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  • CLASSES

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

    BOXED WARNING

    Exfoliative dermatitis, serious rash

    Methotrexate is contraindicated in patients with a severe hypersensitivity to the drug. 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.

    Intrauterine fetal death, pregnancy

    Methotrexate is contraindicated in pregnancy in women who are being treated for nonmalignant diseases (e.g., psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis). Methotrexate can cause intrauterine fetal death and/or congenital anomalies when administered to a pregnant woman. In women of reproductive potential, methotrexate use is not recommended unless the benefits of therapy are expected to outweigh the considered risks. Advise females of reproductive potential to avoid pregnancy while taking methotrexate; counsel these patients on the fetal risk if pregnancy occurs.

    Anemia, bone marrow suppression, herpes infection, immunosuppression, infection, neutropenia, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Patients with psoriasis or rheumatoid arthritis who have preexisting bone marrow suppression such as leukopenia, thrombocytopenia, or significant anemia should not receive methotrexate. 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. Obtain blood counts at baseline and periodically during treatment. In general, hematologic parameters should be monitored at least monthly. Stop the drug immediately in patients with psoriasis or rheumatoid arthritis if significant bone marrow suppression develops. In patients with neoplastic disease, recovery of bone marrow function should be established prior to administering the next course of treatment. Patients with acute leukemia may require treatment despite severe bone marrow suppression. Use is contraindicated in patients with preexisting immunosuppression. Patients with profound neutropenia and fever should be evaluated immediately and usually require broad-spectrum antibiotics. Pancytopenia, including leukopenia, neutropenia, and thrombocytopenia, contraindicates administration of the next dose. Administration should be delayed until the WBC is more than 1,500/mm3, the neutrophil count is more than 200/mm3, and the platelet count is more than 75,000/mm3. Patients with an active infection should be treated for the infection prior to receiving methotrexate. Dosage reduction or discontinuation may be considered in patients who develop severe infections. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. Methotrexate should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Administration requires an experienced clinician whose knowledge and experience includes antimetabolite therapy, due to the potential of serious or fatal adverse reactions. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor patients for bone marrow toxicities. Patients should be informed by their clinicians of the risks involved and be under a clinician's care throughout treatment.

    Diabetes mellitus, hypoalbuminemia, pulmonary disease, pulmonary fibrosis, pulmonary toxicity

    Methotrexate therapy can produce potentially fatal pulmonary toxicity, including acute or chronic interstitial pneumonitis and pulmonary fibrosis. Methotrexate-induced lung disease may occur acutely at any time during therapy, has been reported at low doses, and is not always fully reversible. Pulmonary symptoms, especially a dry, nonproductive cough, may require treatment interruption and careful investigation. Pulmonary function tests may be useful if toxicity is suspected, especially if baseline measurements are available. Therapy should be discontinued if the patient develops pulmonary symptoms such as fever, dry cough, dyspnea, chest pain, hypoxemia, and radiographic evidence of pulmonary infiltrates. Pulmonary reactions are rare but usually occur during the initial period of methotrexate therapy. The following are risk factors for pulmonary toxicity in rheumatoid arthritis patients treated with methotrexate: diabetes mellitus; older age; rheumatoid pleuropulmonary involvement; 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. History of pulmonary disease, extraarticular manifestations of rheumatoid arthritis, smoking (men only), and non-sedentary occupations (women only) have also been suggested as risk factors for methotrexate-induced pulmonary toxicity. Methotrexate should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Only physicians whose knowledge and experience includes antimetabolite therapy should administer methotrexate due to the potential of serious adverse reactions, which can be fatal. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor patients for lung toxicities. Patients should be informed by their physicians of the risks involved and be under a physician's care throughout treatment.

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

    Methotrexate is metabolized by the liver and undergoes enterohepatic circulation. Use is contraindicated in patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic hepatic disease, or other chronic hepatic disease; further, methotrexate should be given cautiously to any patient with a personal or family history of hepatic disease or significant exposure to liver toxins. Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis but generally only after prolonged use. Risk factors for hepatotoxicity include alcoholism, obesity, diabetes mellitus, hyperlipidemia, duration of therapy, and advanced age. In general, monitor liver function every 1 to 2 months and more frequently when initiating or changing therapy, or during periods of increased risk of elevated methotrexate levels (e.g., dehydration). Acutely, liver enzyme elevations are frequently seen, but elevations are usually transient, asymptomatic, and do not appear predictive of subsequent hepatic disease. Persistent abnormalities and/or hypoalbuminemia may be indicators of serious hepatotoxicity and require further evaluation. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported. Fibrosis and cirrhosis may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. In psoriatic patients, hepatotoxicity appears to be a function of the cumulative dose. During psoriasis treatment, liver function tests (LFTs) including albumin should be performed prior to treatment; however, the relationship between abnormal LFTs and hepatotoxicity in patients with psoriasis is not established, and hepatotoxicity is only detectable by biopsy. 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 1 to 1.5 g of methotrexate. However, psoriasis guidelines suggest that 3.5 to 4 g instead of 1 to 1.5 g of cumulative methotrexate may be a more appropriate time frame for the first liver biopsy in patients without preexisting risk factors for hepatotoxicity. The National Psoriasis Foundation suggests 3 options in patients without risk factors for hepatic toxicity who reach a cumulative dose of 3.5 to 4 g oral methotrexate with normal LFTs: perform a liver biopsy, continue to monitor without a biopsy, or switch to an alternative agent if possible. In patients with at least 1 risk factor for hepatic toxicity, consider delayed baseline liver biopsy (after 2 to 6 months of therapy to establish medication efficacy and tolerability and avoid unnecessary biopsies in those who do not tolerate the drug or show a lack of response) with repeated biopsies after every 1 to 1.5 g of methotrexate. Moderate fibrosis or any cirrhosis should lead to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy at 6 months. In rheumatoid arthritis patients, age at first use of methotrexate and duration of methotrexate therapy have been reported as risk factors for hepatotoxicity; other risk factors similar to those seen in psoriasis may also have a role. LFTs should be performed at baseline and every 4 to 8 weeks in patients receiving methotrexate for rheumatoid arthritis. Unlike psoriasis patients, persistent abnormal LFTs may precede hepatotoxicity in patients with rheumatoid arthritis. Pretreatment liver biopsy should be performed in rheumatoid arthritis 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 should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Only physicians whose knowledge and experience includes antimetabolite therapy should administer methotrexate due to the potential of serious adverse reactions, which can be fatal. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor patients for liver toxicities. Patients should be informed by their physicians of the risks involved and be under a physician's care throughout treatment.

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

    Ensure correct formulation selection of preservative-free methotrexate for high-dose administration, intrathecal administration, administration to neonatal infants, and in patients with known benzyl alcohol hypersensitivity. Benzyl alcohol is present in preservative-containing formulations. 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.

    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 the third space fluid prior to treatment and monitor methotrexate serum levels and for signs and symptoms of methotrexate toxicity. A dose reduction or discontinuation may be necessary. Pleural effusions must be drained dry prior to starting high-dose methotrexate therapy.

    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 (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates) are at risk for increased toxicity due to prolonged elevated methotrexate serum concentrations. Obtain renal function tests at baseline and monitor for toxicity in all patients who are receiving methotrexate; monitor renal function every 1 to 2 months in patients with rheumatoid arthritis and psoriasis and more frequently in patients with cancer, when initiating or changing therapy, or in patients with conditions that might increase the risk of elevated methotrexate levels (e.g., dehydration). Nonreversible oliguric renal failure may occur following high-dose methotrexate therapy in patients with delayed methotrexate elimination; nephrotoxicity is caused by the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. NSAIDs should not be given prior to or concomitantly with high-dose methotrexate due to an increased risk of death from severe hematologic and gastrointestinal toxicity. Use caution when administering high-dose methotrexate with other nephrotoxic chemotherapy, such as cisplatin. Ensure adequate hydration and urinary alkalinization during and after high-dose therapy; leucovorin rescue must be administered starting at 24 hours from the start of the methotrexate infusion. Monitor renal function prior to, at 24 hours after the start of the methotrexate infusion, and then at least daily until the methotrexate level is below 0.05 micromolar. Do not initiate therapy in patients unless the serum creatinine (Scr) level is normal and the creatinine clearance (CrCl) is greater than 60 mL/minute. If the SCr level increases by 50% or more compared with a prior value, measure the CrCl to ensure a CrCl greater than 60 mL/minute. Closely monitor fluid and electrolyte status if renal failure develops. Acute, intermittent hemodialysis with a high-flux dialyzer may be useful in these patients. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function; do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, tumor lysis syndrome (TLS)

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and decreased urine output may be indicative of methotrexate-induced tumor lysis syndrome (TLS). Appropriate measures (e.g. aggressive hydration and allopurinol) must be taken to prevent or alleviate severe electrolyte imbalances and renal toxicity during and following chemotherapy administration in patients with large, chemosensitive tumors.

    Diarrhea, gastroenteritis, GI bleeding, GI disease, GI perforation, peptic ulcer disease, stomatitis, ulcerative colitis, vomiting

    Methotrexate should be used with extreme caution in patients with GI disease such as peptic ulcer disease or ulcerative colitis. Unexpectedly severe, sometimes fatal gastrointestinal toxicity and GI bleeding have been reported with concomitant administration of methotrexate (usually in high dosage) and some nonsteroidal anti-inflammatory drugs (NSAIDs). If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, discontinue methotrexate until recovery occurs. If methotrexate is not discontinued, hemorrhagic gastroenteritis and death from GI perforation may occur.

    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 bone necrosis. Prior or concurrent cranial irradiation has been associated with 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 use a sunscreen with a SPF of at least 15 during sunlight (UV) exposure.

    Lymphoma

    Malignant lymphomas may occur in patients receiving low-dose methotrexate. Malignant lymphomas may regress following withdrawal of methotrexate and thus, may not require cytotoxic treatment. Discontinue methotrexate first and if the lymphoma does not regress, institute appropriate treatment.

    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 or breast-feeding or who have alcoholism, alcoholic liver disease, or chronic liver disease; immunodeficiency syndromes; or pre-existing blood dyscrasias

    COMMON BRAND NAMES

    Otrexup, Rasuvo, Rheumatrex, Trexall, Xatmep

    HOW SUPPLIED

    Methotrexate Sodium Intra-Arterial Inj Pwd F/Sol: 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 Sol: 1mL, 25mg
    Methotrexate Sodium Intramuscular Sol: 1mL, 25mg
    Methotrexate Sodium Intrathecal Inj Pwd F/Sol: 1g
    Methotrexate Sodium Intrathecal Inj Sol: 1mL, 25mg
    Methotrexate Sodium Intravenous Inj Pwd F/Sol: 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).
    Oral and Intramuscular dosage (tablet and solution for injection ONLY)
    Adults, Adolescents, and Children

    3.3 mg/m2 PO/IM daily for 4 to 6 weeks or until remission occurs; followed by twice weekly maintenance therapy with a total weekly dose of 30 mg/m2 PO/IM. Children receiving doses of 20 to 30 mg/m2/week (0.65 to 1 mg/kg/week) may have better absorption and fewer GI side effects if methotrexate is administered either IM or subcutaneous. Several different combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The prescriber should be familiar with new advances in antileukemic therapy.

    Intravenous dosage
    Adults, Adolescents, and Children

    3.3 mg/m2 IV daily for 4 to 6 weeks or until remission occurs; followed by 2.5 mg/kg IV every 14 days or 30 mg/m2 IM weekly as maintenance therapy. High dose methotrexate (1 to 10 g/m2 IV or higher) may be given for intensification of a complete remission or treatment of refractory leukemia. High dose therapy may be preceded by a loading dose (e.g., 200 mg/m2), with the full maintenance dose subsequently administered over 1 to 42 hours. Plasma methotrexate concentrations must be monitored, and leucovorin rescue therapy must be provided.

    Oral dosage (oral solution)
    Children and Adolescents

    20 mg/m2/dose PO once weekly initially. Continuation of appropriate dosing requires periodic monitoring of ANC and platelet count to assure sufficient drug exposure and adjust for excessive hematologic toxicity. The recommended dose should be taken once weekly; mistaken daily use has led to fatal toxicity.

    For the treatment of non-Hodgkin's lymphoma (NHL), including Burkitt's lymphoma.
    For cutaneous T-cell lymphoma (CTCL), (a.k.a. mycosis fungoides).
    Oral dosage
    Adults

    In early stages, 5—50 mg PO once weekly. In patients who have responded poorly to once weekly therapy, 15—37.5 mg PO twice weekly has been used. Dose adjustment is guided by patient response and toxicity.

    Intramuscular or Intravenous dosage
    Adults

    In the early stages, 50 mg IM/IV once weekly; 15—37.5 mg IM/IV twice weekly in patients who have responded poorly to once weekly treatment has been used. Dose adjustment is guided by patient response and toxicity. Combination regimens including high-dose methotrexate IV with leucovorin have been used in patients with more advanced disease.

    Intravenous dosage
    Adults, Adolescents and Children

    Many different combination regimens exist but two common ones include m-BACOD (methotrexate 200 mg/m2 IV days 8 and 15 every 21 days in combination with bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone); or ProMACE-CytaBOM (methotrexate 120 mg/m2 IV on day 8 every 28 days in combination with cyclophosphamide, doxorubicin, etoposide, prednisone, cytarabine, bleomycin, and vincristine). High dose methotrexate (1—10 g/m2 IV or higher) may be given for high-grade or refractory NHL or Burkitt's lymphoma. These doses require leucovorin rescue therapy (see Leucovorin dosing) and monitoring of methotrexate levels (see Therapeutic Monitoring). An alternative regimen in children is 200—500 mg/m2 IV every 28 days, in combination with other chemotherapeutic agents.

    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.
    NOTE: The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume within several years. Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adult patients. Therefore, the dosing of intrathecal methotrexate should be based on the age not the body surface area.
    Intrathecal dosage (Preservative-free solutions only)
    Adults, Adolescents and Children >= 3 years

    2—15 mg intrathecally every 2—7 days until CSF is normal. Administration at intervals of < 1 week may result in increased toxicity. Methotrexate is usually administered intrathecally until the CSF cell count returns to normal. For the prophylaxis of meningeal leukemia, the dosage is the same as for treatment but the intervals are extended and vary by treatment protocol. The maximum recommended dose to be given intrathecally is 15 mg. For elderly patients, a dose reduction may be indicated due to a decrease in CSF volume and turnover that occurs with aging.

    Children 24—35 months

    10 mg intrathecally every 2—5 days until CSF is normal. For the prophylaxis of meningeal leukemia, the dosage is the same as for treatment but the intervals are extended and vary by treatment protocol.

    Children 12—23 months

    8 mg intrathecally every 2—5 days until CSF is normal. For the prophylaxis of meningeal leukemia, the dosage is the same as for treatment but the intervals are extended and vary by treatment protocol.

    Infants < 12 months

    6 mg intrathecally every 2—5 days until CSF is normal. For the prophylaxis of meningeal leukemia, the dosage is the same as for treatment but the intervals are extended and vary by treatment protocol.

    Intravenous dosage†
    Adults, Adolescents and Children

    Intermediate and high dose regimens of methotrexate (> 1 g/m2) achieve concentrations in the CSF that are cytotoxic. The use of high-dose methotrexate has been associated with complete responses of CNS leukemia and lymphoma.

    For the treatment of osteogenic sarcoma.
    NOTE: Methotrexate has been designated by the FDA as an orphan drug for the treatment of osteogenic sarcoma.
    As high-dose therapy in non-metastatic osteogenic sarcoma following surgical resection or amputation, in combination with other chemotherapeutic agents.
    Intravenous dosage (Preservative-free solutions only)
    Adults, Adolescents, and Children

    12 grams/m2 IV over 4 hours initially as part of a multiagent chemotherapy regimen; dose frequency differs depending on the chemotherapy regimen. 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 grams/m2 IV for subsequent treatments. Ensure adequate hydration (e.g., 1,000 mL/m2 of IV fluid over 6 hours prior to methotrexate and then 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion and for 2 days after the end of the infusion) and administer oral sodium bicarbonate or a sodium bicarbonate-containing IV fluid to maintain a urinary pH greater than 7 during the methotrexate infusion. Leucovorin rescue must be administered starting at 24 hours from the beginning of the methotrexate infusion; the dosage and duration of leucovorin therapy is dependent on methotrexate levels. Monitor methotrexate levels at the end of the infusion and every 24 hours (starting at 24 hours from the start of the methotrexate infusion) until the methotrexate level is below 0.05 micromolar. Hold subsequent methotrexate doses until hematologic parameters, hepatic function, and renal function have recovered. Do not administer high-dose methotrexate if mucositis is present until there is evidence of healing. Drain any pleural effusion dry prior to high-dose methotrexate infusion.

    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).
    NOTE: Aspirin, NSAIDs, and/or low-dose corticosteroids may be continued with methotrexate, although the possibility of increased toxicity with concomitant use of NSAIDs, including salicylates has not been fully explored.
    NOTE: Consider a switch from oral administration to either intramuscular or subcutaneous administration for patients who have poor compliance, inadequate effectiveness, or gastrointestinal side effects.
    As monotherapy.
    Oral dosage
    Adults

    7.5 mg PO once weekly or 2.5 mg PO every 12 hours for 3 doses weekly. Dosages may be adjusted gradually to achieve an optimal response; do not exceed 20 mg/week PO due to an increased incidence of adverse reactions, especially bone marrow suppression. A maintenance dose of methotrexate 7.5—15 mg PO once weekly has been recommended. Once a response is noted, the dosage should be reduced to the lowest effective dose. Therapeutic response usually begins within 3—6 weeks and the patients may continue to improve for another 12 weeks. The optimal duration of therapy is unknown; however, 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—6 weeks. In a 24-month study of patients who had a poor response to at least one disease-modifying drug, triple therapy with hydroxychloroquine, methotrexate, and sulfasalazine was superior to methotrexate alone. In this study, methotrexate was administered initially at a dose of 7.5 mg PO once weekly and, if the patient was not in remission, the dose was first increased to 12.5 mg/week and then to 17.5 mg/week. Guidelines recommend DMARD monotherapy such as methotrexate for patients with a disease duration < 6 months and low disease activity regardless of poor prognostic feature presence or moderate disease activity without poor prognostic features and is an option for high disease activity without poor prognostic features. For established disease, DMARD monotherapy is recommended for patients with low disease activity without poor prognostic features and methotrexate monotherapy specifically is an option for all other patients. The goal is low disease activity or remission.

    In combination with adalimumab.
    Oral dosage
    Adults

    20 mg PO weekly and adalimumab 40 mg SC every other week. Significantly more methotrexate naive patients with active disease of less than 3 years' duration who received methotrexate and adalimumab had an ACR50 response and a significantly lower mean change from baseline in the modified total Sharp score at years 1 and 2 as compared with the results obtained from patients who got either adalimumab or methotrexate monotherapy. Furthermore, after 2 years of treatment with both drugs, 43% of patients had disease remission defined as 28-joint Disease Activity Score of < 2.6, and 49% had an ACR70 response for at least 6 continuous months. These rates were approximately twice those seen with either drug given as monotherapy. In another study, the addition of adalimumab 20 mg, 40 mg, or 80 mg SC every other week to patients with active rheumatoid arthritis despite methotrexate treatment led to a significantly greater proportion of patients in the combination group who achieved an ACR20 or ACR50 at week 24. For example, 47.8%, 67.2%, and 65.8% of patients who got 20 mg, 40 mg, or 80 mg of adalimumab plus methotrexate had an ACR20, respectively, whereas only 14.5% of patients who continued to get methotrexate monotherapy had the response. Guidelines recommend a TNF blocker +/- methotrexate as an option for patients with a disease duration < 6 months and high disease activity with poor prognostic feature presence. For patients with established disease, adding or switching to an anti-TNF biologic is an option for patients with moderate or high disease activity after 3 months of methotrexate monotherapy or DMARD combination therapy.

    In combination with leflunomide for patients with active disease despite methotrexate monotherapy†.
    Oral dosage
    Adults

    10—20 mg PO per week plus leflunomide 100 mg PO daily for 2 days, then leflunomide 10—20 mg PO daily for 24 weeks led to an ACR20 in 46.2% of 130 patients. In contrast, only 19.5% of 133 patients had an ACR20 with methotrexate monotherapy. For patients with a disease duration < 6 months, guidelines recommend use of combination DMARDs such as leflunomide plus methotrexate for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDS, an option is to add or switch DMARDS and reassess in another 3 months. For patients with low disease activity without poor prognostic features who have moderate or high disease activity after 3 months of DMARD monotherapy, the addition of leflunomide is an option.

    In combination with hydroxychloroquine†.
    Oral dosage
    Adults

    7.5—17.5 mg PO per week plus hydroxychloroquine 200 mg PO twice daily for 2 years led to an ACR20 in 60% of 58 patients with active disease and a disease duration of at least 6 months. Thirty-three of the 58 patients had an inadequate response to previous methotrexate monotherapy, and 25 patients were methotrexate naive. For patients with a disease duration < 6 months, guidelines recommend use of combination DMARDs such as hydroxychloroquine plus methotrexate for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDS, an option is to add or switch DMARDS and reassess in another 3 months. For patients with low disease activity without poor prognostic features who have moderate or high disease activity after 3 months of DMARD monotherapy, the addition of hydroxychloroquine is an option.

    In combination with sulfasalazine†.
    Oral dosage
    Adults

    7.5—17.5 mg PO per week plus sulfasalazine 500—1000 mg PO twice daily for 2 years led to an ACR20 in 49% of 55 patients with active disease and a disease duration of at least 6 months. About half of the patients had an inadequate response to previous methotrexate monotherapy, and about half of the patients were methotrexate naive. For patients with a disease duration < 6 months, guidelines recommend use of combination DMARDs such as sulfasalazine plus methotrexate for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDS, an option is to add or switch DMARDS and reassess in another 3 months. For patients with low disease activity without poor prognostic features who have moderate or high disease activity after 3 months of DMARD monotherapy, the addition of methotrexate is an option.

    In combination with hydroxychloroquine and sulfasalazine†.
    Oral dosage
    Adults

    7.5—17.5 mg PO per week plus sulfasalazine 500—1000 mg PO twice daily and hydroxychloroquine 200 mg PO twice daily for 2 years led to an ACR20 in 78% of 58 patients with active disease and a disease duration of at least 6 months. About half of the patients had an inadequate response to previous methotrexate monotherapy, and about half of the patients were methotrexate naive. For patients with a disease duration < 6 months, guidelines recommend use of combination DMARDs such as sulfasalazine, methotrexate, and hydroxychloroquine for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDS, an option is to add or switch DMARDS and reassess in another 3 months.

    For the treatment of severe, active RA in patients who have had insufficient response to or are intolerant of an adequate trial of first-line therapy including full-dose NSAIDs.
    NOTE: Do not use the methotrexate for subcutaneous use formulation (Otrexup) in patients who require oral, IV, IM, intra-arterial, or intrathecal administration; weekly doses less than 10 mg or greater than 25 mg; or high-dose methotrexate regimens.
    Subcutaneous dosage (Otrexup)
    Adults

    Methotrexate 7.5 mg PO weekly is recommended as initial therapy. Doses may be titrated gradually to achieve the optimal clinical response; doses exceeding 20 mg/week may increase the risk of severe adverse reactions (e.g., myelosuppression). Methotrexate for subcutaneous use (Otrexup) is available in 5-mg increments for doses between 10 and 25 mg; dosing should be individualized. Administering a test dose may be considered to evaluate patients for adverse reactions. 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. In patients with rheumatoid arthritis (RA), the bioavailability of Otrexup was 17% and 13% higher compared with oral methotrexate at doses of 10 mg and 15 mg, respectively; the bioavailabilty of Otrexup was 31% and 36% higher compared with oral methotrexate at doses of 20 mg and 25 mg, respectively. The American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks (primary endpoint) was achieved in 78% of patients with methotrexate-naive, active RA who received methotrexate 15 mg/week subcutaneously compared with 70% of patients who received methotrexate 15 mg/week orally (p < 0.05) in a multicenter, randomized, double-blind, double-dummy, phase IV trial (n = 375). Additionally, 41% of patients in the subcutaneous methotrexate arm achieved an ACR70 response at 24 weeks compared with 33% of patients in the oral methotrexate arm (p < 0.05). In patients who had not achieved an ACR20 response by week 16, patients in the subcutaneous methotrexate arm had a dose increase to 20 mg/week (n = 22) and patients in the oral methotrexate arm were switched to subcutaneous methotrexate 15 mg/week (n = 30) for the final 8 weeks of the study. An ACR20 response was subsequently achieved in 23% of patients in the subcutaneous methotrexate arm and 30% of patients in the (original) oral methotrexate arm. Most patients in this study had very early stage RA , had not received prior disease-modifying anti-rheumatic drug therapy, and were receiving concomitant NSAID and/or corticosteroid therapy. All patients received folic acid 5 mg at 24 hours after the methotrexate dose.

    Subcutanous dosage (Rasuvo)

    NOTE: Do not use the methotrexate for subcutaneous use formulation (Rasuvo) in patients who require oral, IV, IM, intra-arterial, or intrathecal administration; weekly doses less than 7.5 mg, more than 30 mg, or require dose adjustments of less than 2.5 mg increments; or high-dose methotrexate regimens.

    Adults

    Initially, 7.5 mg subcutaneously once weekly. Doses may be titrated gradually to achieve the optimal clinical response; doses exceeding 20 mg/week may increase the risk of severe adverse reactions (e.g., myelosuppression). Methotrexate for subcutaneous use (Rasuvo) is available in 2.5-mg increments for doses between 7.5 and 30 mg; dosing should be individualized. Administering a test dose may be considered to evaluate patients for any extreme sensitivity to adverse effects. Therapeutic response usually begins within 3—6 weeks, with continued improvement for some patients for another 12 weeks or more. Optimal duration of therapy is unknown. Limited data suggest initial clinical improvement may be seen for 2 years with continued therapy. Arthritis usually worsens within 3—6 weeks of discontinuation of therapy. 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. In healthy patients, Rasuvo exposure was 35%, 49%, 51%, and 68% higher than that of oral methotrexate in doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg, respectively. The American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks (primary endpoint) was achieved in 78% of patients with methotrexate-naive, active RA who received methotrexate 15 mg/week subcutaneously compared with 70% of patients who received methotrexate 15 mg/week orally (p < 0.05) in a multicenter, randomized, double-blind, double-dummy, phase IV trial (n = 375). Additionally, 41% of patients in the subcutaneous methotrexate arm achieved an ACR70 response at 24 weeks compared with 33% of patients in the oral methotrexate arm (p < 0.05). In patients who had not achieved an ACR20 response by week 16, patients in the subcutaneous methotrexate arm had a dose increase to 20 mg/week (n = 22) and patients in the oral methotrexate arm were switched to subcutaneous methotrexate 15 mg/week (n = 30) for the final 8 weeks of the study. An ACR20 response was subsequently achieved in 23% of patients in the subcutaneous methotrexate arm and 30% of patients in the (original) oral methotrexate arm. Most patients in this study had very early stage RA , had not received prior disease-modifying anti-rheumatic drug therapy, and were receiving concomitant NSAID and/or corticosteroid therapy. All patients received folic acid 5 mg at 24 hours after the methotrexate dose.

    For the treatment of active polyarticular juvenile idiopathic arthritis.
    NOTE: Aspirin, nonsteroidal anti-inflammatory agents (NSAIDs), and/or low-dose corticosteroids may be continued with methotrexate, although there is a risk of increased toxicity with concomitant use of NSAIDs, including salicylates. Steroids may be slowly tapered in patients who respond to methotrexate therapy.
    Oral dosage
    Children and Adolescents

    10 mg/m2/dose PO once weekly initially. Tailor dose to the individual patient and adjust gradually to achieve optimal response. Although there is experience with doses up to 30 mg/m2/week, doses more than 20 mg/m2/week may result in toxicity (e.g., myelosuppression). Doses between 20 and 30 mg/m2/week may have better absorption and fewer GI side effects if methotrexate is administered intramuscularly or subcutaneously. Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. Among 595 pediatric patients with polyarticular JIA who received 10 mg/m2/week PO, subcutaneously, or IM for 6 months, 72% had an ACR30 response, and no significant difference in the response rate between oral and parenteral administration groups was noted. Of the 133 who did not have an ACR30 response, 40 were randomized to 15 mg/m2/week subcutaneously or IM (Max: 20 mg/m2/week), and 40 received 30 mg/m2/week subcutaneously or IM (Max: 40 mg/m2/week) for 6 months. An ACR30 response was achieved in 62.5% of the lower dose group and in 57.5% of the higher dose group; similar percentages of patients in both groups had an ACR50 or ACR70.

    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. Although there is experience with doses up to 30 mg/m2/week, doses more than 20 mg/m2/week may result in toxicity (e.g., myelosuppression). Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. Administering a test dose may be considered to evaluate patients for adverse reactions. Among 595 pediatric patients with polyarticular JIA who received 10 mg/m2/week PO, subcutaneously, or IM for 6 months, 72% had an ACR30 response, and no significant difference in the response rate between oral and parenteral administration groups was noted. Of the 133 who did not have an ACR30 response, 40 were randomized to 15 mg/m2/week subcutaneously or IM (Max: 20 mg/m2/week), and 40 received 30 mg/m2/week subcutaneously or IM (Max: 40 mg/m2/week) for 6 months. An ACR30 response was achieved in 62.5% of the lower dose group and in 57.5% of the higher dose group; similar percentages of patients in both groups had an ACR50 or ACR70.

    Subcutaneous dosage (Otrexup)

    NOTE: Do NOT use the methotrexate for subcutaneous use formulation (Otrexup) in patients who require oral, IV, IM, intra-arterial, or intrathecal administration; doses less than 10 mg or greater than 25 mg; or high-dose methotrexate regimens.

    Children and Adolescents

    10 mg/m2/dose subcutaneously once weekly initially. Methotrexate for subcutaneous use (Otrexup) is available in 5-mg increments for doses between 10 and 25 mg; dosing should be individualized and adjusted to achieve optimal response. Although there is experience with doses up to 30 mg/m2/week, doses more than 20 mg/m2/week may result in toxicity (e.g., myelosuppression). Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. Administering a test dose may be considered to evaluate patients for adverse reactions. Methotrexate concentrations may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the FDA-approved product labeling. In patients with rheumatoid arthritis (RA), 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. Among 595 pediatric patients with polyarticular JIA who received 10 mg/m2/week PO, subcutaneously, or IM for 6 months, 72% had an ACR30 response, and no significant difference in the response rate between oral and parenteral administration groups was noted. Of the 133 who did not have an ACR30 response, 40 were randomized to 15 mg/m2/week subcutaneously or IM (Max: 20 mg/m2/week), and 40 received 30 mg/m2/week subcutaneously or IM (Max: 40 mg/m2/week) for 6 months. An ACR30 response was achieved in 62.5% of the lower dose group and in 57.5% of the higher dose group; similar percentages of patients in both groups had an ACR50 or ACR70.

    Subcutaneous dosage (Rasuvo)

    NOTE: Do not use the methotrexate for subcutaneous use formulation (Rasuvo) in patients who require oral, IV, IM, intra-arterial, or intrathecal administration; weekly doses less than 7.5 mg, more than 30 mg, or require dose adjustments of less than 2.5 mg increments; or high-dose methotrexate regimens.

    Children and Adolescents

    10 mg/m2 /dose subcutaneously once weekly initially. Methotrexate for subcutaneous use (Rasuvo) is available in 2.5-mg increments for doses between 7.5 and 30 mg; dosing should be individualized and gradually adjusted to achieve an optimal response. Although there is experience with doses up to 30 mg/m2/week, doses more than 20 mg/m2/week may result in toxicity (e.g., myelosuppression). Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. Administering a test dose may be considered to evaluate patients for adverse reactions. Methotrexate concentrations may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the FDA-approved product labeling. In healthy adults, Rasuvo exposure was 35%, 49%, 51%, and 68% higher than that of oral methotrexate in doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg, respectively. Among 595 pediatric patients with polyarticular JIA who received 10 mg/m2/week PO, subcutaneously, or IM for 6 months, 72% had an ACR30 response, and no significant difference in the response rate between oral and parenteral administration groups was noted. Of the 133 who did not have an ACR30 response, 40 were randomized to 15mg/m2/week subcutaneously or IM (Max: 20 mg/m2/week), and 40 received 30 mg/m2/week subcutaneously or IM (Max: 40 mg/m2/week) for 6 months. An ACR30 response was achieved in 62.5% of the lower dose group and in 57.5% of the higher dose group; similar percentages of patients in both groups had an ACR50 or ACR70.

    For the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation.
    NOTE: Ensure that a psoriasis flare is not due to an undiagnosed concomitant disease affecting immune responses.
    Oral dosage
    Adults

    10 to 25 mg PO given as a single weekly dose until response. An alternative regimen is methotrexate 2.5 PO every 12 hours for 3 doses every week. Titrate doses gradually to achieve the optimal clinical response; typically, doses should not exceed 30 mg/week. Once an optimal clinical response has been achieved, the methotrexate dosage should be decreased to the lowest effective dose and to the longest possible rest period. The use of methotrexate may permit the reintroduction of conventional topical therapy, which should be encouraged.

    Intravenous or intramuscular dosage
    Adults

    10 to 25 mg IV/IM given as a single weekly dose until response. Titrate doses gradually to achieve the optimal clinical response; typically, doses should not exceed 30 mg/week. Once an optimal clinical response has been achieved, the methotrexate dosage should be decreased to the lowest effective dose and to the longest possible rest period. The use of methotrexate may permit the reintroduction of conventional topical therapy, which should be encouraged.

    Subcutaneous dosage (Otrexup)

    NOTE: Do NOT use the methotrexate for subcutaneous use formulation (Otrexup) in patients who require oral, IV, IM, intra-arterial, or intrathecal administration; doses less than 10 mg or greater than 25 mg; or high-dose methotrexate regimens.

    Adults

    10 to 25 mg subcutaneously given as a single weekly dose; methotrexate for subcutaneous use (Otrexup) is available in 5-mg increments for doses between 10 and 25 mg. Titrate doses gradually to achieve the optimal clinical response. Typically, methotrexate doses should not exceed 30 mg/week; Otrexup is only indicated for doses up to 25 mg/week. Once an optimal clinical response has been achieved, decrease the dosage to the lowest effective dose and to the longest possible rest period. The use of methotrexate may permit the reintroduction of conventional topical therapy, which should be encouraged. 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. The bioavailability of Otrexup was similar to IM administration at the same dose in patients with rheumatoid arthritis. 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.

    Subcutaneous dosage (Rasuvo)

    NOTE: Do NOT use the methotrexate for subcutaneous use formulation (Rasuvo) in patients who require oral, IV, IM, intra-arterial, or intrathecal administration; doses less than 7.5 mg or greater than 30 mg; or high-dose methotrexate regimens.

    Adults

    10 to 25 mg subcutaneously given as a single weekly dose; methotrexate for subcutaneous use (Rasuvo) is available in 2.5-mg increments for doses between 7.5 and 30 mg. Titrate doses gradually to achieve the optimal clinical response. Typically, methotrexate doses should not exceed 30 mg/week. Once an optimal clinical response has been achieved, decrease the dosage to the lowest effective dose and to the longest possible rest period. The use of methotrexate may permit the reintroduction of conventional topical therapy, which should be encouraged. 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. The bioavailability of Rasuvo was similar to IM administration at the same dose in patients with psoriasis. In healthy patients, Rasuvo exposure was 35%, 49%, 51%, and 68% higher than that or oral methotrexate in doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg, respectively.

    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 asthma†.
    Intramuscular dosage
    Adults

    At least 2 studies have evaluated the efficacy of methotrexate in the treatment of severe, steroid-dependent asthma with one demonstrating benefit and the other showing no difference between methotrexate and placebo. In both studies, methotrexate was administered as a single IM injection once weekly. Doses ranged 15—50 mg IM once weekly in the successful trial and up to 15 mg IM once weekly in the unsuccessful study.

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

    25 mg IM weekly was evaluated in a placebo-controlled, double-blind study of 141 patients with Crohn's disease who had received prednisone for at least 3 months. A beneficial response was attributed to methotrexate during the 16 weeks the patients were followed. Prednisone dosage was gradually tapered according to disease severity/remission. At the end of the study, prednisone doses were lower in the methotrexate group relative to the placebo group.

    Subcutaneous dosage
    Adults

    15 mg SC once weekly for 16 weeks led to a remission in 3 patients with steroid-requiring Crohn's disease (n=10) or ulcerative colitis (n=8). Seven additional patients had disease improvement. Patients who had not achieved a remission with 15 mg SC got 25 mg once weekly for an additional 16 weeks; 2 of 11 patients achieved a remission. In another study, remission was obtained in 12 of 21 patients with Crohn's disease who got 25 mg SC weekly, in 7 of 11 patients who got 20 mg SC once weekly, and in 3 of 6 patients who got 15 mg SC once weekly. Remission was obtained in 5 of 12 patients with ulcerative colitis who got 25 mg SC weekly, in 4 of 6 patients who got 20 mg SC once weekly, and in 1 of 1 patients who got 15 mg SC once weekly.

    For the treatment of ectopic pregnancy†.
    In combination with mifepristone†.
    Intramuscular dosage
    Adult females

    When methotrexate 50 mg/m2 IM was administered in combination with mifepristone PO in women with normal renal function, there was a decreased the risk of medical treatment failure or the need for re-treatment as compared to methotrexate alone. In addition, the combination is associated with faster resolution of the ectopic pregnancy.

    Intramuscular dosage
    Adult females

    In women with normal renal function and unruptured ectopic pregnancies < 3.5 cm in diameter, methotrexate 50 mg/m2 IM has been shown to be safe and effective and to preserve reproductive potential. Serum chorionic gonadotropin levels should be monitored on days 4 and 7 (methotrexate is administered on day 1). If the level does not fall by at least 15% between days 4 and 7, a repeat dose of methotrexate may be required. Continue to monitor serum chorionic gonadotropin levels, weekly until the concentration is <= 15 mIU/ml. If after 3 methotrexate injections, the serum chorionic gonadotropin is not < 15 mIU/ml or if fetal cardiac activity is present, then the ectopic pregnancy is treated with surgery.

    Intratubal dosage
    Adult females

    In one study, 100 mg of methotrexate as a single dose was given via transvaginal intra-amniotic or laparoscopic intratubal injection. Women who were <= 8 weeks gestation were treated, regardless of fetal cardiac activity, size of the mass, or level of serum chorionic gonadotropin. Local administration was safe and effective in this open study.

    For pregnancy termination† prior to the 63rd day of pregnancy in combination with intravaginal misoprostol.
    Intramuscular dosage
    Pregnant females

    In one study, women received methotrexate 50 mg/m2 IM followed by intravaginal misoprostol 5—7 days later. Seven days after the misoprostol dose, patients were offered a second dose if there was evidence of a persistent gestational sac. Ninety-six percent of women had a successful medical abortion after the first or second dose of misoprostol. Seventy-six percent of women successfully aborted within 12 hours after insertion of misoprostol.

    For the treatment of psoriatic arthritis†.
    Oral dosage
    Adults

    Methotrexate starting at 5 to 7.5 mg PO as a single dose once weekly was studied in an open, prospective study. This dose was adjusted according to outcome and tolerance. When a satisfactory response was obtained, the dose was left unchanged for 3 months, then decreased to the lowest amount necessary to maintain control. Patients received a mean dose of 11.2 mg/week and treatment was continued for 6 to 132 months. Thirty-eight patients were judged to have either a good or excellent response. Only 2 patients were judged to have a poor response.

    For the treatment of pruritus† secondary to cholestasis and/or primary biliary cirrhosis†.
    Oral dosage
    Adults

    In one trial, short-term therapy with 7.5—15 mg PO as a single dose weekly decreased pruritus in patients with primary biliary cirrhosis. Histologic findings and hepatic enzyme concentrations also improved during therapy.

    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 (IT) twice weekly for 4 weeks followed by 10 mg IT 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 IT 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; p = 0.007). 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; p = 0.048). Methotrexate 10 mg IT on days 1 and 4 repeated weekly for 8 weeks was compared with IT 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 (p < 0.008) and skin/mucous membrane (p = 0.042) 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. In the treatment of neoplastic disease the maximum tolerated dose of methotrexate varies significantly from 80—900 mg/m2 IV without leucovorin rescue therapy and 900—30,000 mg/m2 IV with leucovorin rescue. The maximum intrathecal dose of methotrexate is 15 mg. Oral doses > 30 mg/m2 are generally not recommended due to poor absorption.

    Elderly

    The maximum tolerated doses of methotrexate may be lower in elderly patients. In general the same guidelines as adult patients should be used: for psoriasis 30 mg/week PO; for rheumatoid arthritis 20 mg/week PO. In the treatment of neoplastic disease the maximum tolerated dose of methotrexate varies significantly from 80—900 mg/m2 IV without leucovorin rescue therapy and 900—30,000 mg/m2 IV with leucovorin rescue. The maximum intrathecal dose of methotrexate is 15 mg. Oral doses > 30 mg/m2 are generally not recommended due to poor absorption.

    Children

    In the treatment of neoplastic disease the maximum tolerated dose of methotrexate varies significantly from 80—900 mg/m2 IV without leucovorin rescue therapy and 900—30,000 mg/m2 IV with leucovorin rescue. The maximum intrathecal dose of methotrexate is 15 mg. Oral doses > 30 mg/m2 are generally not recommended due to poor absorption.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Consider dosage adjustments or alternative treatments in patients with baseline hepatic impairment. Psoriasis or rheumatoid arthritis patients with hepatic impairment due to alcoholism, cirrhosis, or other chronic liver disease should not receive methotrexate. Patients receiving high-dose methotrexate may have a prolonged half-life due to hepatic dysfunction and require additional monitoring and leucovorin therapy.

    Renal Impairment

    Use caution when administering methotrexate to patients with renal impairment. Generally, in patients with CrCl < 60 mL/minute, intermediate- and high-dose regimens are contraindicated. There are several recommendations available in the published literature for dose adjustment in patients with renal impairment. It has been suggested that dosage reductions should be made in patients with impaired renal function proportional to the decrease in creatinine clearance. 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: 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: not recommended.

    ADMINISTRATION

    CAUTION: Observe and exercise usual cautions for handling, preparing, administering, and disposing of cytotoxic drugs.

    Oral Administration

    The oral formulation of methotrexate is preferred for low-dose therapy.
    Methotrexate absorption is dose-dependent; absorption of single doses more than 40 mg/m2 is significantly less than that of lower doses.
    Weekly therapy with Rheumatrex Dose Packs is not intended for doses more than 15 mg PO per week.

    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 a calibrated oral measuring device for accurate dosage administration.
    Storage: Patients may store at room temperature (68 to 77 degrees F) for up to 60 days.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    The preserved solutions contain benzyl alcohol and should not be used for intrathecal, intermediate-, or high-dose therapy.
     
    Reconstitution of lyophilized powders:
    Reconstitute each vial with an appropriate sterile, preservative-free solution such as 5% Dextrose Injection or 0.9% Sodium Chloride Injection. Reconstitute the 25 mg vial to a concentration no greater than 25 mg/mL. The 1 g vial should be reconstituted with 19.4 mL to a concentration of 50 mg/mL.
    Prepare immediately before use. Discard any unused portions.

    Intravenous Administration

    Direct IV injection:
    Inject as a slow push via Y-site or 3-way stopcock into a free-flowing IV infusion.
     
    Intermittent/Continuous IV infusion:
    Further dilute solution in 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, or 0.9% Sodium Chloride Injection.
    Prior to infusion, check vein patency by flushing with 5 to 10 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
    Infuse at a rate prescribed by the physician. Following infusion, flush the IV tubing.
     
    Guidelines for intravenous infusion of intermediate- or high-dose methotrexate (500 mg/m2 over less than 4 hours or more than 1 g/m2 over more than 4 hours):
    Prior to administration, the following laboratory parameters should be confirmed: WBC more than 1,500/mm3, neutrophil count more than 200/mm3, platelet count more than 75,000/mm3, serum bilirubin less than 1.2 mg/dL, normal serum creatinine, and SGPT less than 450 U. Creatinine clearance should be more than 60 mL/minute. If serum creatinine has increased by 50% or more compared to a prior value, creatinine clearance should be measured and documented as more than 60 mL/minute even if the serum creatinine is still within normal limits.
    Previous mucositis should be healed and persistent effusions should be drained prior to administration.
    Patients should 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/hour 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 level determinations 24 hours after stating methotrexate and at least daily until the methotrexate level is below 5 x 10-8 mol/L (0.05 micro-M).

    Intramuscular Administration

    Inject deeply into a large muscle.
    Aspirate prior to injection to avoid injection into a blood vessel.

    Subcutaneous Administration

    Otrexup and Rasuvo are methotrexate formulations for subcutaneous use only.
    Both Otrexup and Rasuvo are single-use auto-injectors. Otrexup is available in 5-mg increments for doses between 10 and 25 mg; Rasuvo is available in 2.5-mg increments for doses between 7.5 and 30 mg. 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 blocked 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 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 preservative-free solutions. The preserved solutions contain benzyl alcohol and should NOT be used for intrathecal therapy.
    Reconstitute the preservative-free powder for injection with preservative-free 0.9% Sodium Chloride Injection. The desired dose should be drawn into a 5 to 10 mL syringe.
    After lumbar puncture is complete, withdraw an amount of CSF equivalent to the volume of methotrexate injection to be administered. If puncture was traumatic, wait 2 days before attempting to administer methotrexate intrathecally.
    Allow CSF (approximately 10% of estimated CSF total volume) to flow into the syringe and mix with the drug.
    Inject intrathecally over 15 to 30 seconds with the bevel of the needle directed upward.

    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:
    - Protect from light
    - 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:
    - Product should be used within 2 months after opening
    - Refrigerate (between 36 and 46 degrees F)
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Exfoliative dermatitis, serious rash

    Methotrexate is contraindicated in patients with a severe hypersensitivity to the drug. 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.

    Geriatric

    Geriatric patients may be at increased risk of methotrexate toxicity due to debility and/or decreased renal or hepatic function. Elderly patients experience an increased incidence of systemic toxicities and treatment-related deaths following high-dose methotrexate as compared to younger patients.

    Intrauterine fetal death, pregnancy

    Methotrexate is contraindicated in pregnancy in women who are being treated for nonmalignant diseases (e.g., psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis). Methotrexate can cause intrauterine fetal death and/or congenital anomalies when administered to a pregnant woman. In women of reproductive potential, methotrexate use is not recommended unless the benefits of therapy are expected to outweigh the considered risks. Advise females of reproductive potential to avoid pregnancy while taking methotrexate; counsel these patients on the fetal risk if pregnancy occurs.

    Breast-feeding

    Methotrexate is contraindicated in breast-feeding women due to the potential for serious adverse reactions from methotrexate in breast fed infants. Previous American Academy of Pediatrics recommendations considered methotrexate incompatible with breast-feeding.

    Anemia, bone marrow suppression, herpes infection, immunosuppression, infection, neutropenia, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Patients with psoriasis or rheumatoid arthritis who have preexisting bone marrow suppression such as leukopenia, thrombocytopenia, or significant anemia should not receive methotrexate. 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. Obtain blood counts at baseline and periodically during treatment. In general, hematologic parameters should be monitored at least monthly. Stop the drug immediately in patients with psoriasis or rheumatoid arthritis if significant bone marrow suppression develops. In patients with neoplastic disease, recovery of bone marrow function should be established prior to administering the next course of treatment. Patients with acute leukemia may require treatment despite severe bone marrow suppression. Use is contraindicated in patients with preexisting immunosuppression. Patients with profound neutropenia and fever should be evaluated immediately and usually require broad-spectrum antibiotics. Pancytopenia, including leukopenia, neutropenia, and thrombocytopenia, contraindicates administration of the next dose. Administration should be delayed until the WBC is more than 1,500/mm3, the neutrophil count is more than 200/mm3, and the platelet count is more than 75,000/mm3. Patients with an active infection should be treated for the infection prior to receiving methotrexate. Dosage reduction or discontinuation may be considered in patients who develop severe infections. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. Methotrexate should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Administration requires an experienced clinician whose knowledge and experience includes antimetabolite therapy, due to the potential of serious or fatal adverse reactions. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor patients for bone marrow toxicities. Patients should be informed by their clinicians of the risks involved and be under a clinician's care throughout treatment.

    Acquired immunodeficiency syndrome (AIDS)

    Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes (i.e., acquired immunodeficiency syndrome (AIDS)) should not receive methotrexate.

    Diabetes mellitus, hypoalbuminemia, pulmonary disease, pulmonary fibrosis, pulmonary toxicity

    Methotrexate therapy can produce potentially fatal pulmonary toxicity, including acute or chronic interstitial pneumonitis and pulmonary fibrosis. Methotrexate-induced lung disease may occur acutely at any time during therapy, has been reported at low doses, and is not always fully reversible. Pulmonary symptoms, especially a dry, nonproductive cough, may require treatment interruption and careful investigation. Pulmonary function tests may be useful if toxicity is suspected, especially if baseline measurements are available. Therapy should be discontinued if the patient develops pulmonary symptoms such as fever, dry cough, dyspnea, chest pain, hypoxemia, and radiographic evidence of pulmonary infiltrates. Pulmonary reactions are rare but usually occur during the initial period of methotrexate therapy. The following are risk factors for pulmonary toxicity in rheumatoid arthritis patients treated with methotrexate: diabetes mellitus; older age; rheumatoid pleuropulmonary involvement; 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. History of pulmonary disease, extraarticular manifestations of rheumatoid arthritis, smoking (men only), and non-sedentary occupations (women only) have also been suggested as risk factors for methotrexate-induced pulmonary toxicity. Methotrexate should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Only physicians whose knowledge and experience includes antimetabolite therapy should administer methotrexate due to the potential of serious adverse reactions, which can be fatal. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor patients for lung toxicities. Patients should be informed by their physicians of the risks involved and be under a physician's care throughout treatment.

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

    Methotrexate is metabolized by the liver and undergoes enterohepatic circulation. Use is contraindicated in patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic hepatic disease, or other chronic hepatic disease; further, methotrexate should be given cautiously to any patient with a personal or family history of hepatic disease or significant exposure to liver toxins. Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis but generally only after prolonged use. Risk factors for hepatotoxicity include alcoholism, obesity, diabetes mellitus, hyperlipidemia, duration of therapy, and advanced age. In general, monitor liver function every 1 to 2 months and more frequently when initiating or changing therapy, or during periods of increased risk of elevated methotrexate levels (e.g., dehydration). Acutely, liver enzyme elevations are frequently seen, but elevations are usually transient, asymptomatic, and do not appear predictive of subsequent hepatic disease. Persistent abnormalities and/or hypoalbuminemia may be indicators of serious hepatotoxicity and require further evaluation. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported. Fibrosis and cirrhosis may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. In psoriatic patients, hepatotoxicity appears to be a function of the cumulative dose. During psoriasis treatment, liver function tests (LFTs) including albumin should be performed prior to treatment; however, the relationship between abnormal LFTs and hepatotoxicity in patients with psoriasis is not established, and hepatotoxicity is only detectable by biopsy. 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 1 to 1.5 g of methotrexate. However, psoriasis guidelines suggest that 3.5 to 4 g instead of 1 to 1.5 g of cumulative methotrexate may be a more appropriate time frame for the first liver biopsy in patients without preexisting risk factors for hepatotoxicity. The National Psoriasis Foundation suggests 3 options in patients without risk factors for hepatic toxicity who reach a cumulative dose of 3.5 to 4 g oral methotrexate with normal LFTs: perform a liver biopsy, continue to monitor without a biopsy, or switch to an alternative agent if possible. In patients with at least 1 risk factor for hepatic toxicity, consider delayed baseline liver biopsy (after 2 to 6 months of therapy to establish medication efficacy and tolerability and avoid unnecessary biopsies in those who do not tolerate the drug or show a lack of response) with repeated biopsies after every 1 to 1.5 g of methotrexate. Moderate fibrosis or any cirrhosis should lead to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy at 6 months. In rheumatoid arthritis patients, age at first use of methotrexate and duration of methotrexate therapy have been reported as risk factors for hepatotoxicity; other risk factors similar to those seen in psoriasis may also have a role. LFTs should be performed at baseline and every 4 to 8 weeks in patients receiving methotrexate for rheumatoid arthritis. Unlike psoriasis patients, persistent abnormal LFTs may precede hepatotoxicity in patients with rheumatoid arthritis. Pretreatment liver biopsy should be performed in rheumatoid arthritis 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 should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy. Only physicians whose knowledge and experience includes antimetabolite therapy should administer methotrexate due to the potential of serious adverse reactions, which can be fatal. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor patients for liver toxicities. Patients should be informed by their physicians of the risks involved and be under a physician's care throughout treatment.

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

    Ensure correct formulation selection of preservative-free methotrexate for high-dose administration, intrathecal administration, administration to neonatal infants, and in patients with known benzyl alcohol hypersensitivity. Benzyl alcohol is present in preservative-containing formulations. 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.

    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 the third space fluid prior to treatment and monitor methotrexate serum levels and for signs and symptoms of methotrexate toxicity. A dose reduction or discontinuation may be necessary. Pleural effusions must be drained dry prior to starting high-dose methotrexate therapy.

    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 (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates) are at risk for increased toxicity due to prolonged elevated methotrexate serum concentrations. Obtain renal function tests at baseline and monitor for toxicity in all patients who are receiving methotrexate; monitor renal function every 1 to 2 months in patients with rheumatoid arthritis and psoriasis and more frequently in patients with cancer, when initiating or changing therapy, or in patients with conditions that might increase the risk of elevated methotrexate levels (e.g., dehydration). Nonreversible oliguric renal failure may occur following high-dose methotrexate therapy in patients with delayed methotrexate elimination; nephrotoxicity is caused by the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. NSAIDs should not be given prior to or concomitantly with high-dose methotrexate due to an increased risk of death from severe hematologic and gastrointestinal toxicity. Use caution when administering high-dose methotrexate with other nephrotoxic chemotherapy, such as cisplatin. Ensure adequate hydration and urinary alkalinization during and after high-dose therapy; leucovorin rescue must be administered starting at 24 hours from the start of the methotrexate infusion. Monitor renal function prior to, at 24 hours after the start of the methotrexate infusion, and then at least daily until the methotrexate level is below 0.05 micromolar. Do not initiate therapy in patients unless the serum creatinine (Scr) level is normal and the creatinine clearance (CrCl) is greater than 60 mL/minute. If the SCr level increases by 50% or more compared with a prior value, measure the CrCl to ensure a CrCl greater than 60 mL/minute. Closely monitor fluid and electrolyte status if renal failure develops. Acute, intermittent hemodialysis with a high-flux dialyzer may be useful in these patients. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function; do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase.

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, tumor lysis syndrome (TLS)

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and decreased urine output may be indicative of methotrexate-induced tumor lysis syndrome (TLS). Appropriate measures (e.g. aggressive hydration and allopurinol) must be taken to prevent or alleviate severe electrolyte imbalances and renal toxicity during and following chemotherapy administration in patients with large, chemosensitive tumors.

    Diarrhea, gastroenteritis, GI bleeding, GI disease, GI perforation, peptic ulcer disease, stomatitis, ulcerative colitis, vomiting

    Methotrexate should be used with extreme caution in patients with GI disease such as peptic ulcer disease or ulcerative colitis. Unexpectedly severe, sometimes fatal gastrointestinal toxicity and GI bleeding have been reported with concomitant administration of methotrexate (usually in high dosage) and some nonsteroidal anti-inflammatory drugs (NSAIDs). If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, discontinue methotrexate until recovery occurs. If methotrexate is not discontinued, hemorrhagic gastroenteritis and death from GI perforation may occur.

    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 bone necrosis. Prior or concurrent cranial irradiation has been associated with 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 use a sunscreen with a SPF of at least 15 during sunlight (UV) exposure.

    Vaccination

    Vaccination during methotrexate should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by 2 weeks or longer. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Lymphoma

    Malignant lymphomas may occur in patients receiving low-dose methotrexate. Malignant lymphomas may regress following withdrawal of methotrexate and thus, may not require cytotoxic treatment. Discontinue methotrexate first and if the lymphoma does not regress, institute appropriate treatment.

    Contraception requirements, infertility, menstrual irregularity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during methotrexate treatment. Pregnancy testing should be performed prior to starting methotrexate in female patients of reproductive potential. These patients should use effective contraception during methotrexate therapy and for at least 1 ovulatory cycle after therapy. 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 therapy due to the risk of male-mediated teratogenicity. Methotrexate may cause infertility; oligospermia and menstrual irregularity/dysfunction have been reported in patients during methotrexate therapy and for a short period after stopping therapy.

    ADVERSE REACTIONS

    Severe

    pancytopenia / Delayed / 1.0-3.0
    peptic ulcer / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    arachnoiditis / Early / Incidence not known
    coma / Early / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    renal tubular obstruction / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    bone fractures / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    optic atrophy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    teratogenesis / Delayed / Incidence not known
    fetal abortion / Delayed / Incidence not known
    fetal death / 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
    lymphadenopathy / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    paresis / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    aphasia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    proteinuria / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    furunculosis / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    phlebitis / Rapid / Incidence not known
    osteoporosis / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    scotomata / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known

    Mild

    nausea / Early / 10.0-11.0
    diarrhea / Early / 1.0-11.0
    vomiting / Early / 10.0-11.0
    alopecia / Delayed / 0.5-10.0
    photosensitivity / Delayed / 3.0-10.0
    dizziness / Early / 0.2-3.0
    pruritus / Rapid / 1.0-3.0
    rash (unspecified) / 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
    pharyngitis / Delayed / Incidence not known
    gingivitis / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    telangiectasia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    acne vulgaris / 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
    gonadal suppression / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (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 platelet inhibitors.
    Acetaminophen; Aspirin, ASA; Caffeine: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Acitretin: (Severe) 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.
    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: (Severe) 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, tPA: (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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Anagrelide: (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 platelet inhibitors.
    Anticoagulants: (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 anticoagulants.
    Antithrombin III: (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 anticoagulants.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders.
    Apixaban: (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 anticoagulants.
    Argatroban: (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 anticoagulants.
    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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Carisoprodol: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Carisoprodol; Codeine: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Dipyridamole: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. (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 platelet inhibitors.
    Aspirin, ASA; Omeprazole: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. (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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Aspirin, ASA; Pravastatin: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (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.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) 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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Betrixaban: (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 anticoagulants.
    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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Bivalirudin: (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 anticoagulants.
    Black Cohosh, Cimicifuga racemosa: (Moderate) Black cohosh, Cimicifuga racemosa, has been reported to cause liver problems; however, causality has not been established. It is possible that black cohosh would act synergistically with other medications that can have adverse effects on the liver. Until more is known, the concurrent use of black cohosh in patients taking methotrexate is not recommended as a precaution.
    Capecitabine: (Minor) Capecitabine may cause leukopenia or other hematologic effects and result in side effects that may be additive to other agents which cause bone marrow or immune suppression such as other antineoplastic agents.
    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.
    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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Cilostazol: (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 platelet inhibitors.
    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) Cisplatin can delay the renal clearance of methotrexate. A dose reduction of methotrexate may be necessary. Concurrent or previous cisplatin administration increases the systemic and renal toxicity of methotrexate.
    Clofarabine: (Moderate) Clofarabine has potent immunosuppressive effects and concurrent use with other agents that suppress the immune system, such as other antineoplastic agents or immunosuppressives, may result in over-immunosuppression. While therapy may be designed to take advantage of this effect, patients may be at an increased risk for the development of severe infections or other side effects. In addition, concomitant use of clofarabine and methotrexate may result in altered clofarabine levels because both agents are substrates of OAT1 and OAT3. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OAT1 and OAT3 substrates.
    Clopidogrel: (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 platelet inhibitors.
    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.
    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: (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 anticoagulants.
    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.
    Dalteparin: (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 anticoagulants.
    Danaparoid: (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 anticoagulants.
    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.
    Desirudin: (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 anticoagulants.
    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.
    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.
    Dipyridamole: (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 platelet inhibitors.
    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: (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 anticoagulants.
    Efalizumab: (Major) The safety and efficacy of efalizumab in combination with other immunosuppressive agents have not been evaluated. Patients receiving immunosuppressives should not receive concurrent therapy with efalizumab because of the potential risk for serious infections and secondary malignancies. The risk is related to the intensity and duration of immunosuppression rather than the specific agents.
    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.
    Enoxaparin: (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 anticoagulants.
    Eptifibatide: (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 platelet inhibitors.
    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.
    Ethotoin: (Major) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as hydantoins, could cause methotrexate-induced toxicity by increasing unbound methotrexate concentrations. In addition, increased phenytoin clearance has been reported with high-dose methotrexate. In patients maintained on phenytoin, the clinical status of the patient should be monitored to assess adequate anticonvulsant coverage and to limit the potential for methotrexate toxicity. In some circumstances serum drug levels will be prudent.
    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.
    Etoposide, VP-16: (Major) Etoposide can slow cellular efflux of methotrexate and methotrexate polyglutamates and increase intracellular retention time in vitro. The clinical significance of this effect is unknown.
    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. (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.
    Fondaparinux: (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 anticoagulants.
    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) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as hydantoins, could cause methotrexate-induced toxicity by increasing unbound methotrexate concentrations. In addition, increased phenytoin clearance has been reported with high-dose methotrexate. In patients maintained on phenytoin, the clinical status of the patient should be monitored to assess adequate anticonvulsant coverage and to limit the potential for methotrexate toxicity. In some circumstances serum drug levels will be prudent.
    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.
    Heparin: (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 anticoagulants.
    Hydantoins: (Major) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as hydantoins, could cause methotrexate-induced toxicity by increasing unbound methotrexate concentrations. In addition, increased phenytoin clearance has been reported with high-dose methotrexate. In patients maintained on phenytoin, the clinical status of the patient should be monitored to assess adequate anticonvulsant coverage and to limit the potential for methotrexate toxicity. In some circumstances serum drug levels will be prudent.
    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) Hydroxychloroquine may reduce the renal clearance of methotrexate; the exact mechanism of this interaction is unknown. The mean AUC of methotrexate was increased 52% and the mean Cmax was reduced 17% when a single dose of methotrexate was given with a dose of hydroxychloroquine (200 mg oral). Close monitoring for evidence of methotrexate toxicity should be done in patients receiving this combination, especially in those with reduced renal function.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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: (Severe) 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.
    Iron Salts: (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.
    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.
    Kava Kava, Piper methysticum: (Major) The concurrent use of kava kava in patients on methotrexate or other medications that may cause rare but significant hepatotoxicity is not recommended. Kava kava, Piper methysticum has been reported to cause liver problems. It is possible that kava kava would act synergistically with other medications that can have adverse effects on the liver, such as methotrexate.
    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.
    Lepirudin: (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 anticoagulants.
    Lesinurad; Allopurinol: (Minor) In vitro studies have shown that allopurinol administered one hour prior to methotrexate may decrease the therapeutic effects of methotrexate.
    Leucovorin: (Major) Leucovorin is a reduced folate that, when given after methotrexate administration, bypasses methotrexate-induced enzyme blockade intracellularly and allows DNA synthesis to proceed. Leucovorin is used clinically as a 'rescue' agent to reduce methotrexate toxicity in normal tissues. Monitoring of methotrexate serum concentrations will determine the appropriate dose and duration of leucovorin therapy. Since leucovorin antagonizes the toxic actions of methotrexate, the timing of leucovorin administration is critical; leucovorin should not be given simultaneously with methotrexate. Typically, leucovorin is given 12-24 hours after administration of methotrexate to 'rescue' normal cells from the toxic effects of methotrexate. Small amounts of leucovorin enter the CSF as 5-methyltetrahydrofolate, as a result, high-doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Excessive methotrexate-induced hematologic and gastrointestinal toxicity may occur if the dosage and duration of leucovorin therapy is inadequate. Leucovorin appears unlikely to interfere with the tumor cell response to methotrexate; tumor cells have higher methotrexate polyglutamate formation intracellularly and are thus more resistant to leucovorin rescue. In order to avoid medication errors, leucovorin should not be referred to as citrovorum factor or folinic acid. The term 'folinic acid' could be confused with folic acid and result in serious systemic methotrexate toxicity should the wrong rescue treatment be prescribed. Only leucovorin (folinic acid) can bypass the inhibition of dihydrofolate reductase and thus, provide an adequate tetrahydrofolate pool.
    Levoleucovorin: (Major) Leucovorin is a reduced folate that, when given after methotrexate administration, bypasses methotrexate-induced enzyme blockade intracellularly and allows DNA synthesis to proceed. Leucovorin is used clinically as a 'rescue' agent to reduce methotrexate toxicity in normal tissues. Monitoring of methotrexate serum concentrations will determine the appropriate dose and duration of leucovorin therapy. Since leucovorin antagonizes the toxic actions of methotrexate, the timing of leucovorin administration is critical; leucovorin should not be given simultaneously with methotrexate. Typically, leucovorin is given 12-24 hours after administration of methotrexate to 'rescue' normal cells from the toxic effects of methotrexate. Small amounts of leucovorin enter the CSF as 5-methyltetrahydrofolate, as a result, high-doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Excessive methotrexate-induced hematologic and gastrointestinal toxicity may occur if the dosage and duration of leucovorin therapy is inadequate. Leucovorin appears unlikely to interfere with the tumor cell response to methotrexate; tumor cells have higher methotrexate polyglutamate formation intracellularly and are thus more resistant to leucovorin rescue. In order to avoid medication errors, leucovorin should not be referred to as citrovorum factor or folinic acid. The term 'folinic acid' could be confused with folic acid and result in serious systemic methotrexate toxicity should the wrong rescue treatment be prescribed. Only leucovorin (folinic acid) can bypass the inhibition of dihydrofolate reductase and thus, provide an adequate tetrahydrofolate pool.
    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.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (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: (Severe) 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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) 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: (Severe) 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.
    Muromonab-CD3: (Minor) The concomitant use of muromonab and methotrexate may cause additive immunosuppression.
    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.
    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; 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.
    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.
    Pentosan: (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 anticoagulants.
    Phenytoin: (Major) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as hydantoins, could cause methotrexate-induced toxicity by increasing unbound methotrexate concentrations. In addition, increased phenytoin clearance has been reported with high-dose methotrexate. In patients maintained on phenytoin, the clinical status of the patient should be monitored to assess adequate anticonvulsant coverage and to limit the potential for methotrexate toxicity. In some circumstances serum drug levels will be prudent.
    Photosensitizing agents: (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.
    Platelet Inhibitors: (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 platelet inhibitors.
    Ponatinib: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and methotrexate, an ABCG2 (BCRP) substrate, may increase the exposure of methotrexate.
    Prasugrel: (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 platelet inhibitors.
    Probenecid: (Severe) 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.
    Purine analogs: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    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.
    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: (Major) Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs, such as methotrexate, and riluzole has not been established. Caution is recommended if methotrexate is to be used concomitantly with riluzole.
    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: (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 anticoagulants.
    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: (Severe) 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: (Severe) 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: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Salsalate: (Severe) Caution should be exercised when salicylates are given in combination with methotrexate. Since both are weak acids, salicylates can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any of these drugs be used cautiously with methotrexate even when methotrexate is used in low doses for the treatment of rheumatoid arthritis. A significantly higher incidence of leukopenia has been reported in patients taking aspirin during methotrexate therapy. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Sargramostim, GM-CSF: (Major) Sargramostim induces the proliferation of hematopoietic progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, sargramostim is contraindicated for use in patients during the 24 hours before or after cytotoxic chemotherapy.
    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.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) 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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Use of other folate antagonists, such as methotrexate, should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of methotrexate.
    Sulfonamides: (Major) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as sulfonamides could cause methotrexate-induced toxicity. Due to the potential toxicity of methotrexate, interactions with sulfonamides can be very serious even if methotrexate is administered in low doses.
    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.
    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, TNK-tPA: (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.
    Ticagrelor: (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 platelet inhibitors.
    Ticlopidine: (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 platelet inhibitors.
    Tinzaparin: (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 anticoagulants.
    Tirofiban: (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 platelet inhibitors.
    Tocilizumab: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as methotrexate.
    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: (Moderate) Use of other folate antagonists, such as methotrexate, should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of methotrexate.
    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: (Severe) 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.
    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: (Severe) 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.
    Vinblastine: (Major) Monitor for increased serum concentrations and toxicities of methotrexate when administered concurrently with vinblastine. Although an interaction between vinblastine and methotrexate has not been reported by the manufacturer, it is prudent to consider that vinblastine may have similar interactions as those for other vinca alkaloids, including interactions with methotrexate. When given <= 1 hour prior to methotrexate, vincristine increases the cellular retention of methotrexate by inhibiting methotrexate efflux from the cell; however, the window of opportunity for this interaction is short, and the effects are not clinically seen in vivo. Therapeutic synergy has been noted when methotrexate is given 8 to 48 hours before vincristine; the mechanism for this interaction has not been clearly defined.
    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.
    Vinorelbine: (Major) Monitor for increased serum concentrations and toxicities of methotrexate when administered concurrently with vinorelbine. Although an interaction between vinorelbine and methotrexate has not been reported by the manufacturer, it is prudent to consider that vinorelbine may have similar interactions as those for other vinca alkaloids, including interactions with methotrexate. When given <= 1 hour prior to methotrexate, vincristine increases the cellular retention of methotrexate by inhibiting methotrexate efflux from the cell; however, the window of opportunity for this interaction is short, and the effects are not clinically seen in vivo. Therapeutic synergy has been noted when methotrexate is given 8 to 48 hours before vincristine; the mechanism for this interaction has not been clearly defined.
    Vorapaxar: (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 platelet inhibitors.
    Warfarin: (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 anticoagulants.
    Yellow Fever Vaccine, Live: (Severe) 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

    Methotrexate is contraindicated in pregnancy in women who are being treated for nonmalignant diseases (e.g., psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis). Methotrexate can cause intrauterine fetal death and/or congenital anomalies when administered to a pregnant woman. In women of reproductive potential, methotrexate use is not recommended unless the benefits of therapy are expected to outweigh the considered risks. Advise females of reproductive potential to avoid pregnancy while taking methotrexate; counsel these patients on the fetal risk if pregnancy occurs.

    MECHANISM OF ACTION

    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 many biochemical reactions. Some of these reactions influence cell proliferation including the synthesis of thymidylic acid, DNA nucleotide precursors, and inosinic acid, a purine precursor required for DNA and RNA synthesis. The inhibition of thymidylate synthesis appears to the most important effect of methotrexate and results in a greater inhibition of DNA synthesis than RNA synthesis. The intracellular concentration of methotrexate affects its activity. At a sustained plasma concentration of 10 nmol/l, blockade of thymidine is noted; at methotrexate plasma concentrations of 100 nmol/l, inhibition of both purines and thymidine is achieved. Tissues that have a high rate of cellular metabolism, such as neoplasms, hair follicles, the lining of the GI tract, fetal cells, and bone marrow are most sensitive to the effects of methotrexate. Methotrexate is cycle-specific inhibiting cells primarily in the S-phase. At higher doses (> 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 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 > 100 µM). 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 (i.e., > 500 mg/m2 over < 4 hours or > 1 g/m2 over > 4 hours) 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 (< 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.Methotrexate has immunosuppressive properties and can thus, exhibit anti-inflammatory activity. The enzyme, AICAR transformylase, catalyzes the last step in the de novo biosynthesis of inosine monophosphate. Thus, purine nucleotide biosynthesis is blocked to some extent, which may cause immunosuppression. Also, AICA or its metabolites may be immunotoxic. Furthermore, inhibition of AICAR transformylase leads to AICA riboside accumulation, which inhibits adenosine deaminase. Inhibition of adenosine deaminase results in increased adenosine concentrations. Lymphocyte proliferation is inhibited by adenosine's interaction 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. 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. A significant increase in urinary AICA concentrations occurred after 6 weeks of methotrexate 7.5—10 mg/week as compared with baseline concentrations from 40 patients with rheumatoid arthritis. Furthermore, receipt of 5 mg daily of leucovorin (folinic acid) but not of folate significantly reduced urinary AICA concentrations. Only leucovorin (folinic acid) can bypass the inhibition of dihydrofolate reductase and thus, provide an adequate tetrahydrofolate pool.

    PHARMACOKINETICS

    Methotrexate may be given orally, intravenously, intramuscularly, subcutaneously, or intrathecally. The volume of distribution of methotrexate approximates total body water. Methotrexate is 50—60% bound to serum plasma proteins, primarily albumin. Since methotrexate is a weak acid, it may be displaced from protein binding sites by other weak acids, such as chloramphenicol, phenytoin, tetracyclines, salicylates, and sulfonamides (see Drug Interactions). Methotrexate slowly diffuses into third-space fluids (i.e., ascites or pleural effusions). Methotrexate then slowly diffuses out of these fluid compartments and resulting in a prolonged half-life of methotrexate. These effusions should be evacuated prior to administering methotrexate (see Contraindications). Methotrexate has been detected in breast milk.
     
    After absorption, methotrexate undergoes hepatic and intracellular metabolism to a polyglutamated form (MTX-PG), which can be converted back to methotrexate by hydrolase enzymes. Small amounts of MTX-PG may remain in tissues for an extended period of time. 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. The 7-hydroxy metabolite may account for 7—33% of the drug excreted during the terminal phase of elimination. In addition, methotrexate is subject to metabolism by intestinal flora to an inactive metabolite, DAMPA. However, this metabolite may cross-react with radioimmunoassays for methotrexate. When methotrexate is given intravenously at low doses (30 mg/m2) metabolites account for < 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 elimination of methotrexate is triphasic. The first half-life is approximately 45 minutes and reflects the distribution phase. The second half-life is primarily due to renal clearance and is about 3.5 hours. The terminal half-life is about 10—12 hours and may reflect enterohepatic circulation of methotrexate. The terminal half-life of methotrexate determines the severity of methotrexate-induced hematologic and gastrointestinal toxicity.
     
    Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. The majority of methotrexate is eliminated renally during the first 12 hours after administration. Active tubular secretion of methotrexate occurs. Weak acids such as penicillins or probenecid (see Drug Interactions) inhibit renal excretion. Biliary excretion accounts for < 10% of methotrexate elimination. During high dose methotrexate therapy, the rapid urinary excretion of methotrexate results in high urine concentrations. These high urine concentrations may exceed the solubility of methotrexate and 7-hydroxymethotrexate below pH 7 and may lead to crystallization in the urine and nephrotoxicity. Urine alkalinization and aggressive hydration are, therefore, recommended for high dose therapy. Intense hydration and alkalinization of the urine does not affect the clearance or other plasma pharmacokinetics of methotrexate other than preventing renal damage.

    Oral Route

    Methotrexate is absorbed from the GI tract by active transport. Single oral doses > 40 mg/m2 may not be completely absorbed while lower doses are well absorbed. At an oral dose of 30 mg/m2 the mean bioavailability of methotrexate is 60%. Oral doses > 40 mg/m2 should be divided to avoid saturation of absorption processes. In leukemia and arthritis patients, absorption varies widely; a 20-fold difference between highest and lowest peak concentrations (Cmax 0.11—2.3 micro-M after a 20 mg/m2 dose) has been reported. Food has been shown to delay absorption and to decrease methotrexate Cmax. 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—40 mg) orally and SC, the mean bioavailability after oral administration was 0.64 (range, 0.21—0.96) as compared with subcutaneous administration. After administration of 12.5—25 mg to patients with Crohn's disease, the mean systemic exposure per milligram of methotrexate was 261 nmol x h/L when given orally and 281 nmol x h/L when given orally with 5 mg of oral folic acid, as compared to 360 nmol x h/L when given SC.

    Intramuscular Route

    Methotrexate is well absorbed intramuscularly with a Tmax that differs significantly among patients (30—60 minutes). Similar blood concentrations were obtained after IM or SC administration of weekly doses of 7.5—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. 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. After administration of 12.5—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
    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—9.9 hours following oral and intrathecal administration, respectively.