Avoid or Use Alternate Drug. Concomitant administration of NSAIDs with high dose methotrexate has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and GI toxicity. NSAIDs may reduce tubular secretion of methotrexate and enhance toxicity. .tacrolimusMonitor Closely (1)methotrexate and tacrolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.tafamidisMonitor Closely (1)tafamidis will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.tafamidis meglumineMonitor Closely (1)tafamidis meglumine will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.temsirolimusMonitor Closely (1)methotrexate and temsirolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.tepotinibSerious - Use Alternative (1)tepotinib will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.tetanus toxoid adsorbed or fluidMonitor Closely (1)methotrexate decreases effects of tetanus toxoid adsorbed or fluid by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.tetracyclineMonitor Closely (1)tetracycline increases levels of methotrexate by decreasing elimination. Use Caution/Monitor. If tetracyclines cannot be avoided in patients receiving high-dose methotrexate, closely monitor methotrexate plasma concentrations and patients for signs and symptoms of toxicity.theophyllineMonitor Closely (1)methotrexate increases levels of theophylline by unknown mechanism. Use Caution/Monitor. Methotrexate may decrease the clearance of theophylline. Theophylline levels should be monitored when used concomitantly with methotrexate.ticarcillinMonitor Closely (1)ticarcillin increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. 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.tisagenlecleucelSerious - Use Alternative (1)methotrexate, tisagenlecleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.tocilizumabSerious - Use Alternative (1)tocilizumab and methotrexate both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.tofacitinibSerious - Use Alternative (1)methotrexate, tofacitinib. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.tolmetinSerious - Use Alternative (1)tolmetin increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Concomitant administration of NSAIDs with high dose methotrexate has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and GI toxicity. NSAIDs may reduce tubular secretion of methotrexate and enhance toxicity. .tongkat aliSerious - Use Alternative (1)methotrexate and tongkat ali both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.trastuzumabMonitor Closely (1)trastuzumab, methotrexate. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .trastuzumab deruxtecanMonitor Closely (1)trastuzumab deruxtecan, methotrexate. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Neutropenia or febrile neutropenia incidence were increased when trastuzumab was coadministered with myelosuppressive chemotherapy. .tretinoinMonitor Closely (1)methotrexate, tretinoin. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Patients receiving other agents that may cause hepatotoxicity, including systemic retinoids, could be at increased risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy.tretinoin topicalSerious - Use Alternative (1)methotrexate, tretinoin topical. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Additive hepatotoxicity.trimethoprimMonitor Closely (1)trimethoprim increases toxicity of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Trimethoprim may increase risk of methotrexate-induced bone marrow suppression and megaloblastic anemia. If this drug combination cannot be avoided, closely monitor for signs of hematologic toxicity.Serious - Use Alternative (1)trimethoprim, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Due to an additive antifolate effect, trimethoprim has been shown to rarely increase bone marrow suppression in patients receiving methotrexate.trofinetideSerious - Use Alternative (1)trofinetide will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Trofinetide (an OATP131 and OATP13B inhibitor) may increase plasma levels of OATP131 or OATP13B substrates. Avoid coadministration with sensitive substrates.tucatinibMonitor Closely (1)tucatinib will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.typhoid polysaccharide vaccineMonitor Closely (1)methotrexate decreases effects of typhoid polysaccharide vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.typhoid vaccine liveContraindicated (1)methotrexate decreases effects of typhoid vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.ublituximabMonitor Closely (1)ublituximab and methotrexate both increase immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Owing to potential additive immunosuppressive effects, consider duration of effect and mechanism of action of these therapies if coadministeredustekinumabMonitor Closely (2)ustekinumab, methotrexate. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect. methotrexate and ustekinumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.valoctocogene roxaparvovecMonitor Closely (1)methotrexate and valoctocogene roxaparvovec both increase Other (see comment). Use Caution/Monitor. Medications that may cause hepatotoxicity when combined with valoctogene roxaparvovec may potentiate the risk of elevated liver enzymes. Closely monitor these medications and consider alternative medications in case of potential drug interactions.vancomycinMonitor Closely (1)vancomycin decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Recent exposure to vancomycin, in the absence of overt renal impairment, may adversely affect methotrexate excretion and increase risk of toxicity. Assess renal function, so appropriate methotrexate dose modifications can be made. .varicella virus vaccine liveContraindicated (1)methotrexate decreases effects of varicella virus vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.voclosporinMonitor Closely (1)voclosporin, methotrexate. Either increases toxicity of the other by nephrotoxicity and/or ototoxicity. Modify Therapy/Monitor Closely. Coadministration with drugs associated with nephrotoxicity may increase the risk for acute and/or chronic nephrotoxicity.Minor (1)voclosporin will increase the level or effect of methotrexate by Other (see comment). Minor/Significance Unknown. Information suggests voclosporin (an OATP1B1 inhibitor) may increase in the concentration of OATP1B1 substrates is possible. Monitor for adverse reactions of OATP1B1 substrates when coadministered with voclosporin.warfarinMonitor Closely (1)methotrexate increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor.willow barkMonitor Closely (1)willow bark will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.yellow fever vaccineContraindicated (1)methotrexate decreases effects of yellow fever vaccine by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.zidovudineMonitor Closely (1)methotrexate, zidovudine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of myelosuppression.zoster vaccine liveContraindicated (1)methotrexate decreases effects of zoster vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.zoster vaccine recombinantMonitor Closely (1)methotrexate decreases effects of zoster vaccine recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressive therapies may reduce the effectiveness of zoster vaccine recombinant. >10% Arachnoiditis with intrathecal administration Subacute toxicity with intrathecal administration (paralysis of extremities, cranial nerve palsy, seizure or coma) Demyelinating encephalopathy with cranial irradiation or other systemic chemotherapy Reddening of skin Hyperuricemia Ulcerative stomatitis Glossitis Gingivitis Nausea and vomiting Diarrhea Anorexia Intestinal perforation Mucositis (dose-dependent) Leukopenia Thrombocytopenia Renal failure Azotemia Nephropathy Pharyngitis 1-10% Alopecia Photosensitivity Rash Abdominal distress Malaise Fatigue Chills, fever Decreased resistance to infection Gastrointestinal hemorrhage Myelosuppression Disorders of lung, interstitial pneumonia (acute, chronic) Atrophy of liver, cirrhosis, hepatic fibrosis or necrosis, elevated liver function tests, hepatic failure Black Box Warnings Severe hypersensitivity Contraindicated with history of severe hypersensitivity reactions to methotrexate, including anaphylaxis Embryofetal toxicity Can cause embryofetal toxicity, including fetal death Contraindicated in non-neoplastic diseases during pregnancy Advise females and males of reproductive potential to use effective contraception during and after treatment Benzyl alcohol-containing products Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis; use only preservative-free methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available Serious adverse effects Serious adverse reactions, including death, reported with methotrexate Closely monitor for infections and adverse reactions of bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin Withhold or discontinue methotrexate as appropriate Contraindications Pregnant women with nonmalignant disease Known hypersensitivity; severe reactions observed Cautions Based on published reports and its mechanism of action, can cause embryofetal toxicity, including fetal death; contraindicated in females with nonmalignant disease Hypersensitivity reactions, including anaphylaxis, reported; if hypersensitivity occurs, immediately discontinue and institute appropriate therapy Myelosuppression reported, including severe and life-threatening pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia; obtain blood counts at baseline and periodically; provide supportive care and withhold, reduce dose, or discontinue methotrexate if needed GI toxicity may occur, including diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation; patients with peptic ulcer disease or ulcerative colitis at greater risk; withhold or discontinued for severe GI toxicity and institute supportive care Pulmonary toxicity reported, including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels; pulmonary symptoms (especially a dry, non-productive cough) may require interruption of therapy and careful investigation Pulmonary toxicity reported, including acute or chronic interstitial pneumonitis and irreversible or fatal cases can occur at all dose levels Secondary malignancies can occur at all dose levels; in some cases, lymphoproliferative disease that occurred during therapy with low-dose methotrexate regressed completely following withdrawal of methotrexate; if lymphoproliferative disease occurs, discontinue and institute appropriate treatment if lymphoma does not regress Can induce tumor lysis syndrome with rapidly growing tumors; institute appropriate treatment for prevention and management Can cause impairment of fertility, oligospermia, and menstrual dysfunction; unknown if infertility is reversible; discuss reproduction risks with female and male patients of reproductive potential Methotrexate can exit slowly from third space accumulations resulting in prolonged terminal plasma half-life and toxicity; evacuate significant third-space accumulations prior injection Concomitant radiation therapy increases risk of soft tissue necrosis and osteonecrosis associated with methotrexate Serious adverse reactions, including death, have occurred due to medication errors; most commonly, these errors occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed; ensure that patients receive the recommended dosage Risk associated with benzyl alcohol preservative Formulations with benzyl alcohol can cause severe CNS toxicity or metabolic acidosis, if used in neonates or low-birth weight infants, IT, or in high-dose regimens Use only preservative-free injection for treatment of neonates or low-birth weight infants and for intrathecal use Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available Benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when injection required during pregnancy to treat neoplastic disease Gasping syndrome Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with drugs containing benzyl alcohol Gasping syndrome characterized by CNS depression, metabolic acidosis, and gasping respirations When prescribing in infants (non-neonate, non-low-birth weight), if preservative-free formulation unavailable and use of a benzyl alcohol-containing formulation is necessary, consider combined daily metabolic load of benzyl alcohol from all sources Neurotoxicity Serious neurotoxicity, including generalized and focal seizures, reported in pediatric patients Leukoencephalopathy can occur with intermediate and high-dose IV regimens, IT administration, and low-dose methotrexate therapy; risk increased with prior cranial radiation Transient acute stroke-like syndrome can occur with high-dose regimens; clinical manifestations include confusion, hemiparesis, transient blindness, seizures, and coma Intrathecal (IT) administration IT administration can cause acute chemical arachnoiditis manifested by symptoms such as headache, back pain, nuchal rigidity, and fever May also cause subacute myelopathy characterized by paraparesis or paraplegia Avoid IT use of methotrexate injection that contains the preservative benzyl alcohol