Prior or concurrent cranial irradiation has been associated with an increased risk of leukoencephalopathy. Psoriasis lesions may be aggravated by the concurrent use of methotrexate and ultraviolet radiation therapy. Patients with prior radiation dermatitis or sunburn may experience recall reactions during methotrexate therapy. Due to methotrexate-induced photosensitivity, patients should wear protective clothing and use sunscreen during sunlight (UV) exposure. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue methotrexate depending on the severity of the reaction.

    Anemia, aplastic anemia, bone marrow suppression, infection, leukopenia, neutropenia, thrombocytopenia

    Methotrexate causes bone marrow suppression including neutropenia which can be severe and life-threatening; unexpectedly severe and sometimes fatal bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate along with some nonsteroidal anti-inflammatory drugs. Treatment with Otrexup or Rasuvo is contraindicated in patients with pre-existing blood dyscrasias (e.g. bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia) and should be used with caution, if at all, in patients with pre-existing hematopoietic impairment.  Methotrexate should be used with extreme caution in the presence of active infection; potentially fatal infection may also occur with methotrexate therapy including opportunistic infections and reactivation of latent viral infections; if a patient presents with pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia should be considered. Obtain blood counts at baseline and at least monthly during treatment; monitor more frequently during initial dosing, dose changes, or during periods of increased risk of elevated methotrexate blood levels. Monitor patients for possible clinical complications of myelosuppression including signs and symptoms of infection. Provide supportive care, withhold treatment, reduce the dose, or discontinue methotrexate as clinically appropriate; subcutaneous formulations of methotrexate should be stopped immediately if there is a significant drop in blood counts. Withhold or discontinue methotrexate in patients who develop serious infections.

    Requires an experienced clinician

    Administration of methotrexate requires an experienced clinician whose knowledge and experience include the use of antimetabolite therapy due to the potential for serious or fatal adverse reactions. Subcutaneous methotrexate should only be used in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Toxic effects may be related in frequency and severity to dose or frequency of administration, but have been seen at all doses and can occur at any time during therapy; most adverse reactions are reversible if detected early and appropriate corrective measures are taken, although deaths have been reported. Patients should be closely monitored for toxicities and should be informed by their physician of the risks involved in treatment. In patients receiving high-dose IV methotrexate, administer IV fluids and urine alkalinization before the first dose, continuing throughout treatment, to maintain adequate hydration and urine output as well as a urinary pH of 7 or higher. Administer leucovorin rescue in all patients receiving methotrexate injection at doses greater than 500 mg/m2, and consider the use of leucovorin for patients receiving doses between 100 mg/m2 to 400 mg/m2. Monitor methotrexate concentrations at baseline and periodically (every 1 to 2 months) during treatment with subcutaneous or oral administration; monitor methotrexate levels at least daily in patients receiving high-dose IV methotrexate, adjusting hydration and leucovorin dosing as needed. Consider the use of glucarpidase in patients who have toxic plasma methotrexate concentrations (greater than 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function.

    Diabetes mellitus, hypoalbuminemia, pulmonary disease, pulmonary toxicity, tobacco smoking

    Methotrexate therapy can produce potentially fatal pulmonary toxicity including acute or chronic interstitial pneumonitis. Risk factors in rheumatoid arthritis patients include diabetes mellitus, older age, rheumatoid pleuropulmonary involvement, and previous use of the disease modifying drugs sulfasalazine, gold, or penicillamine; and hypoalbuminemia; in nondiabetic patients, hypoalbuminemia and previous use of disease modifying drugs are the most important risk factors. A history of pulmonary disease, extra-articular manifestations of rheumatoid arthritis, tobacco smoking (men only), and non-sedentary occupations (women only) have also been suggested as risk factors for methotrexate-induced pulmonary toxicity. Methotrexate-induced lung disease may occur acutely at any time during therapy, has been reported at all dose levels, and is not always fully reversible. Obtain a chest x-ray at baseline. Pulmonary function tests may be useful if toxicity is suspected, especially if baseline measurements are available. Monitor patients for signs of pulmonary toxicity. Pulmonary symptoms (especially a dry, nonproductive cough) or a nonspecific pneumonitis may require treatment interruption or discontinuation and careful investigation; additional symptoms include fever, dry cough, dyspnea, hypoxemia, and radiographic evidence of pulmonary infiltrates.

    Alcoholism, hepatic disease, hepatitis, hepatotoxicity, hyperlipidemia, obesity

    Methotrexate is metabolized by the liver and undergoes enterohepatic circulation. Treatment with Otrexup or Rasuvo is contraindicated in patients with alcoholism, alcoholic liver disease, or other chronic hepatic disease.  Avoid the use of other formulations of methotrexate in patients with chronic liver disease unless the benefits clearly outweigh the risks; the safety of methotrexate in patients with liver disease is unknown.  Methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and liver failure but generally only after prolonged use (2 years or more). Risk factors for hepatotoxicity include alcoholism, obesity, diabetes mellitus, steatohepatitis, hyperlipidemia, previous significant exposure to liver toxins, family history of inheritable liver disease, duration of therapy, and advanced age. In rheumatoid arthritis (RA) patients, age at first use of methotrexate and duration of methotrexate therapy have been reported as risk factors for hepatotoxicity; previously mentioned risk factors may also have a role. In general, monitor liver function tests (LFTs) and albumin at baseline and every 1 to 2 months during treatment; increase the frequency of monitoring when initiating or changing therapy, or during periods of increased risk of elevated methotrexate levels. Interrupt or discontinue methotrexate treatment as clinically appropriate. Acutely, liver enzyme elevations are frequently seen, but elevations are usually transient, asymptomatic, and do not usually require modification of methotrexate therapy or appear to be predictive of subsequent hepatic disease. Persistent abnormalities and/or hypoalbuminemia may be indicators of serious hepatotoxicity and require further evaluation as they may precede fibrosis or cirrhosis.   However, in patients with psoriasis, LFTs and albumin are often normal despite developing fibrosis or cirrhosis which may be detectable only by biopsy; for this reason, periodic liver biopsies are recommended for psoriatic patients undergoing long-term treatment. Hepatotoxicity in these patients appears to be a function of the cumulative dose and generally occurs after a cumulative dose of 1.5 g or more. Manufacturer recommendations for liver biopsy in psoriatic patients are to obtain biopsies prior to therapy or shortly after initiating therapy (i.e., within 2 to 4 months), at a methotrexate cumulative dose of 1.5 g, and after each additional 1 to 1.5 g of methotrexate.  However, psoriasis guidelines suggest that every 3.5 to 4 g instead of 1 to 1.5 g of cumulative methotrexate may be a more appropriate interval for liver biopsy in patients without preexisting risk factors for hepatotoxicity.   The joint American Academy of Dermatology and National Psoriasis Foundation guidelines recommend a noninvasive assessment of liver fibrosis (e.g., serologic tests and liver stiffness assessment by transient elastography) at baseline rather than a liver biopsy, regardless of the presence of risk factors. Consider a GI or hepatology consult or imaging with vibration-controlled transient elastography, or both, for abnormal baseline laboratory results or risk factors for fibrosis; an annual GI/hepatology consult and/or vibration-controlled transient elastography should occur if methotrexate is continued despite abnormal baseline results. Moderate fibrosis or any cirrhosis should lead to discontinuation of the methotrexate; mild fibrosis normally suggests a repeat biopsy at 6 months. Pretreatment liver biopsy should be performed in RA patients with a history of excessive alcohol consumption, persistently abnormal baseline LFTs, or chronic hepatitis B or C infection. During treatment of rheumatoid arthritis, liver biopsy should be performed if there are persistent LFT abnormalities or if there is a decrease in serum albumin below the normal range (in the setting of well-controlled rheumatoid arthritis). Methotrexate may be continued with monitoring for RA patients if the liver biopsy shows mild changes (Roenigk grades I, II, or IIIa); it should be discontinued in any patient with persistently abnormal LFTs who refuses liver biopsy, or in patients with moderate to severe changes on biopsy (Roenigk grade IIIb or IV).

    Dehydration, nephrotoxicity, renal disease, renal failure, renal impairment

    Methotrexate is eliminated primarily by the kidney and clearance is dependent on dosage and route of administration. Patients who have renal impairment or renal disease or are receiving concurrent nephrotoxic drugs are at risk for increased toxicity due to prolonged elevated methotrexate serum concentrations. Irreversible acute renal failure and nephrotoxicity may occur following high-dose intravenous (IV) methotrexate therapy, although it has also been reported in patients receiving subcutaneous and oral administration of methotrexate. Nephrotoxicity is primarily caused by the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Obtain renal function tests at baseline and monitor for toxicity in all patients who are receiving methotrexate; a dose reduction or discontinuation of methotrexate therapy may be necessary in patients with renal impairment or in patients experiencing nephrotoxicity. Monitor renal function periodically during treatment (e.g., every 1 to 2 months) and as clinically indicated in patients receiving oral or subcutaneous formulations of methotrexate and more frequently when initiating or changing therapy or in patients with conditions that might increase the risk of elevated methotrexate levels (e.g., dehydration).  In patients receiving high-dose IV methotrexate, alkalinize the urine before the first dose, continuing throughout treatment to maintain a urinary pH of 7 or higher; this pH is necessary to prevent precipitation of methotrexate or its metabolites in the renal tubules. Administer hydration and leucovorin rescue as recommended. Monitor serum creatinine and electrolytes at baseline and at least daily during therapy; also monitor methotrexate concentrations at least daily, adjusting hydration and leucovorin dosing as needed. Consider the use of glucarpidase in patients who have toxic plasma methotrexate concentrations (greater than 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, effective methotrexate clearance has been reported with acute, intermittent hemodialysis using a high-flux filter.

    Ascites, pleural effusion

    Methotrexate elimination is reduced in patients with third space effusions (e.g., ascites or pleural effusion) and methotrexate levels may be elevated for a prolonged period resulting in increased toxicity. Remove significant third space fluid prior to treatment. Carefully monitor such patients for toxicity; a dose reduction or discontinuation of therapy may be necessary.

    Tumor lysis syndrome (TLS)

    Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome (TLS) in patients with rapidly growing tumors. Institute appropriate treatment for prevention and management of TLS prior to starting treatment with methotrexate.

    Diarrhea, gastrointestinal toxicity, GI disease, peptic ulcer disease, stomatitis, ulcerative colitis

    Methotrexate should be used with extreme caution in patients with GI disease such as peptic ulcer disease or ulcerative colitis as they are at greater risk of developing severe gastrointestinal toxicity. Interrupt or discontinue methotrexate for severe gastrointestinal toxicity including diarrhea and ulcerative stomatitis and begin appropriate supportive care; otherwise, hemorrhagic enteritis and death from GI perforation may occur. Also interrupt therapy for vomiting or other toxicities which may result in dehydration. Unexpectedly severe, sometimes fatal gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) and some nonsteroidal anti-inflammatory drugs (NSAIDs).   

    Benzyl alcohol hypersensitivity, ensure correct formulation selection, intrathecal administration, neonates

    Ensure correct formulation selection of preservative-free methotrexate injection for intrathecal administration, administration to neonates or low-birth weight infants, and administration to patients with known benzyl alcohol hypersensitivity; do not use benzyl alcohol-containing formulations for high-dose methotrexate regimens unless immediate treatment is required and preservative-free formulations are not available. Benzyl alcohol is present in preservative-containing injection formulations and can cause severe central nervous system toxicity or metabolic acidosis. Fatal gasping syndrome (including symptoms of gasping respiration, hypotension, bradycardia, and cardiovascular collapse) has been reported in neonates who received IV solutions containing benzyl alcohol. High-dose therapy is indicated for osteosarcoma; leucovorin rescue and careful monitoring are necessary. Hold subsequent methotrexate doses until hematologic parameters, hepatic function, and renal function have recovered.

    New primary malignancy

    A new primary malignancy, specifically malignant lymphomas or other lymphoproliferative disease, may occur in patients treated with methotrexate at all dose levels. Lymphoproliferative disease that occurs during therapy with low-dose methotrexate may completely regress following withdrawal of methotrexate and thus, may not require cytotoxic treatment. Discontinue methotrexate if lymphoproliferative disease occurs; if it does not regress, institute appropriate treatment.

    Neurotoxicity

    Methotrexate can cause severe acute and chronic neurotoxicity including leukoencephalopathy which can be progressive, irreversible, and fatal; generalized and focal seizures have occurred in pediatric patients. Prior or concurrent cranial irradiation has been associated with an increased risk of leukoencephalopathy. Monitor patients for signs of neurotoxicity and withhold or discontinue treatment with methotrexate when appropriate. Avoid the intrathecal use of methotrexate injection that contains benzyl alcohol due to the risk of serious neurotoxicity.

    Intrauterine fetal death, pregnancy

    Methotrexate is contraindicated for use during pregnancy in women who are being treated for nonmalignant diseases (e.g., psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis). Pregnancy should be avoided by females of reproductive potential during methotrexate treatment and for at least 6 months after the last dose; however, because the benzyl alcohol preservative can cross the placenta, use the preservative-free formulation of IV methotrexate if treatment of a neoplastic disease is necessary during pregnancy. Methotrexate can cause intrauterine fetal death and/or congenital anomalies when administered to pregnant women based on case reports, literature reviews, and observational studies. Women who are pregnant or who become pregnant while receiving methotrexate should be apprised of the potential hazard to the fetus. Exposure to methotrexate during the first trimester of pregnancy in women has been associated with an increased incidence of spontaneous abortions and congenital anomalies, including facial dysmorphism, central nervous system abnormalities, skull anomalies, intellectual impairment, and cardiac anomalies. Intrauterine growth restriction and functional abnormalities have been reported with methotrexate exposures in the second and third trimesters. In a prospective multicenter study, the rate of spontaneous abortion/miscarriage in pregnant women exposed to 30 mg per week or less of methotrexate was 42.5% compared to 22.5% in unexposed patients with autoimmune disease and 17.3% in unexposed patients with non-autoimmune disease. Of the live births, the rate of major birth defects was higher in women exposed to methotrexate after conception than in unexposed patients with autoimmune disease (adjusted odds ratio [OR], 1.8) and unexposed patients with non-autoimmune disease (adjusted OR, 3.1); major birth defects associated with methotrexate-exposed pregnancies were not always consistent with methotrexate-associated adverse developmental outcomes. 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.

    Contraception requirements, infertility, male-mediated teratogenicity, menstrual irregularity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during methotrexate treatment. Pregnancy testing should be performed before starting methotrexate in female patients of reproductive potential. These patients should use effective contraception during methotrexate therapy and for at least 6 months after the final methotrexate dose. Women who become pregnant while receiving methotrexate should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during methotrexate therapy and for at least 3 months after the final methotrexate dose due to the risk of male-mediated teratogenicity; methotrexate may cause chromosomal damage to sperm cells. Methotrexate may cause infertility; oligospermia in men and menstrual irregularity or dysfunction in women have been reported during methotrexate therapy and after stopping therapy. It is not known whether infertility is reversible in affected female or male patients.

    DEA CLASS

    Rx

    DESCRIPTION

    Folate antimetabolite
    Used for malignant (e.g., breast cancer, non-Hodgkin lymphoma, ALL) and nonmalignant diseases (e.g., rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis); intrathecal methotrexate used for prophylaxis and treatment of meningeal leukemia
    Use is contraindicated in patients with a nonmalignant diagnosis who are pregnant; due to the potential for serious or fatal adverse reactions, treatment with methotrexate requires an experienced physician

    COMMON BRAND NAMES

    Otrexup, Rasuvo, Rheumatrex, Trexall, Xatmep

    HOW SUPPLIED

    Methotrexate Sodium Intra-Arterial Inj Pwd F/Sol: 1g
    Methotrexate Sodium Intra-Arterial Inj Pwd: 1g
    Methotrexate Sodium Intra-Arterial Inj Sol: 1mL, 25mg
    Methotrexate Sodium Intra-Arterial Sol: 1mL, 25mg
    Methotrexate Sodium Intramuscular Inj Pwd F/Sol: 1g
    Methotrexate Sodium Intramuscular Inj Pwd: 1g
    Methotrexate Sodium Intramuscular Inj Sol: 1mL, 25mg
    Methotrexate Sodium Intramuscular Sol: 1mL, 25mg
    Methotrexate Sodium Intrathecal Inj Pwd F/Sol: 1g
    Methotrexate Sodium Intrathecal Inj Pwd: 1g
    Methotrexate Sodium Intrathecal Inj Sol: 1mL, 25mg
    Methotrexate Sodium Intravenous Inj Pwd F/Sol: 1g
    Methotrexate Sodium Intravenous Inj Pwd: 1g
    Methotrexate Sodium Intravenous Inj Sol: 1mL, 25mg
    Methotrexate Sodium Intravenous Sol: 1mL, 25mg
    Methotrexate Sodium/Rheumatrex/Trexall Oral Tab: 2.5mg, 5mg, 7.5mg, 10mg, 15mg
    Otrexup Subcutaneous Sol: 0.4mL, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg
    Rasuvo Subcutaneous Inj Sol: 0.15mL, 0.2mL, 0.25mL, 0.3mL, 0.35mL, 0.4mL, 0.45mL, 0.5mL, 0.6mL, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg
    Xatmep Oral Sol: 1mL, 2.5mg

    DOSAGE & INDICATIONS

    For the treatment of acute lymphocytic leukemia (ALL).
    NOTE: Methotrexate has been designated as an orphan drug by the FDA for the treatment of ALL.
    For the treatment of ALL, as part of a combination chemotherapy regimen.
    Intravenous dosage
    Adults

    10 to 5,000 mg/m2 IV; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy (500 mg/m2 IV or greater); consider leucovorin rescue following intermediate-dose methotrexate therapy (100 to less than 500 mg/m2 IV). Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. As maintenance therapy following remission, methotrexate has been administered as 2.5 mg/kg IV every 14 days.

    Infants, Children, and Adolescents

    10 to 5,000 mg/m2 IV; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy (500 mg/m2 IV or greater); consider leucovorin rescue following intermediate-dose methotrexate therapy (100 to less than 500 mg/m2 IV). Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. As maintenance therapy following remission, methotrexate has been administered as 2.5 mg/kg IV every 14 days.

    Intramuscular dosage
    Adults

    20 to 30 mg/m2 intramuscularly (IM) per week; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. As maintenance therapy following remission, methotrexate has been administered IM twice weekly for a total weekly dose of 30 mg/m2.

    Infants, Children, and Adolescents

    20 to 30 mg/m2 intramuscularly (IM) per week; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. As maintenance therapy following remission, methotrexate has been administered IM twice weekly for a total weekly dose of 30 mg/m2.

    Oral dosage
    Adults

    20 mg/m2 orally once weekly as maintenance therapy following remission. Dosage may be adjusted to maintain a target absolute neutrophil count and/or for hematologic toxicity.

    Infants, Children, and Adolescents

    20 mg/m2 orally once weekly as maintenance therapy following remission. Dosage may be adjusted to maintain a target absolute neutrophil count and/or for hematologic toxicity.

    For the treatment of non-Hodgkin's lymphoma (NHL).
    NOTE: The recommended dose, infusion time, and dosing schedule of methotrexate varies depending on which specific type of NHL is being treated and its use as a single agent or as part of combination therapy; therefore, refer to individual protocols for specific dosage and schedule.
    For the treatment of cutaneous NHL.
    Intravenous dosage
    Adults

    5 to 75 mg IV a single agent; recommended dosage varies based on individual protocols.

    Infants, Children, and Adolescents

    5 to 75 mg IV a single agent; recommended dosage varies based on individual protocols.

    For the treatment of NHL, in combination with other therapies.
    Intravenous dosage
    Adults

    10 to 8,000 mg/m2 IV; dose and schedule are individualized based on concurrent drugs used. Administer leucovorin rescue following high-dose methotrexate therapy (500 mg/m2 IV or greater); consider leucovorin rescue following intermediate-dose methotrexate therapy (100 to less than 500 mg/m2 IV). Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. Methotrexate 1,000 mg/m2 or 3,000 mg/m2 as an IV infusion over 24 hours followed by leucovorin rescue has been studied.

    Oral dosage
    Adults

    2.5 mg orally 2 to 4 times per week (maximum, 10 mg per week) has been administered in patients with relapsed or refractory NHL, as part of a metronomic combination chemotherapy regimen.

    For the treatment of central nervous system NHL.
    Intravenous dosage
    Adults

    8,000 mg/m2 IV infusion over 4 hours as a single agent or 3,000 to 8,000 mg/m2 in combination with immunochemotherapy. Administer leucovorin rescue following high-dose methotrexate therapy. Additionally, give IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment.

    Infants, Children, and Adolescents

    8,000 mg/m2 IV infusion over 4 hours as a single agent or 3,000 to 8,000 mg/m2 in combination with immunochemotherapy. Administer leucovorin rescue following high-dose methotrexate therapy. Additionally, give IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment.

    Intrathecal dosage
    Adults

    12 to 15 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.

    Children 9 years and older and Adolescents

    12 to 15 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.

    Children 3 to 8 years

    12 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.

    Children 2 years

    10 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.

    Children 1 year

    8 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.

    Infants

    6 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.

    For the treatment of epidermoid head and neck cancer.
    Intravenous dosage
    Adults, Adolescents and Children

    40 mg/m2 IV on days 1 and 15, every 21 days; alone or in combination with bleomycin and cisplatin.

    Oral dosage
    Adults

    25—50 mg/m2 PO once every 7 days have been used.

    Children

    7.5—30 mg/m2 PO every 7—14 days.

    For the treatment of lung cancer, especially squamous cell or small cell lung cancer (SCLC).
    Intravenous dosage
    Adults

    Many different regimens exist; common combination regimens include: methotrexate 20 mg/m2 IV as a single dose with cisplatin, doxorubicin, and cyclophosphamide, every 28 days; methotrexate 40 mg/m2 IV for one dose with etoposide and cisplatin; and methotrexate 100 mg/m2 IV for one dose along with cyclophosphamide, vincristine, and doxorubicin.

    Oral dosage
    Adults

    10 mg/m2 PO twice weekly x 4 doses every 3 weeks in combination with lomustine and cyclophosphamide.

    For the treatment or prophylaxis of leukemic meningitis.
    For the treatment of leukemic meningitis.
    Intrathecal dosage
    Adults

    12 to 15 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.

    Elderly patients

    12 to 15 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. A dose reduction may be necessary in elderly patients. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.

    Children 9 years and older and Adolescents

    12 to 15 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.

    Children 3 to 8 years

    12 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.

    Children 2 years

    10 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.

    Children 1 year

    8 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.

    Infants

    6 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.

    For prophylaxis of leukemic meningitis.
    Intrathecal dosage
    Adults

    12 to 15 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.

    Elderly patients

    12 to 15 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols. A dose reduction may be necessary in geriatric patients.

    Children 9 years and older and Adolescents

    12 to 15 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.

    Children 3 to 8 years

    12 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.

    Children 2 years

    10 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.

    Children 1 year

    8 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.

    Infants

    6 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.

    For the treatment of osteogenic sarcoma.
    NOTE: Methotrexate has been designated an orphan drug by the FDA for the treatment of osteogenic sarcoma.
    For the treatment of osteosarcoma, as part of a combination chemotherapy regimen.
    Intravenous dosage (Preservative-free solutions only)
    Adults

    12 g/m2 (maximum dose, 20 g) IV over 4 hours; dose and schedule are individualized based on factors such as patient comorbidities, disease state, and prior treatments. Administer leucovorin rescue following high-dose methotrexate therapy. Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. If the initial dose does not produce a peak serum methotrexate concentration of 1,000 micromolar at the end of the methotrexate infusion, increase to methotrexate 15 g/m2 IV for subsequent treatments. When used in combination with other chemotherapy agents, high-dose methotrexate followed by leucovorin rescue resulted in prolonged relapse-free survival in patients with non-metastatic osteosarcoma who had undergone surgical resection or amputation for the primary tumor.

    Infants, Children, and Adolescents

    12 g/m2 (maximum dose, 20 g) IV over 4 hours; dose and schedule are individualized based on factors such as patient comorbidities, disease state, and prior treatments. Administer leucovorin rescue following high-dose methotrexate therapy. Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. If the initial dose does not produce a peak serum methotrexate concentration of 1,000 micromolar at the end of the methotrexate infusion, increase to methotrexate dose to 15 g/m2 IV for subsequent treatments. When used in combination with other chemotherapy agents, high-dose methotrexate followed by leucovorin rescue resulted in prolonged relapse-free survival in patients with non-metastatic osteosarcoma who had undergone surgical resection or amputation for the primary tumor.

    For the treatment of gestational trophoblastic disease including choriocarcinoma and hydatidiform mole.
    For gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole.
    Oral or Intramuscular dosage
    Adults

    15—30 mg PO/IM once daily for 5 days. Repeat after 1 or more weeks, dependent on the response or toxicity.

    For high-risk gestational trophoblastic disease in combination with leucovorin, etoposide, actinomycin D, cyclophosphamide, and vincristine (EMA-CO regimen).
    Intravenous dosage
    Adults

    100 mg/m2 IV push on day 1, followed by 200 mg/m2 IV infusion over 12 hours on day 1 in combination with leucovorin, etoposide, actinomycin D, cyclophosphamide, and vincristine (EMA-CO regimen), repeated every 2—3 weeks depending on toxicity. Leucovorin 15 mg PO/IM every 12 hours for 4 doses should begin on day 2, 24 hours after initiating methotrexate infusion. Multiple studies have been reported with cure rates ranging from 70—90% in women with high-risk gestational trophoblastic disease. Results are typically better in women who receive EMA-CO as primary therapy and in women without metastatic disease. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity. Complete response is typically defined as three consecutive weekly human chorionic gonadotropin (hCG) levels that are undetectable or less than the upper limit of normal. In studies, treatment was continued for 2—3 additional courses after complete hCG response.

    For high-risk gestational trophoblastic disease in combination with leucovorin, etoposide, actinomycin D, and cisplatin (EMA-EP regimen).
    Intravenous dosage
    Adults

    100 mg/m2 IV push on day 1, followed by 200 mg/m2 IV infusion over 12 hours on day 1 in combination with leucovorin, etoposide, actinomycin D, and cisplatin (EMA-EP regimen), repeated every 2—3 weeks depending on toxicity. Leucovorin 15 mg PO/IM every 12 hours for 4 doses should begin on day 2, 24 hours after initiating methotrexate infusion. Studies in patients with chemorefractory high-risk gestational trophoblastic disease have shown response rates of > 90% with salvage treatment with EMA-EP. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity.

    For the treatment of rheumatoid arthritis (RA).
    For subcutaneous treatment of severe, active rheumatoid arthritis (RA).
    Subcutaneous dosage (Otrexup ONLY)
    Adults

    7.5 mg subcutaneously once weekly is recommended as initial therapy. Titrate doses gradually to achieve an optimal clinical response. Usual Otrexup Max: Doses exceeding 20 mg/week subcutaneously may increase the risk of severe adverse reactions (e.g., myelosuppression). Therapeutic response usually begins within 3 to 6 weeks, and the patient may continue to improve for another 12 weeks. Once a response is noted, reduce to the lowest effective dose. The optimal duration of therapy is unknown. Limited data indicate that clinical improvement is maintained for at least 2 years with continued treatment. When methotrexate is discontinued, RA usually worsens within 3 to 6 weeks. SWITCHING FROM OTHER ROUTES: Methotrexate bioavailability may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer.

    Subcutanous dosage (Rasuvo ONLY)
    Adults

    7.5 mg subcutaneously once weekly is the initial recommended dose (Rasuvo). Titrate doses gradually to achieve the optimal clinical response. Usual Rasuvo Max: Doses exceeding 20 mg/week subcutaneously may increase the risk of severe adverse reactions (e.g., myelosuppression). Therapeutic response usually begins within 3 to 6 weeks, and the patient may continue to improve for another 12 weeks. Once a response is noted, reduce to the lowest effective dose. The optimal duration of therapy is unknown. Limited data indicate that clinical improvement is maintained for at least 2 years with continued treatment. When methotrexate is discontinued, RA usually worsens within 3 to 6 weeks. SWITCHING FROM OTHER ROUTES: Methotrexate bioavailability may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer.

    Oral dosage
    Adults

    Initially, 7.5 mg PO once weekly. Titrate gradually to achieve an optimal clinical response. Usual Max: 20 mg/week PO due to an increased incidence of adverse reactions (e.g., bone marrow suppression) with higher doses. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. Therapeutic response usually begins within 3 to 6 weeks; however, patient response may occur up to 12 weeks after methotrexate initiation. Once a response is noted, reduce to the lowest effective dose. The optimal duration of therapy is unknown. Limited data indicate that clinical improvement is maintained for at least 2 years with continued treatment. When methotrexate is discontinued, RA usually worsens within 3 to 6 weeks.[24250]

    For the treatment of active juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA) (i.e., polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis with predominant joint inflammation).
    Oral dosage
    Children and Adolescents

    10 mg/m2/dose PO once weekly initially. Individualize dosage and titrate gradually to achieve optimal clinical response. Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. At high doses (more than 15 mg/m2/week), the parenteral route is preferred due to decreased oral bioavailability and increased gastrointestinal side effects of the oral formulation. Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alpha inhibitor is recommended.

    Subcutaneous dosage (Otrexup ONLY)
    Children and Adolescents

    10 mg/m2/dose subcutaneously once weekly initially (Otrexup). Titrate doses gradually to achieve optimal clinical response. Otrexup Max: Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. SWITCHING FROM OTHER ROUTES: Methotrexate bioavailability may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alpha inhibitor is recommended.

    Subcutaneous dosage (Rasuvo ONLY)
    Children and Adolescents

    10 mg/m2/dose subcutaneously once weekly initially. Titrate doses gradually to achieve an optimal clinical response. Max: Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity.  Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. SWITCHING FROM OTHER ROUTES: Methotrexate bioavailability may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alpha inhibitor is recommended.

    Intramuscular dosage
    Children and Adolescents

    10 mg/m2/dose IM once weekly initially. Tailor dose to the individual patient and adjust gradually to achieve optimal response. Max: Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alfa inhibitor is recommended.

    For the treatment of moderate to severe plaque psoriasis.
    Oral dosage
    Adults

    10 to 25 mg PO once weekly given as a single weekly dose. Titrate doses gradually to achieve an optimal clinical response. Max: 30 mg/week PO. Once an optimal clinical response has been achieved, decrease to the lowest effective dose and to the longest possible rest period. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. Per guidelines, methotrexate may be used as a first-line systemic drug for the treatment of adults with severe plaque psoriasis.

    Subcutaneous dosage (Otrexup ONLY)
    Adults

    10 to 25 mg subcutaneously once weekly as a single weekly dose. Titrate gradually to achieve an optimal clinical response. Otrexup Max: 25 mg/week subcutaneously. Once an optimal clinical response has been achieved, decrease to the lowest effective dose and to the longest possible rest period. The use of methotrexate may permit the return to topical therapy, which should be encouraged. SWITCHING DOSE FORMS: Methotrexate concentrations may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer. INTENDED USE: For the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, in patients with an established diagnosis (e.g., biopsy or after dermatologic consultation). It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses. Per guidelines, methotrexate may be used as a first-line systemic drug for the treatment of adults with moderate to severe plaque psoriasis.

    Subcutaneous dosage (Rasuvo ONLY)
    Adults

    10 to 25 mg subcutaneously once weekly as a single weekly dose. Titrate gradually to achieve an optimal clinical response. Rasuvo Max: 30 mg/week subcutaneously. Once an optimal clinical response has been achieved, decrease to the lowest effective dose and to the longest possible rest period. The use of methotrexate may permit the return to topical therapy, which should be encouraged. SWITCHING DOSE FORMS: Methotrexate concentrations may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer. INTENDED USE: For the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, in patients with an established diagnosis (e.g., biopsy or after dermatologic consultation). It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses. Per guidelines, methotrexate may be used as a first-line systemic drug for the treatment of adults with moderate to severe plaque psoriasis.

    Intravenous or Intramuscular dosage (generic methotrexate sodium injection solution)
    Adults

    10 to 25 mg IV/IM given as a single weekly dose until response. Titrate doses gradually to achieve the optimal clinical response. Max: 30 mg/week IV or IM. Once an optimal clinical response has been achieved, decrease to the lowest effective dose and to the longest possible rest period. The use of methotrexate may permit return to topical therapy, which should be encouraged. INTENDED USE: For the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, in patients with an established diagnosis (e.g., biopsy or after dermatologic consultation). It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses. Per guidelines, methotrexate may be used as a first-line systemic drug for the treatment of adults with moderate to severe plaque psoriasis.

    For the treatment of mycosis fungoides.
    Intravenous dosage
    Adults

    5 to 50 mg IV once weekly as a single agent has resulted in clinical responses in 50% of patients with early stage disease; the dosage may be reduced or discontinued based on patient response and/or hematologic toxicity. Methotrexate 15 to 37.5 mg IV twice weekly has been used in patient who had a poor response with weekly therapy. Higher doses of methotrexate with leucovorin rescue have also been given in patient with advanced stage disease.

    Infants, Children, and Adolescents

    5 to 50 mg IV once weekly as a single agent has resulted in clinical responses in 50% of patients with early stage disease; the dosage may be reduced or discontinued based on patient response and/or hematologic toxicity. Methotrexate 15 to 37.5 mg IV twice weekly has been used in patient who had a poor response with weekly therapy. Higher doses of methotrexate with leucovorin rescue have also been given in patient with advanced stage disease.

    Oral dosage
    Adults

    25 to 75 mg orally once weekly as a single agent or methotrexate 10 mg/m2 orally twice weekly as part combination chemotherapy.

    For the treatment of bladder cancer†.
    As first-line chemotherapy for the treatment of advanced or metastatic bladder cancer, in combination with vinblastine, doxorubicin, and cisplatin†.
    Intravenous dosage
    Adults

    30 mg/m2 IV on days 1, 15, and 22 in combination with vinblastine, doxorubicin, and cisplatin repeated every 28 days (MVAC regimen) for up to 6 cycles has been evaluated in patients with advanced or metastatic transitional cell carcinoma of the bladder in 2 randomized, phase III trials. Some patients received granulocyte colony-stimulating factor (G-CSF) following chemotherapy.

    As neoadjuvant treatment for muscle-invasive bladder cancer, in combination with other chemotherapy agents†.
    Intravenous dosage
    Adults

    Neoadjuvant therapy with methotrexate as a part of MCV, MVAC, and with cisplatin has been studied. Methotrexate 30 mg/m2 IV bolus and vinblastine 4 mg/m2 IV bolus on days 1 and 8 plus cisplatin 100 mg/m2 IV infusion on day 2 repeated every 21 days (MCV regimen) for 3 cycles prior to local radical treatment (LRT) with cystectomy, full-dose external-beam radiotherapy, or preoperative radiotherapy and cystectomy resulted in a nonsignificantly higher 3-year overall survival (OS) rate compared with LRT alone (55.5% vs. 50%; hazard ratio (HR) = 0.85; 95% CI, 0.71 to 1.02; p = 0.075) in a randomized phase III trial in 976 patients; however, the 10-year OS rate was significantly improved in the MCV arm in a long-term analysis (36% vs. 30%; HR = 0.84; 0.72 to 0.99; p = 0.037). Folinic acid 15 mg orally or IV every 6 hours for 4 doses was given 24 hours after each methotrexate dose. Five treatment-related deaths occurred in the MCV arm. In another randomized, phase III trial in 317 patients, neoadjuvant therapy with methotrexate 30 mg/m2 on days 1, 15, and 22 in combination with vinblastine 3 mg/m2 IV on days 2, 15, and 22; doxorubicin 30 mg/m2 on day 2; and cisplatin 70 mg/m2 on day 2 repeated every 28 days (MVAC regimen) for 3 cycles followed by radical cystectomy led to a nonsignificantly improved median OS time (77 vs. 46 months; adjusted p = 0.06 ) compared with radical cystectomy alone, although significantly more patients were pathologically free from disease at cystectomy in the MVAC arm (48% vs. 15%; p < 0.001). Similarly, 3 cycles of methotrexate 250 mg/m2 IV (with leucovorin 15 mg orally every 6 hours for 8 doses starting 24 hours after each methotrexate dose) plus cisplatin 100 mg/m2 IV administered every 3 weeks prior to cystectomy did not significantly improve the 5-year OS rate compared with cystectomy alone (53% vs. 46%) despite a significantly improved rate of tumor downstaging (to T0) (26.4% vs. 11.5%; p = 0.001).

    For the adjuvant treatment of early breast cancer, in combination with 5-fluorouracil and cyclophosphamide (CMF)†.
    Intravenous dosage
    Adults

    40 mg/m2 IV plus fluorouracil 600 mg/m2 IV on days 1 and 8, in combination with cyclophosphamide 100 mg/m2 by mouth on days 1 through 14, repeated every 28 days for 6 cycles.

    For the treatment of desmoid tumor† or aggressive fibromatosis not amenable to surgery or radiotherapy, in combination with vinblastine.
    Intravenous dosage
    Adults

    30 mg/m2/dose IV in combination with vinblastine 6 mg/m2/dose IV every 7 to 10 days for 1 year resulted in a partial response (PR) rate of 40% and a minor response or stable disease in 60% in a phase II study in 30 patients (age range, 4 to 68 years) with recurrent or primary inoperable aggressive fibromatosis. At a median follow-up of 75 months (range, 14 to 125 months), 29 patients were alive and the overall actuarial progression-free interval at 5 and 10 years was 67%.

    Infants >= 7 months, Children, and Adolescents

    30 mg/m2/dose IV in combination with vinblastine 6 mg/m2/dose IV every 7 to 10 days for 1 year resulted in a partial response (PR) rate of 40% and a minor response or stable disease in 60% in a phase II study of 30 patients (age range, 4 to 68 years). At a median follow-up of 75 months (range, 14 to 125 months), 29 patients were alive and the overall actuarial progression-free interval at 5 and 10 years was 67%. In another phase II study of 26 children, methotrexate 30 mg/m2/dose IV and vinblastine 5 mg/m2/dose IV weekly for 26 weeks then every other week for an additional 26 weeks led to an ORR of 19.2% and a 3-year progression-free survival rate of 32.5%. Serious adverse effects in this study included grade 4 neutropenia (n=5), mood alteration (n=1), and uncomplicated generalized seizure (n=1).

    For the treatment of active Crohn's disease†.
    Intramuscular or Subcutaneous dosage
    Adults

    The American College of Gastroenterology states that methotrexate (15 to 25 mg IM or subcutaneously once weekly) may be used in treatment of active Crohn's disease and for maintenance treatment of luminal CD after steroid-induced remission. A common dosing regimen is 25 mg subcutaneous once weekly for treatment of active disease with dose-reduction to 15 mg subcutaneous once weekly for maintenance of remission. Max: 25 mg/week IM or subcutaneously. Consider folic acid supplementation during treatment.

    Oral dosage
    Adults

    The American College of Gastroenterology states that methotrexate 12.5 to 15 mg PO once weekly can be used as adjunctive therapy for reducing immunogenicity against biologic therapy. Data demonstrating efficacy of oral methotrexate for maintaining remission of CD are lacking. Due to potential gastrointestinal absorption issues, parenteral therapy is recommended by ACG for active and maintenance therapy. It is perceived that patients with normal small bowel absorption may be started on or switched from parenteral to oral methotrexate at 15 mg to 25 mg PO once weekly; however, controlled efficacy data are lacking for this approach.

    For the treatment of ectopic pregnancy†.
    Single-dose regimen.
    Intramuscular dosage
    Adult Females

    Administer 50 mg/m2 IM as a single dose on day 1. Measure hCG concentration on posttreatment day 4 and 7. If hCG decreases by 15% or more between days 4 and 7, continue to measure hCG weekly until at nonpregnant level. If hCG decreases by less than 15% between days 4 and 7, give a repeat dose of 50 mg/m2 IM and repeat hCG measurements. If hCG does not decrease after 2 doses, consider surgical management. If hCG plateaus or increases during follow-up testing, consider administering additional methotrexate for treatment of a persistent ectopic pregnancy. Refer to published guidelines for proper patient selection and management.

    Two-dose regimen.
    Intramuscular dosage
    Adult Females

    Administer 50 mg/m2 IM on day 1. Give a second dose of 50 mg/m2 IM on day 4 and measure the hCG concentration. On day 7, repeat hCG measurement. If hCG decreases by 15% or more between days 4 and 7, continue to measure hCG weekly until at nonpregnant level. If hCG decreases by less than 15% between days 4 and 7, give another dose of methotrexate 50 mg/m2 IM on day 7 and recheck hCG on day 11. If hCG decreases by 15% or more between days 7 and 11, monitor hCG weekly until at nonpregnant level. If hCG decreases by less than 15% between days 7 and 11, give another repeat dose of methotrexate 50 mg/m2 IM on day 11 and measure hCG on day 14. If hCG does not decrease after 4 doses, consider surgical management. If hCG plateaus or increases during follow-up, consider administering additional methotrexate for treatment of persistent ectopic pregnancy. Refer to published guidelines for proper patient selection and management. A systematic review and meta-analysis suggest that the 1-dose and 2-dose protocols have comparable risk of adverse effects; some studies suggest that the 2-dose regimen is more effective in patients with higher initial hCG levels. The resolution of hCG levels is significantly faster in patients successfully treated with the 2-dose methotrexate regimen vs. the single-dose regimen.[63662] [63666]

    Fixed multiple-dose regimen.
    Intramuscular dosage
    Adult Females

    Administer methotrexate 1 mg/kg IM on days 1, 3, 5, 7; alternate with leucovorin 0.1 mg/kg IM on days 2, 4, 6, 8. Measure hCG concentrations on methotrexate dose days and continue until hCG has decreased by 15% from the previous measurement. If the hCG decreases by 15% or more at any measurement, discontinue methotrexate (i.e., give no further doses in the protocol) and measure hCG weekly until at nonpregnant levels (thus patients may ultimately need 1, 2, 3, or 4 doses of this protocol). If hCG does not decrease after 4 doses, consider surgical management. Refer to published guidelines for proper patient management and selection for treatment, including management of patients whose hCG concentrations plateau or increase during the protocol.[63662] [63666]

    For the treatment of active psoriatic arthritis†.
    Oral or Subcutaneous dosage
    Adults

    Efficacy not established; off-label use has long been recommended in treatment guidelines. 7.5 mg PO once weekly initially, then slowly titrate to the common target dose of 15 mg PO once weekly. In patients with persistently active psoriatic arthritis (PsA), the dosage can be increased to 20 mg/week PO and then to 25 mg/week PO if needed. Usual target efficacious dose: 15 mg to 25 mg/week PO. Similar dosages have been given subcutaneously, using appropriate subcutaneous formulations. Despite a long history of use, specific evidence for MTX monotherapy in the treatment of PsA is not robust and remains inconclusive. In the MIPA trial, a low-dose MTX regimen was not more effective than placebo for synovitis (ACR20, etc.) and the only beneficial effect of MTX was for patient and assessor global symptom scores and skin scores. The authors note that trials continue to study the role of MTX along with biologics in PsA patients (combination therapy).[63889] GUIDELINES: Guidelines state that in treatment-naive PsA patients, methotrexate may be considered instead of a TNF-alpha blocker if the patient does not have severe PsA, does not have severe psoriasis, prefers oral therapy, the patient expresses concern over starting a biologic as the first therapy, or has contraindications to TNF-inhibiting (TNFi) biologics (e.g., congestive heart failure, previous serious infections, recurrent infections, or demyelinating disease). Methotrexate may also be beneficial in patients with PsA who also have plaque psoriasis (skin involvement), and is the preferred conventional DMARD in such patients when conventional DMARDs are chosen. Experts note that the impact of MTX on radiologic damage due to PsA remains unproven, but that in some healthcare environments, MTX must be used before treatments of proven effectiveness (e.g., TNFi agents) are prescribed.[62838] [63834] [63884] [56046]

    For the treatment of systemic lupus erythematosus (SLE)† including polymyositis† or dermatomyositis†.
    Intramuscular and Intravenous dosage
    Adults

    5—10 mg IV/IM once weekly. Doses may be increased by 5—10 mg to a maximum dose of 50 mg weekly or until toxicity appears. Subcutaneous receipt of methotrexate was as effective as IV administration to 15 patients with cutaneous lupus erythematosus. All patients had responded to 7.5—20 mg IV once weekly and received 7.5—20 mg SC once weekly for 2—11 months.

    Oral dosage
    Children

    In a small study methotrexate 5—10 mg/week PO was added to current SLE treatment (prednisone with or without cyclophosphamide). Eight of ten patients showed marked improvement with tapering of prednisone and discontinuation of cyclophosphamide.

    Adults

    7.5 mg/week PO initially titrated monthly by 2.5 mg/week as needed to a max of 20 mg/week to patients with moderately active disease despite stable conventional therapy led to decreased SLE disease activity, as measured by the SLAM-R score, (p = 0.006) and a reduced corticosteroid dose (p = 0.01). In another study, 15 mg/week PO led to a reduction in the mean SLE Disease Activity Index (SLEDAI) from 12.2 +/- 3.99 to 4 +/- 3.75 (p = 0.001) and a reduction in the mean prednisolone dose from 17.4 +/- 12.8 mg/day to 8.8 +/- 5.36 mg/day (p = 0.01) among 22 patients without renal and central nervous involvement who had been treated with corticosteroids for at least 6 months without achieving remission. A significant reduction in the SLEDAI was also noted among recipients of methotrexate 10 mg/week PO in another small, open-label study. Consider immunosuppressive agents such as methotrexate for patients unresponsive to antimalarials and/or glucocorticoids or for patients unable to reduce steroids below doses acceptable for chronic use.

    For the treatment of sarcoidosis†.
    Oral dosage
    Adults

    Several reports have documented the efficacy of methotrexate in patients with steroid-dependent sarcoidosis. In one report, patients received methotrexate 10 mg PO once weekly (range: 7.5—15 mg/week) for an average of 30 months. Beneficial effects were observed in all 5 patients within 8—12 weeks allowing for a reduction in the corticosteroid dosage. In another study, 50 patients were treated with oral methotrexate once weekly at a dosage titrated to the WBC for at least 2 years. Improvement in vital capacity was noted in 33 of 50 patients.

    For the treatment of carcinomatous meningitis†.
    Intrathecal dosage (Preservative-free solutions only)
    Adults

    10 mg intrathecally twice weekly for 4 weeks followed by 10 mg intrathecally once weekly for 4 doses then every other week for 4 doses (with leucovorin 10 mg orally every 6 hours for 8 doses starting 24 hours after each methotrexate dose) led to a nonsignificantly different response rate (20% vs. 26%) compared with liposomal cytarabine in a multicenter, randomized study. Unless contraindicated, all patients also received dexamethasone 4 mg twice daily on days 1 to 5 of each treatment cycle. The median overall survival (OS) times were not significantly different in the methotrexate and liposomal cytarabine arms (78 vs. 105 days); however, treatment with intrathecal liposomal cytarabine was associated with significantly improved progression-free survival (PFS) in a multivariate analysis. The median time to neurological progression was significantly shortened in patients who received methotrexate compared with liposomal cytarabine (30 vs. 58 days). In a multicenter, randomized trial in 100 patients with neoplastic meningitis from solid tumors, PFS time was not significantly different with intracerebrospinal fluid methotrexate or liposomal cytarabine therapy (37.5 vs. 35 days). In an unplanned retrospective subgroup analysis, PFS was significantly increased when methotrexate was given intraventricularly (via a ventricular reservoir) compared with intralumbar administration (43 vs. 19 days). Methotrexate 10 mg intrathecally on days 1 and 4 repeated weekly for 8 weeks was compared with intrathecal thiotepa in a randomized trial in 52 patients with previously untreated neoplastic meningitis. The median OS times were 15.9 weeks in the methotrexate arm and 14.1 weeks in the thiotepa arm. After 8 weeks of therapy, no patient experienced a complete response or improvement. Eight patients in each treatment arm converted from a positive to a negative cytology after therapy. Patients in the methotrexate arm experienced significantly more neurologic and skin/mucous membrane toxicity compared with patients in the thiotepa arm.

    For the treatment of locally advanced or metastatic penile cancer† in combination with cisplatin and bleomycin.
    Intravenous dosage
    Adults

    25 mg/m2 IV bolus on days 1 and 8 in combination with cisplatin 75 mg /m2 IV on day 1 and bleomycin 10 units/m2 IV on days 1 and 8, repeated every 21 days. Treatment was given for 6 cycles if a complete remission was achieved. Patients who achieved stable disease or a partial response, continued treatment until disease progression. Bleomycin was discontinued after a maximum cumulative dose of 200 units/m2 was given.

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: The suggested maximum tolerated dose (MTD) for methotrexate is dependent on the disease state, performance status, and other chemotherapy agents or radiation given in combination.
    NOTE: The correct dose of methotrexate in the treatment of neoplastic disease will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.

    Adults

    For psoriasis 30 mg/week PO; for rheumatoid arthritis 20 mg/week PO. See specific injection product for maximal weekly injection doses, as these vary by product and route given.
    In the treatment of neoplastic disease the maximum tolerated dose of methotrexate varies significantly from 80 to 900 mg/m2 IV without leucovorin rescue therapy and 900 to 30,000 mg/m2 IV with leucovorin rescue. The maximum intrathecal dose of methotrexate is 15 mg. Oral doses greater than 30 mg/m2 are generally not recommended due to poor absorption.

    Geriatric

    The maximum tolerated doses of methotrexate may be lower in elderly patients. See adult maximum listings.

    Children

    For polyarticular juvenile idiopathic arthritis: 20 to 30 mg/m2/week (0.65 to 1 mg/kg/week) is a usual maximum dose.
     
    In the treatment of neoplastic disease, the maximum tolerated dose of methotrexate varies significantly from 80 to 900 mg/m2 IV without leucovorin rescue therapy and 900 to 30,000 mg/m2 IV with leucovorin rescue. The maximum intrathecal dose of methotrexate is 15 mg. Oral doses greater than 30 mg/m2 are generally not recommended due to poor absorption.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Subcutaneous formulations of methotrexate are contraindicated in patients with alcoholic liver disease or other chronic liver disease. Closely monitor other patients with hepatic impairment for adverse reactions; consider reducing the dose of methotrexate or consider alternative treatments. The safety of methotrexate in patients with hepatic impairment is unknown.

    Renal Impairment

    Carefully monitor patients with creatinine clearance (CrCl) less than 90 mL/min for adverse reactions; consider reducing the dose of methotrexate or consider alternative treatments as appropriate. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, effective clearance has been reported with acute, intermittent hemodialysis using a high-flux dialyzer. Treatment should be individualized for the patient and the disease being treated. The following is an example dosing nomogram that has been suggested when methotrexate is used for the treatment of neoplastic diseases:
    CrCl 60 mL/minute or higher: No dosage adjustment needed.
    CrCl 46 to 60 mL/minute: Administer 65% of standard dose.
    CrCl 31 to 45 mL/minute: Administer 50% of standard dose.
    CrCl 30 mL/minute or less: Not recommended.

    ADMINISTRATION

    CAUTION: Observe and exercise usual cautions for handling, preparing, administering, and disposing of cytotoxic drugs.
    Discuss with the patient the importance of carefully following all dosage instructions including taking the recommended dose as directed. Serious reactions reported with medication errors, including death; these errors most often occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed.
    When switching the dosing regimen from oral administration to IV, IM, or subcutaneous administration, consider potential differences in bioavailability; an alternative dosing regimen may be necessary.

    Oral Administration
    Oral Solid Formulations

    Do not administer to patients who are unable to swallow a tablet.

    Oral Liquid Formulations

    Instruct patients and caregivers that the recommended dose should be taken weekly as directed. Mistaken daily use of the recommended dose has led to fatal toxicity.
    Measure using an accurate milliliter measuring device; a household teaspoon is not an accurate measuring device and could lead to overdosage.
    Provide patients with an appropriate measuring device and instructions for measuring the correct dose.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Methotrexate injection that is preservative-free may be administered by IV, IM, subcutaneous, or intrathecal injection.
    Methotrexate injection containing benzyl alcohol may be administered by IV, IM, or subcutaneous injection.
    Only use preservative-free methotrexate injection, which does not contain benzyl alcohol, for the 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.
     
    Reconstitution of lyophilized powders:
    Reconstitute each 1 g vial with 19.4 mL of an appropriate sterile, preservative-free solution such as 5% Dextrose Injection or 0.9% Sodium Chloride Injection, to a concentration of 50 mg/mL.
    Prepare immediately before use. Discard any unused portions.

    Intravenous Administration

    Dilution:
    Methotrexate injection may be further diluted in 0.9% Sodium Chloride Injection. High doses of methotrexate administered by IV infusion may be diluted in 5% Dextrose Injection.
    Storage of methotrexate containing benzyl alcohol: After dilution, methotrexate should be used within 4 hours at room temperature (20 to 25 degrees C) or within 24 hours under refrigeration (2 to 8 degrees C).
     
    Guidelines for intravenous methotrexate therapy with leucovorin rescue:
    Prior to administration, the following laboratory parameters should be confirmed: WBC more than 1,500 cells/mm3, neutrophil count more than 200 cells/mm3, platelet count more than 75,000 cells/mm3, serum bilirubin less than 1.2 mg/dL, and ALT (SGPT) less than 450 units/L.
    Adequate renal function must be documented; creatinine clearance (CrCl) must be more than 60 mL/minute before initiation of therapy. If serum creatinine has increased by 50% or more compared to a prior value, creatinine clearance must be measured and documented as more than 60 mL/minute even if the serum creatinine is still within normal limits.
    Previous mucositis should have evidence of healing.
    Persistent pleural effusions should be drained dry prior to administration.
    Patients must be well hydrated. Administer 1 L/m2 of intravenous fluids over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2 per hour (3 L/m2 per day) during the methotrexate infusion and for 2 days after the infusion has been completed.
    Alkalinize the urine using sodium bicarbonate to maintain the urine pH more than 7 during the methotrexate infusion and leucovorin therapy. This can be done orally or by incorporating the sodium bicarbonate in the intravenous fluids.
    Repeat serum creatinine and methotrexate serum concentrations 24 hours after stating methotrexate and at least once daily until the methotrexate level is below 5 times 10-8 mol/L (0.05 microMolar).

    Subcutaneous Administration

    Otrexup and Rasuvo are methotrexate formulations for subcutaneous use only.
    Both Otrexup and Rasuvo are single-use auto-injectors. Otrexup is yellow in color, and Rasuvo is yellow-to-brown in color. Neither formulation should have lumps or particles floating in it.
    Administer Otrexup and Rasuvo in the abdomen or thigh; do NOT administer within 2 inches of the navel, on the arms, on any other areas of the body, or on skin that is tender, bruised, red, scaly, hard, or has scars or stretch marks.
    If self-injection is deemed appropriate, patients or caregivers should practice injections using a training device with guidance from a health care professional.
     
    Use of the Otrexup auto-injector:
    Immediately before use, twist cap to remove; flip the safety clip.
    Place needle end of Otrexup against thigh or stomach (abdomen) at a 90-degree angle and firmly push until you hear a click; hold for 3 seconds before removing the auto-injector.
    Press a cotton ball or gauze on the area for 10 seconds; do not rub the injection site.
    After use, the viewing window will be half-blocked with a red flag to show that the medicine was given. If the viewing window is not blocked, call your doctor, pharmacist, or 1-855-Otrexup (1-855-687-3987) for help.
    Do not inject another Otrexup dose without talking to your doctor.
     
    Use of the Rasuvo auto-injector:
    Immediately prior to use, pull the yellow cap straight off. Do not twist the cap.
    Pinch a pad of skin surrounding a cleaned injection site (thigh or abdomen) with the thumb and forefinger. Position the uncapped transparent end of the auto-injector at a 90-degree angle to the skin. Without pressing the button, push firmly onto the skin until the stop point is felt which will unlock the yellow injection button.
    Press the yellow injection button until a click is heard which indicates the start of the injection. Hold Rasuvo against the skin until all medication is injected. This can take up to 5 seconds. It is not necessary to keep the button of the Rasuvo auto-injector pressed down after the injection has begun.
    To avoid incomplete injection, do not remove Rasuvo from the skin before the end of the injection. Look at the transparent control zone while injecting to make sure the entire dose is injected. When movement stops, the injection is complete.
    Pull straight up (perpendicular to the skin) to remove Rasuvo from the injection site. The protective needle shield should automatically move into place.
    Visually inspect the transparent control zone to ensure there is no liquid left in the syringe. If there is liquid left, not all of the medicine was injected. The physician should be contacted. Do not use another Rasuvo unless advised by the doctor.

    Intrathecal Administration

    Use only preservative-free methotrexate injection, which does not contain benzyl alcohol, for intrathecal use.
    If using methotrexate lyophilized powder for injection, reconstitute with preservative-free 0.9% Sodium Chloride Injection to a concentration of 1 mg/mL prior to withdrawing the appropriate dose.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Otrexup:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Rasuvo:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Rheumatrex:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Trexall:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Xatmep:
    - Avoid excessive heat (above 104 degrees F)
    - Product must be used within 60 days after removal from refrigeration to room temperature (77 degrees F)
    - Protect from freezing
    - Refrigerate (between 36 and 46 degrees F)
    - See package insert for detailed storage information
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Serious hypersensitivity reactions or anaphylaxis

    Methotrexate is contraindicated in patients with a history of serious hypersensitivity reactions or anaphylaxis to the drug. Immediately discontinue methotrexate and begin appropriate therapy if signs or symptoms of anaphylaxis or other serious hypersensitivity reaction occur.  

    Serious rash

    Serious rash and occasionally fatal dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Recovery has been reported with methotrexate discontinuation. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue methotrexate depending on the severity of the reaction.

    Radiation therapy, sunburn, sunlight (UV) exposure

    Methotrexate is a radiation sensitizer. Methotrexate given concurrently with radiation therapy may increase the risk of soft tissue necrosis and osteonecrosis. Prior or concurrent cranial irradiation has been associated with an increased risk of leukoencephalopathy. Psoriasis lesions may be aggravated by the concurrent use of methotrexate and ultraviolet radiation therapy. Patients with prior radiation dermatitis or sunburn may experience recall reactions during methotrexate therapy. Due to methotrexate-induced photosensitivity, patients should wear protective clothing and use sunscreen during sunlight (UV) exposure. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue methotrexate depending on the severity of the reaction.

    Anemia, aplastic anemia, bone marrow suppression, infection, leukopenia, neutropenia, thrombocytopenia

    Methotrexate causes bone marrow suppression including neutropenia which can be severe and life-threatening; unexpectedly severe and sometimes fatal bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate along with some nonsteroidal anti-inflammatory drugs. Treatment with Otrexup or Rasuvo is contraindicated in patients with pre-existing blood dyscrasias (e.g. bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia) and should be used with caution, if at all, in patients with pre-existing hematopoietic impairment.  Methotrexate should be used with extreme caution in the presence of active infection; potentially fatal infection may also occur with methotrexate therapy including opportunistic infections and reactivation of latent viral infections; if a patient presents with pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia should be considered. Obtain blood counts at baseline and at least monthly during treatment; monitor more frequently during initial dosing, dose changes, or during periods of increased risk of elevated methotrexate blood levels. Monitor patients for possible clinical complications of myelosuppression including signs and symptoms of infection. Provide supportive care, withhold treatment, reduce the dose, or discontinue methotrexate as clinically appropriate; subcutaneous formulations of methotrexate should be stopped immediately if there is a significant drop in blood counts. Withhold or discontinue methotrexate in patients who develop serious infections.

    Requires an experienced clinician

    Administration of methotrexate requires an experienced clinician whose knowledge and experience include the use of antimetabolite therapy due to the potential for serious or fatal adverse reactions. Subcutaneous methotrexate should only be used in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Toxic effects may be related in frequency and severity to dose or frequency of administration, but have been seen at all doses and can occur at any time during therapy; most adverse reactions are reversible if detected early and appropriate corrective measures are taken, although deaths have been reported. Patients should be closely monitored for toxicities and should be informed by their physician of the risks involved in treatment. In patients receiving high-dose IV methotrexate, administer IV fluids and urine alkalinization before the first dose, continuing throughout treatment, to maintain adequate hydration and urine output as well as a urinary pH of 7 or higher. Administer leucovorin rescue in all patients receiving methotrexate injection at doses greater than 500 mg/m2, and consider the use of leucovorin for patients receiving doses between 100 mg/m2 to 400 mg/m2. Monitor methotrexate concentrations at baseline and periodically (every 1 to 2 months) during treatment with subcutaneous or oral administration; monitor methotrexate levels at least daily in patients receiving high-dose IV methotrexate, adjusting hydration and leucovorin dosing as needed. Consider the use of glucarpidase in patients who have toxic plasma methotrexate concentrations (greater than 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function.

    Acquired immunodeficiency syndrome (AIDS)

    The use of methotrexate in HIV-seropositive patients has been associated with rapid progression of immunosuppression, some with fatal outcomes. Treatment with Otrexup or Rasuvo is contraindicated in patients who have overt or laboratory evidence of immunodeficiency syndromes (i.e., acquired immunodeficiency syndrome (AIDS)); other formulations of methotrexate should not be used in this population unless absolutely necessary.    

    Diabetes mellitus, hypoalbuminemia, pulmonary disease, pulmonary toxicity, tobacco smoking

    Methotrexate therapy can produce potentially fatal pulmonary toxicity including acute or chronic interstitial pneumonitis. Risk factors in rheumatoid arthritis patients include diabetes mellitus, older age, rheumatoid pleuropulmonary involvement, and previous use of the disease modifying drugs sulfasalazine, gold, or penicillamine; and hypoalbuminemia; in nondiabetic patients, hypoalbuminemia and previous use of disease modifying drugs are the most important risk factors. A history of pulmonary disease, extra-articular manifestations of rheumatoid arthritis, tobacco smoking (men only), and non-sedentary occupations (women only) have also been suggested as risk factors for methotrexate-induced pulmonary toxicity. Methotrexate-induced lung disease may occur acutely at any time during therapy, has been reported at all dose levels, and is not always fully reversible. Obtain a chest x-ray at baseline. Pulmonary function tests may be useful if toxicity is suspected, especially if baseline measurements are available. Monitor patients for signs of pulmonary toxicity. Pulmonary symptoms (especially a dry, nonproductive cough) or a nonspecific pneumonitis may require treatment interruption or discontinuation and careful investigation; additional symptoms include fever, dry cough, dyspnea, hypoxemia, and radiographic evidence of pulmonary infiltrates.

    Alcoholism, hepatic disease, hepatitis, hepatotoxicity, hyperlipidemia, obesity

    Methotrexate is metabolized by the liver and undergoes enterohepatic circulation. Treatment with Otrexup or Rasuvo is contraindicated in patients with alcoholism, alcoholic liver disease, or other chronic hepatic disease.  Avoid the use of other formulations of methotrexate in patients with chronic liver disease unless the benefits clearly outweigh the risks; the safety of methotrexate in patients with liver disease is unknown.  Methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and liver failure but generally only after prolonged use (2 years or more). Risk factors for hepatotoxicity include alcoholism, obesity, diabetes mellitus, steatohepatitis, hyperlipidemia, previous significant exposure to liver toxins, family history of inheritable liver disease, duration of therapy, and advanced age. In rheumatoid arthritis (RA) patients, age at first use of methotrexate and duration of methotrexate therapy have been reported as risk factors for hepatotoxicity; previously mentioned risk factors may also have a role. In general, monitor liver function tests (LFTs) and albumin at baseline and every 1 to 2 months during treatment; increase the frequency of monitoring when initiating or changing therapy, or during periods of increased risk of elevated methotrexate levels. Interrupt or discontinue methotrexate treatment as clinically appropriate. Acutely, liver enzyme elevations are frequently seen, but elevations are usually transient, asymptomatic, and do not usually require modification of methotrexate therapy or appear to be predictive of subsequent hepatic disease. Persistent abnormalities and/or hypoalbuminemia may be indicators of serious hepatotoxicity and require further evaluation as they may precede fibrosis or cirrhosis.   However, in patients with psoriasis, LFTs and albumin are often normal despite developing fibrosis or cirrhosis which may be detectable only by biopsy; for this reason, periodic liver biopsies are recommended for psoriatic patients undergoing long-term treatment. Hepatotoxicity in these patients appears to be a function of the cumulative dose and generally occurs after a cumulative dose of 1.5 g or more. Manufacturer recommendations for liver biopsy in psoriatic patients are to obtain biopsies prior to therapy or shortly after initiating therapy (i.e., within 2 to 4 months), at a methotrexate cumulative dose of 1.5 g, and after each additional 1 to 1.5 g of methotrexate.  However, psoriasis guidelines suggest that every 3.5 to 4 g instead of 1 to 1.5 g of cumulative methotrexate may be a more appropriate interval for liver biopsy in patients without preexisting risk factors for hepatotoxicity.   The joint American Academy of Dermatology and National Psoriasis Foundation guidelines recommend a noninvasive assessment of liver fibrosis (e.g., serologic tests and liver stiffness assessment by transient elastography) at baseline rather than a liver biopsy, regardless of the presence of risk factors. Consider a GI or hepatology consult or imaging with vibration-controlled transient elastography, or both, for abnormal baseline laboratory results or risk factors for fibrosis; an annual GI/hepatology consult and/or vibration-controlled transient elastography should occur if methotrexate is continued despite abnormal baseline results. Moderate fibrosis or any cirrhosis should lead to discontinuation of the methotrexate; mild fibrosis normally suggests a repeat biopsy at 6 months. Pretreatment liver biopsy should be performed in RA patients with a history of excessive alcohol consumption, persistently abnormal baseline LFTs, or chronic hepatitis B or C infection. During treatment of rheumatoid arthritis, liver biopsy should be performed if there are persistent LFT abnormalities or if there is a decrease in serum albumin below the normal range (in the setting of well-controlled rheumatoid arthritis). Methotrexate may be continued with monitoring for RA patients if the liver biopsy shows mild changes (Roenigk grades I, II, or IIIa); it should be discontinued in any patient with persistently abnormal LFTs who refuses liver biopsy, or in patients with moderate to severe changes on biopsy (Roenigk grade IIIb or IV).

    Dehydration, nephrotoxicity, renal disease, renal failure, renal impairment

    Methotrexate is eliminated primarily by the kidney and clearance is dependent on dosage and route of administration. Patients who have renal impairment or renal disease or are receiving concurrent nephrotoxic drugs are at risk for increased toxicity due to prolonged elevated methotrexate serum concentrations. Irreversible acute renal failure and nephrotoxicity may occur following high-dose intravenous (IV) methotrexate therapy, although it has also been reported in patients receiving subcutaneous and oral administration of methotrexate. Nephrotoxicity is primarily caused by the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Obtain renal function tests at baseline and monitor for toxicity in all patients who are receiving methotrexate; a dose reduction or discontinuation of methotrexate therapy may be necessary in patients with renal impairment or in patients experiencing nephrotoxicity. Monitor renal function periodically during treatment (e.g., every 1 to 2 months) and as clinically indicated in patients receiving oral or subcutaneous formulations of methotrexate and more frequently when initiating or changing therapy or in patients with conditions that might increase the risk of elevated methotrexate levels (e.g., dehydration).  In patients receiving high-dose IV methotrexate, alkalinize the urine before the first dose, continuing throughout treatment to maintain a urinary pH of 7 or higher; this pH is necessary to prevent precipitation of methotrexate or its metabolites in the renal tubules. Administer hydration and leucovorin rescue as recommended. Monitor serum creatinine and electrolytes at baseline and at least daily during therapy; also monitor methotrexate concentrations at least daily, adjusting hydration and leucovorin dosing as needed. Consider the use of glucarpidase in patients who have toxic plasma methotrexate concentrations (greater than 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, effective methotrexate clearance has been reported with acute, intermittent hemodialysis using a high-flux filter.

    Ascites, pleural effusion

    Methotrexate elimination is reduced in patients with third space effusions (e.g., ascites or pleural effusion) and methotrexate levels may be elevated for a prolonged period resulting in increased toxicity. Remove significant third space fluid prior to treatment. Carefully monitor such patients for toxicity; a dose reduction or discontinuation of therapy may be necessary.

    Tumor lysis syndrome (TLS)

    Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome (TLS) in patients with rapidly growing tumors. Institute appropriate treatment for prevention and management of TLS prior to starting treatment with methotrexate.

    Diarrhea, gastrointestinal toxicity, GI disease, peptic ulcer disease, stomatitis, ulcerative colitis

    Methotrexate should be used with extreme caution in patients with GI disease such as peptic ulcer disease or ulcerative colitis as they are at greater risk of developing severe gastrointestinal toxicity. Interrupt or discontinue methotrexate for severe gastrointestinal toxicity including diarrhea and ulcerative stomatitis and begin appropriate supportive care; otherwise, hemorrhagic enteritis and death from GI perforation may occur. Also interrupt therapy for vomiting or other toxicities which may result in dehydration. Unexpectedly severe, sometimes fatal gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) and some nonsteroidal anti-inflammatory drugs (NSAIDs).   

    Vaccination

    Vaccination during methotrexate therapy may be ineffective because the antibody response is suboptimal. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated infections (e.g., vaccinia) after administration of live vaccines in patients receiving methotrexate. Hypogammaglobinemia has been reported rarely. Update immunizations prior to initiation of methotrexate therapy according to guidelines; the interval between live vaccines and initiation of methotrexate should be in accordance with vaccination guidelines for patients on immunosuppressive agents. In pediatric patients with juvenile idiopathic arthritis (JIA), data suggests non-live vaccines are, in general, adequately immunogenic and safe. Live-attenuated vaccines can be safely and effectively administered to JIA patients receiving methotrexate, unless they are also receiving additional immunosuppressive drugs or biologics. In these cases, evidence on safety is lacking. Live-attenuated booster vaccinations can be considered on an individual basis. There is no data regarding a safe time interval for administration of live vaccines after cessation of methotrexate.

    Benzyl alcohol hypersensitivity, ensure correct formulation selection, intrathecal administration, neonates

    Ensure correct formulation selection of preservative-free methotrexate injection for intrathecal administration, administration to neonates or low-birth weight infants, and administration to patients with known benzyl alcohol hypersensitivity; do not use benzyl alcohol-containing formulations for high-dose methotrexate regimens unless immediate treatment is required and preservative-free formulations are not available. Benzyl alcohol is present in preservative-containing injection formulations and can cause severe central nervous system toxicity or metabolic acidosis. Fatal gasping syndrome (including symptoms of gasping respiration, hypotension, bradycardia, and cardiovascular collapse) has been reported in neonates who received IV solutions containing benzyl alcohol. High-dose therapy is indicated for osteosarcoma; leucovorin rescue and careful monitoring are necessary. Hold subsequent methotrexate doses until hematologic parameters, hepatic function, and renal function have recovered.

    New primary malignancy

    A new primary malignancy, specifically malignant lymphomas or other lymphoproliferative disease, may occur in patients treated with methotrexate at all dose levels. Lymphoproliferative disease that occurs during therapy with low-dose methotrexate may completely regress following withdrawal of methotrexate and thus, may not require cytotoxic treatment. Discontinue methotrexate if lymphoproliferative disease occurs; if it does not regress, institute appropriate treatment.

    Neurotoxicity

    Methotrexate can cause severe acute and chronic neurotoxicity including leukoencephalopathy which can be progressive, irreversible, and fatal; generalized and focal seizures have occurred in pediatric patients. Prior or concurrent cranial irradiation has been associated with an increased risk of leukoencephalopathy. Monitor patients for signs of neurotoxicity and withhold or discontinue treatment with methotrexate when appropriate. Avoid the intrathecal use of methotrexate injection that contains benzyl alcohol due to the risk of serious neurotoxicity.

    Folate deficiency

    Folate deficiency may increase the incidence of methotrexate-related adverse reactions. Administer folic acid or folinic acid to patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and psoriasis to decrease the risk of adverse reactions. However, avoid the use of products containing folic acid or folinic acid in patients with neoplastic diseases unless clinically indicated, as they may also decrease the clinical effectiveness of methotrexate.

    Geriatric

    Cautious dose selection recommended in geriatric patients (age 65 or older) who may be at increased risk of adverse reactions due to a higher frequency of decreased renal or hepatic function, reduced folate stores, concomitant disease, or concomitant drug therapy. Closely monitor these patients for early signs of hepatic, bone marrow, and renal toxicity; serum methotrexate levels may also be helpful including in patients receiving treatment for non-neoplastic diseases. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may overestimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Based on postmarketing experience, the incidence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. Clinical studies of methotrexate did not include sufficient numbers of geriatric patients 65 years of age and older to determine whether they respond differently than younger patients.

    Intrauterine fetal death, pregnancy

    Methotrexate is contraindicated for use during pregnancy in women who are being treated for nonmalignant diseases (e.g., psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis). Pregnancy should be avoided by females of reproductive potential during methotrexate treatment and for at least 6 months after the last dose; however, because the benzyl alcohol preservative can cross the placenta, use the preservative-free formulation of IV methotrexate if treatment of a neoplastic disease is necessary during pregnancy. Methotrexate can cause intrauterine fetal death and/or congenital anomalies when administered to pregnant women based on case reports, literature reviews, and observational studies. Women who are pregnant or who become pregnant while receiving methotrexate should be apprised of the potential hazard to the fetus. Exposure to methotrexate during the first trimester of pregnancy in women has been associated with an increased incidence of spontaneous abortions and congenital anomalies, including facial dysmorphism, central nervous system abnormalities, skull anomalies, intellectual impairment, and cardiac anomalies. Intrauterine growth restriction and functional abnormalities have been reported with methotrexate exposures in the second and third trimesters. In a prospective multicenter study, the rate of spontaneous abortion/miscarriage in pregnant women exposed to 30 mg per week or less of methotrexate was 42.5% compared to 22.5% in unexposed patients with autoimmune disease and 17.3% in unexposed patients with non-autoimmune disease. Of the live births, the rate of major birth defects was higher in women exposed to methotrexate after conception than in unexposed patients with autoimmune disease (adjusted odds ratio [OR], 1.8) and unexposed patients with non-autoimmune disease (adjusted OR, 3.1); major birth defects associated with methotrexate-exposed pregnancies were not always consistent with methotrexate-associated adverse developmental outcomes. 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.

    Contraception requirements, infertility, male-mediated teratogenicity, menstrual irregularity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during methotrexate treatment. Pregnancy testing should be performed before starting methotrexate in female patients of reproductive potential. These patients should use effective contraception during methotrexate therapy and for at least 6 months after the final methotrexate dose. Women who become pregnant while receiving methotrexate should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during methotrexate therapy and for at least 3 months after the final methotrexate dose due to the risk of male-mediated teratogenicity; methotrexate may cause chromosomal damage to sperm cells. Methotrexate may cause infertility; oligospermia in men and menstrual irregularity or dysfunction in women have been reported during methotrexate therapy and after stopping therapy. It is not known whether infertility is reversible in affected female or male patients.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from methotrexate, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. Methotrexate has been detected in human breast milk with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production, however previous American Academy of Pediatrics recommendations considered methotrexate incompatible with breast-feeding.

    ADVERSE REACTIONS

    Severe

    spontaneous fetal abortion / Delayed / 0-42.5
    pancytopenia / Delayed / 1.0-3.0
    anaphylactoid reactions / Rapid / Incidence not known
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
    GI perforation / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    arachnoiditis / Early / Incidence not known
    coma / Early / Incidence not known
    seizures / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    pulmonary toxicity / Early / Incidence not known
    renal tubular obstruction / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    pericarditis / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    bone fractures / Delayed / Incidence not known
    optic atrophy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    teratogenesis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    stomatitis / Delayed / 2.0-11.0
    thrombocytopenia / Delayed / 3.0-10.0
    leukopenia / Delayed / 1.0-3.0
    anemia / Delayed / 0-1.0
    pneumonitis / Delayed / 1.0-1.0
    dysuria / Early / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    melena / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    aphasia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    neurotoxicity / Early / Incidence not known
    paresis / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    furunculosis / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    osteoporosis / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    scotomata / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    folate deficiency / Delayed / Incidence not known

    Mild

    nausea / Early / 10.0-11.0
    diarrhea / Early / 1.0-11.0
    vomiting / Early / 10.0-11.0
    photosensitivity / Delayed / 0-10.0
    alopecia / Delayed / 0.5-10.0
    dizziness / Early / 0.2-3.0
    pruritus / Rapid / 1.0-3.0
    rash / Early / 0.2-3.0
    headache / Early / 0-1.2
    anorexia / Delayed / 0-1.0
    fever / Early / 0-1.0
    infection / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    hyperhidrosis / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    ocular irritation / Rapid / 0-1.0
    epistaxis / Delayed / 0-1.0
    tinnitus / Delayed / 0-1.0
    vaginal discharge / Delayed / 0-1.0
    gingivitis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    telangiectasia / Delayed / Incidence not known
    ecchymosis / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    fatigue / Early / Incidence not known
    malaise / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    vitamin B6 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and methotrexate may increase methotrexate exposure and increase the risk for methotrexate toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Methotrexate is a BCRP transporter substrate.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Acitretin: (Contraindicated) The combination of methotrexate and acitretin is contraindicated. An increased risk of hepatitis has been reported from the combined use of methotrexate and the retinoid etretinate. Acitretin is the principal active component of etretinate. Although no longer available commercially in the United States, etretinate has been shown to increase methotrexate serum concentrations and cases of hepatotoxicity (e.g., hepatitis) have also been reported in patients receiving etretinate and methotrexate concomitantly.
    Acyclovir: (Moderate) Closely monitor renal function if concomitant use with acyclovir and methotrexate is necessary. Both drugs can cause nephrotoxicity, which may be additive when used together.
    Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. The apparent clearance of adalimumab was decreased by 29 percent after a single dose and by 44 percent after multiple doses of methotrexate. The mean steady state trough concentration of adalimumab was 8 to 9 mcg, ml with concomitant methotrexate versus 5 mcg, ml without methotrexate use. However, no dose adjustment for either drug is needed when methotrexate and adalimumab are used together.
    Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL-2 in combination with chemotherapy agents have not been established; however, concurrent or sequential use of these agents is common but results in various pharmacodynamic drug interaction risks. Aldesleukin is associated with serious adverse reactions affecting many organ systems. Concurrent administration of antineoplastic agents possessing nephrotoxic, myelotoxic, or hepatotoxic effects (e.g., methotrexate), may increase toxicity in these organ systems.
    Alefacept: (Contraindicated) Patients receiving other immunosuppressives should not receive concurrent therapy with alefacept; there is the possibility of excessive immunosuppression and subsequent risks of infection and other serious side effects.
    Allopurinol: (Minor) In vitro studies have shown that allopurinol administered one hour prior to methotrexate may decrease the therapeutic effects of methotrexate.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Aminosalicylate sodium, Aminosalicylic acid: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Amlodipine; Celecoxib: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Apixaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Asparaginase Erwinia chrysanthemi: (Major) L-Asparaginase with methotrexate has shown both therapeutic synergistic and antagonistic effects depending upon the schedule of administration of these agents. When methotrexate is given 3 to 24 hours prior to L-asparaginase, L-asparaginase blocks the antifolate effects of methotrexate and decreases methotrexate toxicity. If L-asparaginase is given prior to methotrexate, the efficacy of methotrexate is decreased.
    Aspirin, ASA: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Caffeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Carisoprodol: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Dipyridamole: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Omeprazole: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates. (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Aspirin, ASA; Oxycodone: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Aspirin, ASA; Pravastatin: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Basiliximab: (Minor) Because basiliximab is an immunosuppressant, additive effects may be seen with other immunosuppressives such as methotrexate.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Betrixaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Bexarotene: (Major) Concomitant use of systemic retinoids, such as bexarotene, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy. Topical retinoid products do not appear to pose this increased risk for liver problems.
    Bismuth Subsalicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Bupivacaine; Meloxicam: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Celecoxib: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Certolizumab pegol: (Moderate) The safety and efficacy of certolizumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with certolizumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy who received certolizumab.
    Chloramphenicol: (Minor) Chloramphenicol may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Chloramphenicol may also displace methotrexate from protein binding sites leading to increased methotrexate levels.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cholestyramine: (Major) The bile-acid sequestrant cholestyramine is well-known to cause drug interactions by binding and decreasing the oral administration of many drugs. Cholestyramine enhances the clearance of methotrexate from the systemic circulation. This interaction has been used therapeutically in patients with methotrexate toxicity. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine.
    Choline Salicylate; Magnesium Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Ciprofloxacin: (Moderate) Renal tubular transport of methotrexate may be inhibited by coadministration with ciprofloxacin. This may potentially lead to increased methotrexate plasma concentrations and increase the risk of methotrexate associated toxic reactions. Therefore, patients on methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
    Cisplatin: (Moderate) Closely monitor renal function if concomitant use with cisplatin and methotrexate is necessary. Both drugs can cause nephrotoxicity, which may be additive when used together.
    Clofarabine: (Major) Avoid the concomitant use of clofarabine and methotrexate due to the risk of additive hepatotoxicity. Coadministration may also increase the risk of additive nephrotoxicity. Additionally, taking these drugs together may alter clofarabine concentrations; clofarabine and methotrexate are both substrates of OAT1 and OAT3.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Colchicine; Probenecid: (Contraindicated) Probenecid inhibits renal elimination of methotrexate, which can cause increased plasma levels and toxicity of methotrexate. In addition, methotrexate can increase uric acid production. Probenecid has also been associated with decreased clearance of methotrexate from the CSF. Concomitant use of methotrexate and probenecid is not recommended because of the increased risk of uric acid neuropathy. If coadministration is necessary, patients receiving this combination should be closely monitored.
    Cyclosporine: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as methotrexate, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully. Additionally, concurrent administration of methotrexate and cyclosporine in patients with rheumatoid arthritis can elevate methotrexate concentrations and decrease the levels of the 7-hydroxy-methotrexate metabolite. Of 20 patients with rheumatoid arthritis that received methotrexate and cyclosporine, the mean peak methotrexate concentration increased 26%, the mean methotrexate AUC increased 18%, and the AUC of the 7-hydroxy-methotrexate metabolite decreased 80% as compared with patients that received methotrexate alone. Cyclosporine concentrations do not appear to be altered, but data is from only 6 patients. Monitoring of methotrexate and cyclosporine concentrations during concurrent cyclosporine therapy is recommended.
    Cytarabine, ARA-C: (Minor) Pre-treatment with methotrexate enhances Ara-CTP formation resulting in increased cytarabine induced cytotoxicity. Simultaneous administration of cytarabine and methotrexate is associated with increased retention of Ara-CTP within the cell.
    Dabigatran: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Daclatasvir: (Minor) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
    Dantrolene: (Moderate) Concomitant administration of methotrexate and dantrolene may result in elevated methotrexate concentrations. Elevated methotrexate concentrations were noted in a girl who received oral dantrolene a day before intravenous methotrexate 12 g/m2 (18 grams). The methotrexate concentration was 418 micromol/L twenty-four hours after the dose. The threshold value of 0.2 micromol/L was reached 324 hours after the start of the methotrexate infusion despite administration of carboxypeptidase-G2, an enzyme that hydrolyzes methotrexate to nontoxic metabolites, at hours 54 and 78. Three weeks later, a methotrexate dose of 10 grams was well-tolerated with a standard decrease in plasma concentrations. The clearance of methotrexate may have been impaired by dantrolene or the metabolite 5-hydroxydantrolene. Also, altered protein binding may have occurred; both dantrolene and methotrexate bind to albumin.
    Dapsone: (Major) Drugs with similar pharmacologic activity, such as dapsone, may lead to additive antifolate effects and bone marrow suppression when used with methotrexate.
    Dexlansoprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Dichlorphenamide: (Major) Concomitant use of dichlorphenamide and methotrexate is not recommended because of an increased risk of methotrexate-related adverse effects. This combination should be avoided, since increased methotrexate exposure may cause severe toxicity. Monitor closely for signs of methotrexate toxicity if coadministration cannot be avoided, including signs and symptoms of bone marrow toxicity/ immunosuppression (sore throat, fever, reduced blood counts, unusual bruising or bleeding) and liver toxicity, as examples. Increased methotrexate exposure is possible. Methotrexate is a sensitive OAT1 substrate. Dichlorphenamide inhibits OAT1.
    Diclofenac: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Diclofenac; Misoprostol: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Diflunisal: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Diphenhydramine; Ibuprofen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Diphenhydramine; Naproxen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Direct Oral Anticoagulants (DOACs): (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking methotrexate. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with methotrexate. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Elbasvir; Grazoprevir: (Moderate) Administering methotrexate with elbasvir; grazoprevir may result in elevated methotrexate plasma concentrations. Methotrexate is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors. (Minor) Administering methotrexate with elbasvir; grazoprevir may result in elevated methotrexate plasma concentrations. Methotrexate is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
    Eltrombopag: (Moderate) Eltrombopag is an inhibitor of OATP1B1 and Breast Cancer Resistance Protein (BCRP). Drugs that are substrates for these transporters, such as methotrexate, may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for increased methotrexate toxicity if these drugs are coadministered. In a clinical study, administration of a single dose of rosuvastatin, another substrate of both OATP1B1 and BCRP, in combination with eltrombopag increased plasma rosuvastatin AUC by 55% and the Cmax by 103%. A 50% rosuvastatin dosage reduction was recommended.
    Esomeprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Esomeprazole; Naproxen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection. (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone has been associated with hepatotoxicity; caution is recommended in combining 17-alpha-alkylated androgens in combination with other medications that have potential hepatotoxic effects (e.g., methotrexate). Monitor liver function periodically; if liver function becomes abnormal or clinical symptoms (e.g., jaundice) develop, discontinue the androgen and determine the etiology. Androgen-induced jaundice is reversible whtih medication discontinuation.
    Ethanol: (Major) Ethanol (alcohol) may increase the risk for liver-related side effects of methotrexate. Patients should be advised to avoid intake of alcoholic beverages during methotrexate therapy. Patients who are noncompliant with alcohol restrictions (e.g., alcoholism) should not receive methotrexate.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Folic acid may compete with methotrexate for entry into cells. However, in some situations, folic acid supplementation may be used to decrease adverse reactions such as mouth sores in patients receiving methotrexate for arthritis and other non-malignant diseases. Folic acid, vitamin B9, is NOT effective for methotrexate rescue therapy since folic acid requires dihydrofolate reductase for bioactivation and methotrexate inhibits this enzyme. Therefore folic acid should not be used to prevent toxicity of moderate- to high-dose methotrexate therapy. (Minor) L-methylfolate should be used cautiously in patients taking methotrexate. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with methotrexate. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Etodolac: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Famotidine; Ibuprofen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Floxuridine: (Minor) Methotrexate given 3 to 24 hours before 5-FU increases the formation of fluorouridine triphosphate and enhances cell kill and toxicity. When 5-FU is given within 24 hours prior to methotrexate, the cytotoxicity of methotrexate is decreased. Floxuridine is metabolized to 5-FU. Like 5-FU, the scheduling of floxuridine and methotrexate when used together is critical. It appears that the more favorable sequence is administering methotrexate prior to 5-FU due to increased RNA toxicity of 5-FU.
    Fluorouracil, 5-FU: (Minor) Methotrexate given 3 to 24 hours before 5-FU increases the formation of fluorouridine triphosphate and enhances cell kill and toxicity. When 5-FU is given within 24 hours prior to methotrexate, the cytotoxicity of methotrexate is decreased. Thus, the scheduling of these agents in combination is critical. It appears that the more favorable sequence is administering methotrexate prior to 5-FU due to increased RNA toxicity of 5-FU.
    Flurbiprofen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Folic Acid, Vitamin B9: (Moderate) Folic acid may compete with methotrexate for entry into cells. However, in some situations, folic acid supplementation may be used to decrease adverse reactions such as mouth sores in patients receiving methotrexate for arthritis and other non-malignant diseases. Folic acid, vitamin B9, is NOT effective for methotrexate rescue therapy since folic acid requires dihydrofolate reductase for bioactivation and methotrexate inhibits this enzyme. Therefore folic acid should not be used to prevent toxicity of moderate- to high-dose methotrexate therapy.
    Food: (Moderate) Concurrent administration of oral methotrexate with food may delay the absorption of methotrexate and decrease the maximum serum concentration. (Moderate) Food or drink that acidifies the urine such as cola can cause elevated methotrexate concentrations. In a patient, acute renal failure was noted 24 hours after drug receipt despite baseline normal renal function. The patient had repeated episodes of reduced urinary pH despite sodium bicarbonate administration. The urinary pH went from 8.5 to 6.5 after the patient consumed 330 ml of Coca-Cola. Urinary pH was maintained at 8 or higher once the patient stopped consuming cola. The plasma methotrexate concentration fell and urinary function eventually returned to normal. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and creatinine concentrations are essential for safe methotrexate administration.
    Foscarnet: (Moderate) The risk of renal toxicity may be increased if foscarnet is used in conjuction with other nephrotoxic agents, such as methotrexate. Avoid concurrent use, unless the potential benefits outweigh the risks to the patient.
    Fosphenytoin: (Major) Avoid concomitant use of methotrexate and fosphenytoin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; fosphenytoin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Fostamatinib: (Moderate) Monitor for methotrexate toxicities that may require methotrexate dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP substrate may increase the concentration of the BCRP substrate. The active metabolite of fostamatinib, R406, is a BCRP inhibitor; methotrexate is a substrate for BCRP. Coadministration of fostamatinib with another BCRP substrate increased the BCRP substrate AUC by 95% and Cmax by 88%.
    Furosemide: (Moderate) Furosemide undergoes significant renal tubular secretion. Concomitant administration of furosemide with other drugs that undergo significant renal tubular secretion, such as methotrexate, may result in decreased effect of furosemide and, conversely, decreased elimination of the other drug. High dose treatment of both furosemide and other drugs that undergo renal tubular secretion may result in increased toxicity of both drugs.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as methotrexate, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and methotrexate as coadministration may increase serum concentrations of methotrexate and increase the risk of adverse effects. Methotrexate is a substrate of breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and methotrexate as coadministration may increase serum concentrations of methotrexate and increase the risk of adverse effects. Methotrexate is a substrate of breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of BCRP.
    Golimumab: (Moderate) The safety and efficacy of golimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.
    Hydrocodone; Ibuprofen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Hydroxychloroquine: (Moderate) Concomitant use of hydroxychloroquine may increase the risk of adverse effects with methotrexate. In a small study, the methotrexate AUC was increased when administered with hydroxychloroquine.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Ibrutinib: (Moderate) Use ibrutinib and methotrexate together with caution; plasma concentrations of methotrexate may increase resulting in increased toxicity. Ibrutinib is a BCRP inhibitor in vitro; methotrexate is a BCRP substrate with a narrow therapeutic index.
    Ibuprofen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Ibuprofen; Oxycodone: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Ibuprofen; Pseudoephedrine: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Indomethacin: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Infliximab: (Moderate) Rheumatoid arthritis patients who received methotrexate in combination with infliximab had higher serum concentrations of infliximab as compared to those who received infliximab alone. Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
    Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Isotretinoin: (Major) Concomitant use of systemic retinoids, such as isotretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy.
    Itraconazole: (Moderate) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with itraconazole, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
    Ketoprofen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Ketorolac: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Lamotrigine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering methotrexate, which also inhibits this enzyme.
    Lansoprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Lansoprazole; Naproxen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection. (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    L-Asparaginase Escherichia coli: (Major) L-Asparaginase with methotrexate has shown both therapeutic synergistic and antagonistic effects depending upon the schedule of administration of these agents. When methotrexate is given 3 to 24 hours prior to L-asparaginase, L-asparaginase blocks the antifolate effects of methotrexate and decreases methotrexate toxicity. If L-asparaginase is given prior to methotrexate, the efficacy of methotrexate is decreased.
    Leflunomide: (Major) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs. The potential for hepatotoxicity should also be considered when such medications would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure. In a small phase III study of leflunomide with methotrexate, 33% of the patients had LFT enzyme elevations of 2-fold the upper limit of normal (ULN) or greater. All of these resolved with either continuation of the medications with dosage adjustment or leflunomide discontinuation. Furthermore, 3.8% of 133 patients with normal LFTs on methotrexate had an ALT serum concentration at least 3 times the ULN with leflunomide addition. In contrast, 0.8% of 130 patients with placebo addition met the criteria. If leflunomide and methotrexate are used concomitantly, the American College of Rheumatology guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. Also, laboratory monitoring for leflunomide needs to be conducted.
    Lesinurad; Allopurinol: (Minor) In vitro studies have shown that allopurinol administered one hour prior to methotrexate may decrease the therapeutic effects of methotrexate.
    Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking methotrexate. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with methotrexate. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
    Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as methotrexate. The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Magnesium Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Mefenamic Acid: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Meloxicam: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Methoxsalen: (Major) Methotrexate may increase the photosensitizing effects of photosensitizing agents used for photodynamic therapy.
    Methyltestosterone: (Moderate) Methyltestosterone has been associated with hepatotoxicity; caution is recommended in combining 17-alpha-alkylated androgens in combination with other medications that have potential hepatotoxic effects (e.g., methotrexate). Monitor liver function periodically; if liver function becomes abnormal or clinical symptoms (e.g., jaundice) develop, discontinue the androgen and determine the etiology. Androgen-induced jaundice is reversible whtih medication discontinuation.
    Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as methotrexate. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Nabumetone: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Naproxen: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Naproxen; Pseudoephedrine: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Naproxen; Sumatriptan: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as methotrexate. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
    Neomycin: (Moderate) Oral neomycin has been shown to inhibit the gastrointestinal absorption of methotrexate. Caution is warranted with concomitant use.
    Nitisinone: (Moderate) Monitor for increased methotrexate-related adverse effects if coadministered with nitisinone. Increased methotrexate exposure is possible. Nitisinone inhibits OAT3. Methotrexate is an OAT3 substrate.
    Nonsteroidal antiinflammatory drugs: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Omeprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Omeprazole; Sodium Bicarbonate: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Osimertinib: (Moderate) Monitor for an increase in methotrexate-related adverse reactions if coadministration with osimertinib is necessary. Methotrexate is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with methotrexate due to the risk of increased oxaliplatin-related adverse reactions. Methotrexate is known to be potentially nephrotoxic; because platinum-containing drugs like oxaliplatin are eliminated primarily through the kidney, oxaliplatin clearance may be decreased by coadministration with nephrotoxic agents.
    Oxaprozin: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pantoprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Paromomycin: (Minor) Paromomycin may decrease the absorption and bioavailability of oral methotrexate. Paromomycin may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.
    Pegaspargase: (Major) L-Asparaginase with methotrexate has shown both therapeutic synergistic and antagonistic effects depending upon the schedule of administration of these agents. When methotrexate is given 3-24 hours prior to L-Asparaginase Escherichia coli, the L-asparaginase blocks the antifolate effects of methotrexate and decreases methotrexate toxicity. If L-asparaginase is given prior to methotrexate, the efficacy of methotrexate is decreased. This could be due to inhibition of protein synthesis preventing progression to the S-phase of the cell cycle. Alternatively, L-asparaginase pretreatment may inhibit methotrexate polyglutamation, which is required for intracellular retention of methotrexate. Cells are refractory to methotrexate for up to 10 days following a single dose of L-asparaginase. During the period following L-asparaginase protein inhibition, there is a period of increased DNA synthesis that leads to increased sensitivity to methotrexate. Since the active component of pegaspargase is L-asparaginase, the same drug-drug interactions reported with L-asparaginase would be expected with pegaspargase. It is recommended to give L-asparaginase or pegaspargase at least 10-14 days prior to methotrexate or shortly after methotrexate administration.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Penicillins: (Major) Penicillins may reduce the renal clearance of methotrexate. Increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with concurrent administration of high or low doses of methotrexate and penicillins. Patients should be carefully monitored while receiving this combination.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with methotrexate. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Phenytoin: (Major) Avoid concomitant use of methotrexate and phenytoin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; phenytoin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Photosensitizing agents (topical): (Major) Methotrexate may increase the photosensitizing effects of photosensitizing agents used for photodynamic therapy.
    Piroxicam: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Porfimer: (Major) Avoid coadministration of porfimer with methotrexate due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like methotrexate may increase the risk of a photosensitivity reaction.
    Probenecid: (Contraindicated) Probenecid inhibits renal elimination of methotrexate, which can cause increased plasma levels and toxicity of methotrexate. In addition, methotrexate can increase uric acid production. Probenecid has also been associated with decreased clearance of methotrexate from the CSF. Concomitant use of methotrexate and probenecid is not recommended because of the increased risk of uric acid neuropathy. If coadministration is necessary, patients receiving this combination should be closely monitored.
    Proton pump inhibitors: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Pyrimethamine: (Major) Drugs with similar pharmacologic activity, such as pyrimethamine, may lead to additive antifolate effects and bone marrow suppression when used with methotrexate. Concurrent use of pemetrexed and methotrexate is unlikely, however, the combination should be avoided.
    Pyrimethamine; Sulfadoxine: (Major) Drugs with similar pharmacologic activity, such as pyrimethamine, may lead to additive antifolate effects and bone marrow suppression when used with methotrexate. Concurrent use of pemetrexed and methotrexate is unlikely, however, the combination should be avoided.
    Rabeprazole: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Regorafenib: (Moderate) Monitor for an increase in methotrexate-related adverse reactions if coadministration with regorafenib is necessary. Methotrexate is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Reteplase, r-PA: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Rilonacept: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and methotrexate. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Rituximab: (Moderate) These drugs are commonly used together. However, coadministration of rituximab with immunosuppressive DMARDs, like methotrexate, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of methotrexate did not alter the pharmacokinetics of rituximab.
    Rituximab; Hyaluronidase: (Moderate) These drugs are commonly used together. However, coadministration of rituximab with immunosuppressive DMARDs, like methotrexate, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of methotrexate did not alter the pharmacokinetics of rituximab.
    Rivaroxaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Rofecoxib: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Rolapitant: (Major) Avoid the concurrent use of methotrexate and rolapitant if possible; if coadministration is necessary, monitor methotrexate levels and watch for methotrexate-related adverse effects. Methotrexate is a substrate of the Breast Cancer Resistance Protein (BCRP), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
    Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as methotrexate. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
    Salicylates: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Salsalate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
    Sapropterin: (Moderate) Significant increases in serum phenylalanine concentrations have been noted after methotrexate infusions of 58 g/m2 to 46 patients with an unknown PKU status. Increased concentrations occurred at the end of the infusion in 95% of methotrexate cycles, but large inter-individual variations in the concentrations existed. Individual predispositions may exist, as maximal phenylalanine concentrations were of the same magnitude in a given patient. Phenylalanine concentrations returned to baseline concentrations 24 hours after the end of the methotrexate infusion. Methotrexate has been shown to decrease endogenous tetrahydrobiopterin (BH4) concentrations by inhibiting the enzyme dihydropteridine reductase; a similar reaction could be expected in patients receiving sapropterin. Dihydropteridine reductase recycles quinonoid dihydropterin (q-BH2) back to the active cofactor BH4. Reduction of BH4 could make management of hyperphenylalaninemia more difficult. Drugs that inhibit folate metabolism should be used with caution in patients taking sapropterin.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Simeprevir: (Minor) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with simeprevir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with methotrexate. Taking these medications together may increase the plasma concentrations of methotrexate. Methotrexate is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Voxilaprevir is an BCRP inhibitor.
    Streptokinase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Sulfadiazine: (Moderate) Concurrent use of sulfadiazine and methotrexate may increase the incidence of methotrexate-related adverse events. Methotrexate is partially bound to albumin, and toxicity may be increased because of displacement by sulfonamides.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid concurrent use of sulfamethoxazole and methotrexate. Sulfonamides can displace methotrexate from plasma protein binding sites and compete with renal transport of methotrexate, thus increasing free methotrexate concentrations. Increased bone marrow suppression has been reported in patients receiving methotrexate and sulfamethoxazole; trimethoprim, potentially due to decreased tubular secretion and/or additive antifolate effects. (Major) Avoid concurrent use of trimethoprim and methotrexate. Increased bone marrow suppression has been reported in patients receiving methotrexate and sulfamethoxazole; trimethoprim, potentially due to decreased tubular secretion and/or additive antifolate effects.
    Sulfasalazine: (Moderate) Concurrent use of sulfasalazine and methotrexate may increase the incidence of methotrexate-related adverse events. Methotrexate is partially bound to albumin, and toxicity may be increased because of displacement by sulfonamides.
    Sulfonylureas: (Major) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as oral sulfonylureas could cause methotrexate-induced toxicity. Due to the potential toxicity of methotrexate, interactions with sulfonylureas can be very serious even if methotrexate is administered in low doses such as in the treatment of rheumatic diseases.
    Sulindac: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Tacrine: (Major) Concomitant administration of tacrine with methotrexate may cause additive hepatotoxicity. Tacrine should be used with great caution in patients receiving other medications with known hepatotoxic potential.
    Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and methotrexate due to the potential for increased plasma concentrations of methotrexate increasing the risk of adverse effects. Methotrexate dose adjustment may be needed with coadministration. Methotrexate is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Tedizolid: (Moderate) If possible, stop use of oral methotrexate temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for methotrexate-associated adverse events. Methotrexate plasma concentrations may be increased when oral methotrexate is administered concurrently with oral tedizolid. Methotrexate is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Temozolomide: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as methotrexate may result in additive effects.
    Tenecteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Teniposide: (Moderate) Use methotrexate and teniposide together with caution; increased methotrexate levels and increased methotrexate toxicity may occur. The plasma clearance of methotrexate was slightly increased when these agents were co-administered in a pharmacokinetic study. Additionally, increased intracellular methotrexate levels were observed in vitro in the presence of teniposide.
    Teriflunomide: (Major) Teriflunomide is an inhibitor of the hepatic uptake transporter organic anion transporting polypeptide OATP1B1 and the renal uptake organic anion transporter OAT3, while methotrexate is a substrate of both of these transporters. Concomitant use may produce greater potential for hepatotoxicity. The potential for hepatotoxicity should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
    Tetracyclines: (Moderate) Oral antibiotics such as tetracyclines may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Tetracyclines may displace methotrexate from protein binding sites leading to increased methotrexate levels. A case report describes a patient who received oral doxycycline in combination with her eleventh course of high-dose methotrexate. Methotrexate serum concentrations indicated a prolonged half-life and the patient developed severe gastrointestinal toxicity and myelosuppression including neutropenic fever. This resulted in two prolonged hospital stays and a delay in her next course of chemotherapy.
    Theophylline, Aminophylline: (Moderate) Methotrexate may decrease the clearance of aminophylline. Aminophylline levels should be closely monitored when used concurrently with methotrexate. In a small number of patients with either leukemia or lymphoma and acute methotrexate neurotoxicity, theophylline attenuated methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations. (Moderate) Methotrexate may decrease the clearance of theophylline. Theophylline levels should be closely monitored when used concurrently with methotrexate. In a small number of patients with either leukemia or lymphoma and acute methotrexate neurotoxicity, theophylline attenuated methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations.
    Thiazide diuretics: (Moderate) Coadministration of thiazide diuretics and antineoplastic agents such as methotrexate may result in reduced renal excretion of the antineoplastic agent and therefore increased myelosuppressive effects.
    Thrombolytic Agents: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Tolmetin: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Tretinoin, ATRA: (Major) Concomitant use of systemic retinoids, such as tretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy. Topical retinoid products do not appear to pose this increased risk for liver problems.
    Trimethoprim: (Major) Avoid concurrent use of trimethoprim and methotrexate. Increased bone marrow suppression has been reported in patients receiving methotrexate and sulfamethoxazole; trimethoprim, potentially due to decreased tubular secretion and/or additive antifolate effects.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Urokinase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
    Valacyclovir: (Moderate) Closely monitor renal function if concomitant use with valacyclovir and methotrexate is necessary. Both drugs can cause nephrotoxicity, which may be additive when used together.
    Valdecoxib: (Major) In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may increase the risk of GI bleeding in patients with methotrexate-induced myelosuppression or mask fever, pain, swelling and other signs and symptoms of an infection.
    Vancomycin: (Moderate) Recent exposure to vancomycin, in the absence of overt renal impairment, may adversely affect methotrexate excretion and increase risk of toxicity. Assessing renal function in patients who have received vancomycin may be prudent, so appropriate methotrexate dose modifications can be made. In a case report, two patients who had received a methotrexate-containing chemotherapy regimen initially displayed appropriate methotrexate clearance. However, administration of vancomycin in between chemotherapy treatment cycles appears to have caused markedly prolonged methotrexate clearance (i.e., 170 to 231 hours to reach serum methotrexate concentrations of less than 0.2 micro-M). Subclinical renal impairment was documented in both cases following vancomycin administration, which eventually resolved; subsequent methotrexate cycles, of the same dose, showed appropriate clearance.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with methotrexate is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like methotrexate may increase the risk of a photosensitivity reaction.
    Vincristine Liposomal: (Major) Monitor for increased serum concentrations and toxicities of methotrexate when administered concurrently with vincristine. When given 0 to 1 hour prior to methotrexate, vincristine increases the cellular retention of methotrexate by inhibiting methotrexate efflux from the cell. Since the window of opportunity for a synergistic interaction is short, the effects in vivo are clinically not seen. Therapeutic synergism is noted when methotrexate is given 8 to 48 hours before vincristine. The mechanism for this interaction has not been clearly defined.
    Vincristine: (Major) Monitor for increased serum concentrations and toxicities of methotrexate when administered concurrently with vincristine. When given 0 to 1 hour prior to methotrexate, vincristine increases the cellular retention of methotrexate by inhibiting methotrexate efflux from the cell. Since the window of opportunity for a synergistic interaction is short, the effects in vivo are clinically not seen. Therapeutic synergism is noted when methotrexate is given 8 to 48 hours before vincristine. The mechanism for this interaction has not been clearly defined.
    Warfarin: (Major) Avoid concomitant use of methotrexate and warfarin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; warfarin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
    Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Due to the potential for serious adverse reactions in nursing infants from methotrexate, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. Methotrexate has been detected in human breast milk with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production, however previous American Academy of Pediatrics recommendations considered methotrexate incompatible with breast-feeding.

    MECHANISM OF ACTION

    Methotrexate competitively inhibits dihydrofolate reductase, which is the enzyme responsible for converting folic acid to reduced folate cofactors (i.e., tetrahydrofolate). Reduced folates are required for metabolic transfer of 1-carbon units in the synthesis of thymidylate and purine nucleotides. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues that have a high rate of cellular metabolism such as malignant cells, bone marrow, fetal cells, hair follicles, buccal and intestinal mucosa, and cells of the urinary bladder are generally more sensitive to the effects of methotrexate. Methotrexate is cycle-specific and inhibits cells primarily in the S-phase. At doses greater than 30 mg/m2, methotrexate inhibits cells in the S-phase and slows the entry of cells from G1- into S-phase. Methotrexate may inhibit protein synthesis due to the reduction of reduced folate cofactors. This may be the mechanism by which higher doses of methotrexate arrest cells in the G1-phase. The duration of exposure to methotrexate once the initial threshold for cytotoxicity is exceeded is a critical factor in the cellular toxicity of methotrexate. Therefore, prolonged exposure even at low plasma concentrations of methotrexate may result in serious toxicity and increased cytotoxicity.
     
    Methotrexate may enter the cell by one of two transport systems. The primary process by which methotrexate enters the cell is the reduced-folate carrier that has a high affinity for reduced folates and methotrexate, and the second is the human folate receptor, which has a higher affinity for folic acid and reduced folates than methotrexate. Methotrexate may also enter the cell by passive diffusion, but this mechanism is not usually critical unless methotrexate is given at high doses (serum concentrations greater than 100 micromol). Once inside the cell, methotrexate undergoes polymerization of the glutamic acid side chain, similar to endogenous folates, to form methotrexate polyglutamate (MTX-PG). While both methotrexate and MTX-PG competitively inhibit dihydrofolate reductase, MTX-PG has enhanced binding to and inhibition of the enzyme and due to its large size, has reduced efflux out of the cell as compared to the parent compound. As compared with the parent drug, polyglutamate derivatives also have a greater ability to inhibit other folate-dependent enzymes such as thymidylate synthetase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase. The process of polyglutamation happens more readily in tumor cells than in benign mammalian cells, which partially explains selectivity of methotrexate for tumor cells. Formation of MTX-PG is dependent upon intracellular methotrexate concentrations and the duration of exposure. High-dose methotrexate therapy takes advantage of these mechanisms to overcome resistance to conventional dose therapy. The high extracellular concentrations achieved with high-dose therapy may facilitate the entry of methotrexate into the cell and may bypass resistance secondary to changes in membrane transport systems. Due to increased methotrexate exposure and intracellular concentrations, the formation of MTX-PG may be increased with high-dose methotrexate therapy.
     
    Methotrexate resistance may develop through a number of mechanisms. Resistance may be due to decreased intracellular influx of methotrexate, decreased binding of methotrexate to dihydrofolate reductase, or increased activity or concentration of dihydrofolate reductase. A fourth mechanism, decreased formation of MTX-PG, can also occur and may be important for resistance to high-dose methotrexate. Reduced MTX-PG formation is time dependent with resistance occurring only during short-term exposure (less than 24 hours) but not during prolonged exposure. Decreased intracellular transport of methotrexate and increased synthesis of dihydrofolate reductase are common mechanisms of acquired resistance to methotrexate. Myelocytic leukemia blast cells are intrinsically resistant to methotrexate. The resistance seems to be due to decreased retention of methotrexate in cells as a result of reduced polyglutamation.
     
    The mechanism of action in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and in psoriasis is unknown. Methotrexate has immunosuppressive properties and can thus, exhibit anti-inflammatory activity. The efficacy of methotrexate for rheumatoid arthritis is likely multifactorial; however, inhibition of AICAR transformylase appears to be a main mechanism, as an inverse relationship between urinary AICA concentrations and disease activity has been noted. The enzyme AICAR transformylase which is inhibited by methotrexate catalyzes the last step in the de novo biosynthesis of inosine monophosphate, which may cause immunosuppression. Also, AICA or its metabolites may be immunotoxic. Furthermore, inhibition of AICAR transformylase by methotrexate and its metabolites leads to AICA riboside accumulation, which inhibits adenosine deaminase. This results in increased adenosine concentrations which inhibit lymphocyte proliferation by the interaction of adenosine with A2 and A3 receptors. Therefore, at low doses, methotrexate may selectively inhibit replication and function of T and B lymphocytes. In addition, methotrexate can suppress the secretion of interleukin-1, interferon-gamma, and tumor necrosis factor, increase the secretion of interleukin-4, impair the release of histamine from basophils, and decrease chemotaxis of neutrophils.

    PHARMACOKINETICS

    Methotrexate may be given orally, IV, IM, subcutaneously, or intrathecally. After IV administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate is 50% bound to serum plasma proteins. It may be displaced from plasma albumin by various compounds including chloramphenicol, phenytoin, tetracyclines, salicylates, and sulfonamides. Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally; high CSF concentrations of the drug may be attained by intrathecal administration. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed joints than in joints without inflammation. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints.
     
    After absorption, methotrexate undergoes hepatic and intracellular metabolism to a polyglutamated form (MTX-PG), which can be converted back to methotrexate by hydrolase enzymes. The retention of MTX-PG varies with the cells of different tissues and tumors. A small amount of methotrexate is metabolized to 7-hydroxymethotrexate by aldehyde oxidase. Methotrexate also undergoes minor metabolism to 7-hydroxymethotrexate; this may account for 7% to 33% of the drug excreted during the terminal phase of elimination. Accumulation may become significant following high doses. The aqueous solubility of 7-hydroxymethotrexate is 3-to 5-fold lower than the solubility of methotrexate. In addition, methotrexate is subject to metabolism by intestinal flora after oral administration to an inactive metabolite, DAMPA. However, this metabolite may cross-react with radioimmunoassays for methotrexate. When methotrexate is given at low doses (30 mg/m2) metabolites account for less than 10% of the drug excreted. When the same dose is given orally, approximately 35% of the dose is excreted as metabolites. This has lead to the conclusion that the majority of methotrexate metabolism occurs primarily in the GI tract and through enterohepatic circulation. The terminal half-life of methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, rheumatoid arthritis, or low-dose antineoplastic therapy (less than 30 mg/m2). Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg. Following IV administration of high-dose methotrexate, the terminal half-life is 8 to 15 hours. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. Methotrexate can exit slowly from third space accumulations resulting in prolonged terminal plasma half-life and toxicity.
     
    Renal excretion by glomerular filtration and active tubular secretion is the primary route of elimination and is dependent upon dosage and route of administration. After IV administration, 80% to 90% of an administered dose is excreted unchanged in the urine within 24 hours. Biliary excretion accounts for less than 10% of methotrexate elimination. The rate of methotrexate clearance varies widely and is generally decreased at higher doses. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent on the duration of exposure rather than the peak level achieved; delayed drug clearance has been identified as a major factor responsible for methotrexate toxicity. Pharmacokinetic monitoring of serum methotrexate concentrations may help identify patients at high risk for toxicity and guide leucovorin dosing.
     
    Affected cytochrome P450 isoenzymes and transporters: None

    Oral Route

    Oral absorption of methotrexate appears to be dose dependent. Peak plasma concentrations are attained within 0.75 to 6 hours following administration. Single oral doses greater than 80 mg/m2 may not be completely absorbed, possibly due to a saturation effect, while lower doses are well absorbed; there appears to be a plateau effect on bioavailability at doses of 15 mg or higher. At an oral dose of 30 mg/m2 or less, the mean bioavailability of methotrexate is about 60%; the absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Oral administration with food did not affect the AUC of methotrexate; however, the Cmax decreased by 50% and absorption was delayed. In addition, oral methotrexate is subject to first-pass metabolism in the liver that may decrease bioavailability and systemic exposure. Among adults with rheumatoid arthritis who got a median dose of 30 mg weekly (range, 25 mg to 40 mg) orally and subcutaneously, the mean bioavailability after oral administration was 0.64 (range, 0.21 to 0.96) as compared with subcutaneous administration. After administration of 12.5 to 25 mg to patients with Crohn's disease, the mean systemic exposure per milligram of methotrexate was 261 nmol x hour/L when given orally and 281 nmol x hour/L when given orally with 5 mg of oral folic acid, as compared to 360 nmol x hour/L when given subcutaneously.

    Intramuscular Route

    Methotrexate is generally completely absorbed from parenteral routes of administration, with a Tmax of 30 to 60 minutes after IM injection. Similar blood concentrations were obtained after IM or subcutaneous administration of weekly doses of 7.5 mg to 22.5 mg to 8 patients; 4 had rheumatoid arthritis, 2 had psoriatic arthritis, 1 had polymyositis, and 1 had Wegener's granulomatosis.

    Subcutaneous Route

    The bioavailability of a subcutaneous methotrexate formulation (Otrexup) was similar to IM administration at the same dose in patients with rheumatoid arthritis; systemic exposure of methotrexate was higher with subcutaneous administration of Otrexup compared to oral administration at the same dose. The bioavailability of Otrexup was 17% and 13% higher compared with oral methotrexate at doses of 10 mg and 15 mg, respectively; the bioavailability of Otrexup was 31% and 36% higher compared with oral methotrexate at doses of 20 mg and 25 mg, respectively. Otrexup absorption is similar when administered in the abdomen or thigh. In a relative bioavailability study of a different subcutaneous formulation of methotrexate (Rasuvo) in healthy subjects, the AUC of methotrexate at doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg was 35%, 49%, 51%, and 68% higher than the same dose of orally administered methotrexate, respectively. In another relative bioavailability study in psoriasis patients, the AUC of Rasuvo at a dose of 30 mg was similar to the same dose of methotrexate administered IM. After administration of 12.5 mg to 25 mg to patients with Crohn's disease, the mean systemic exposure per milligram of methotrexate was 360 nanomole (nmol) x hour/L when given subcutaneously, as compared to 261 nmol x hour/L when given orally and 281 nmol x hour/L when given orally with 5 mg of oral folic acid.

    Other Route(s)

    Intrathecal injection
    Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration. After intrathecal injection of methotrexate, absorption into the systemic circulation occurs slowly and may result in prolonged plasma concentrations. A pharmacokinetic analysis which included 2 patients (ages 9 and 17 years) demonstrated that intrathecal administration of a dose of 12 mg/m2 produced plasma concentrations 24 hours post-dose that were 10-fold greater than those after oral administration. Pharmacologically significant plasma concentrations were present more than twice as long with intrathecal administration compared to oral administration. The duration of maintenance of significant plasma concentrations of methotrexate following intrathecal administration exceeded 24 hours in both patients and reached 48 hours in 1 patient. Plasma half-lives were 1.9 and 5 to 9.9 hours following oral and intrathecal administration, respectively.