methotrexate (Rx)

Acute Lymphoblastic Leukemia

Indicated for adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen

IV: Varies from 10-5,000 mg/m²; dose varies and depends disease state, patient risk category, concurrent drugs used, phase of treatment and response to treatment  

Use leucovorin rescue in accordance with high-dose methotrexate IV regimen guidelines

Meningeal Leukemia

Indicated for prophylaxis and treatment of meningeal leukemia in adult and pediatric patients

Use preservative-free methotrexate for intrathecal (IT) injection

Treatment: 12 mg IT; not to exceed 15 mg/dose every 2-7 days; administer 1 additional dose after cell count on CSF returns to normal

Prophylaxis: 12-15 mg IT no more than once weekly

Patients with Down syndrome: Administer leucovorin rescue with methotrexate IT

Non-Hodgkin Lymphoma

Indicated for treatment of adults and pediatric patients with Non-Hodgkin lymphoma (NHL)

Recommended dosage varies; refer to specific institutional protocol

See leucovorin rescue protocols for intermediate- and high-dose methotrexate regimens

Combination with other antineoplastics

• Range 10-8,000 mg/m² IV
• Part of combination chemotherapy regimen: 1,000-3,000 mg/m² IV infusion over 24 hr followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Single agent

• Cutaneous forms of NHL: 5-75 mg IV

CNS-directed therapy

• Single agent: 8,000 mg/m² IV infusion over 4 hr
• Combination with immunochemotherapy: 3,000-8,000 mg/m² IV infusion followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Osteosarcoma

Indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen

12 g/m² IV over 4 hr on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery in combination with other chemotherapy  

If peak serum methotrexate <454 mcg/mL at end of initial infusion, dose may be increased to 15 g/m² in subsequent treatments

Not to exceed 20 g/dose

Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Breast Cancer

Indicated for breast cancer as part of a combination chemotherapy regimen

40 mg/m² IV as a component of a cyclophosphamide- and fluorouracil-based multidrug regimen  

Squamous Cell Carcinoma of the Head and Neck

Indicated for squamous cell carcinoma of the head and neck as a single-agent

40-60 mg/m2 IV qWeek  

Gestational Trophoblastic Neoplasia

Indicated for adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen

30-200 mg/m2 or 0.4-1 mg/kg IV or IM  

High-risk GTN: 300 mg/m² IV infused over 12 hr as a component of a multidrug regimen

Rheumatoid Arthritis

Indicated for management of severe, active rheumatoid arthritis (RA) in adults who have had an insufficient response or intolerance to an adequate trial of first-line therapy including full dose NSAIDs

Initial: 7.5 mg PO/IV/IM as a single weekly dose, OR

2.5 mg PO q12hr for 3 sequential doses per week

Increase dose to optimum response; single dose not to exceed 20 mg/week PO (increased risk of bone marrow suppression); reduce to lowest possible effective dose

Otrexup (SC): If used as initial therapy, start at lowest available dose (ie, 10 mg SC qWeek)

Rasuvo or RediTrex (SC), initial dose: 7.5 mg as a single SC dose once weekly; adjust autoinjector dose by 2.5 mg increments as clinically required

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions

Psoriasis

For symptomatic control of severe, recalcitrant, disabling psoriasis in adults not adequately responsive to other forms of therapy; use only with established diagnosis (by biopsy and/or after dermatologic consultation)

Initial: 10-25 mg weekly in single PO/SC/IM/IV dose; not to exceed 30 mg/wk

Gradually adjust dose to achieve to optimal clinical response; use lowest dose and longest rest period possible with return to conventional topical therapy encouraged

Trexall: May give weekly dose divided as 2.5 mg PO q12hr for 3 sequential doses

Otrexup (SC): If used as initial therapy, start a lowest available dose (ie, 10 mg SC qWeek)

Rasuvo or RediTrex (SC): 10-25 mg SC once weekly

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions

Dosage Modifications

Renal impairment

• Methotrexate elimination reduced with CrCl <90 mL/min
• Patients with renal impairment are at increased risk for adverse effects; carefully monitor for toxicity
• Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens
• Some patients may require dose reduction or, in some cases, discontinuation

Hepatic impairment

• Safety in patients with hepatic impairment is unknown
• Patients with hepatic impairment may be at increased risk for adverse reactions based on methotrexate elimination characteristics
• Consider dose reduction or discontinuing with hepatic impairment as appropriate

Dosing Considerations

Otrexup and Rasuvo (SC injections) are not indicated for neoplastic disease

If switching from PO to SC (Otrexup, Rasuvo), consider higher bioavailability with SC compared with PO (see Pharmacology Absorption section)

Ectopic Pregnancy (Off-label)

50 mg/m² IM; measure serum hCG levels on days 4 and 7; may repeat dose on day 7 if necessary  

If hCG levels decrease <15% between days 4 and 7, administer methotrexate 50 mg/m² IM; if hCG ≥15% between days 4 and 7, discontinue treatment and measure hCG weekly until reaching nonpregnant levels

Myasthenia Gravis (Orphan)

Orphan designation for treatment of myasthenia gravis

Orphan Sponsor

• University of Kansas Medical Center; 3901 Rainbow Blvd, MSN 2012; Kansas City, KS 66160

Proliferative Vitreoretinopathy (Orphan)

Orphan designation for prevention of proliferative vitreoretinopathy (PVR)

Orphan Sponsor

• Helio Vision, Inc; 1000 Winter Street, 4th Floor; Waltham, Massachusetts 02451

Ectopic Pregnancy (Orphan)

Orphan designation for treatment of ectopic pregnancy

Orphan sponsor

• Antares Pharma, Inc; Princeton Crossroads Corporate Center; 100 Princeton South Suite 300; Ewing, New Jersey 08628

Polyarticular Juvenile Idiopathic Arthritis

Management of active polyarticular juvenile idiopathic arthritis (pJIA) in children who have had an insufficient response or intolerance to an adequate trial of first-line therapy including full dose NSAIDs

Initial: 10 mg/m² PO/IM/SC qWeek  

If switching from PO to SC (Otrexup, Rasuvo, RediTrex), consider higher bioavailability with SC compared with PO (see Pharmacology Absorption section)

Dosing Considerations (PJIA)

• Data with doses up to 30 mg/m²/wk in children exist, although there are too few published studies to assess how doses >20 mg/m²/wk might affect the risk of serious toxicity in children, especially bone marrow suppression
• Experience does suggest, however, that children receiving 20 to 30 mg/m²/wk (0.65-1 mg/kg/wk) may have better absorption and fewer GI side effects if methotrexate is administered either IM or SC
• Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions

Meningeal Leukemia

Indicated for prophylaxis and treatment of meningeal leukemia in adult and pediatric patients

Use preservative-free methotrexate for intrathecal (IT) injection

Treatment: Dose may be given at intervals of ≥2 days up to twice weekly; however, administration at intervals of <1 week may result in increased subacute toxicity

Prophylaxis: Administered no more than once weekly

Patients with Down syndrome: Administer leucovorin rescue with methotrexate IT

Age-based dosing

<1 year: 6 mg IT

1 to <2 years: 8 mg IT

2 to <3 years: 10 mg IT

3 to <9 years: 12 mg IT

≥9 years: 12-15 mg IT

Acute Lymphoblastic Leukemia

Indicated for treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy regimen

IV: Varies from 10-5,000 mg/m2; dose varies and depends disease state, patient risk category, concurrent drugs used, phase of treatment and response to treatment  

Oral solution (Xatmep): 20 mg/m² PO qWeek

Use leucovorin rescue in accordance with high-dose methotrexate IV regimen guidelines

Non-Hodgkin Lymphoma

Indicated for treatment of adults and pediatric patients with Non-Hodgkin lymphoma (NHL)

Recommended dosage varies; refer to specific institutional protocol

See leucovorin rescue protocols for intermediate- and high-dose methotrexate regimens

Combination with other antineoplastics

• Range 10-8,000 mg/m² IV
• Part of combination chemotherapy regimen: 1,000-3,000 mg/m² IV infusion over 24 hr followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Single agent

• Cutaneous forms of NHL: 5-75 mg IV

CNS-directed therapy

• Single agent: 8,000 mg/m² IV infusion over 4 hr
• Combination with immunochemotherapy: 3,000-8,000 mg/m² IV infusion followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines

Osteosarcoma

• Indicated for adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen
• 12 g/m² IV over 4 hr on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery in combination with other chemotherapy
• Not to exceed 20 g/dose
• Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines
• If peak serum methotrexate <454 mcg/mL at end of initial infusion, dose may be increased to 15 g/m² in subsequent treatments

Dosage Modifications

Renal impairment

• Methotrexate elimination reduced with CrCl <90 mL/min
• Patients with renal impairment are at increased risk for adverse effects; carefully monitor for toxicity
• Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens
• Some patients may require dose reduction or, in some cases, discontinuation

Hepatic impairment

• Safety in patients with hepatic impairment is unknown
• Patients with hepatic impairment may be at increased risk for adverse reactions based on methotrexate elimination characteristics
• Consider dose reduction or discontinuing with hepatic impairment as appropriate

Dosing Considerations

May impair fertility, cause oligospermia, and menstrual dysfunction; exclude pregnancy before initiating treatment

Otrexup and Rasuvo (SC injections) are not indicated for neoplastic disease

If switching from PO to SC (Otrexup, Rasuvo), consider higher bioavailability with SC compared with PO (see Pharmacology Absorption section)

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

Leucovorin rescue

• Administer leucovorin rescue doses ≥500 mg/m² (ie, high-dose)
• Consider leucovorin rescue for doses 100 to <500 mg/m² (ie, intermediate-dose)

Supportive care

• For high-dose regimens, the following are recommended; also consider for intermediate-dose regimens
• Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy
• Administer IV fluids starting before first dose and continue throughout treatment to maintain hydration and urine output
• Alkalinize urine starting before first dose and continue throughout treatment to maintain urine pH ≥7
• Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed
• Glucarpidase: Administer in patients with toxic plasma methotrexate concentrations (>1 micromole/L) and delayed methotrexate clearance owing to impaired renal function

Monitor closely for early signs of bone marrow suppression, and renal or hepatic toxicity

Contraindicated (10)

• acitretin

  acitretin, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. Risk of additive hepatotoxicity.

• influenza virus vaccine quadrivalent, intranasal

  methotrexate decreases effects of influenza virus vaccine quadrivalent, intranasal by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• measles mumps and rubella vaccine, live

  methotrexate decreases effects of measles mumps and rubella vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• measles, mumps, rubella and varicella vaccine, live

  methotrexate decreases effects of measles, mumps, rubella and varicella vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• rotavirus oral vaccine, live

  methotrexate decreases effects of rotavirus oral vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• smallpox (vaccinia) vaccine, live

  methotrexate decreases effects of smallpox (vaccinia) vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• typhoid vaccine live

  methotrexate decreases effects of typhoid vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• varicella virus vaccine live

  methotrexate decreases effects of varicella virus vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• yellow fever vaccine

  methotrexate decreases effects of yellow fever vaccine by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• zoster vaccine live

  methotrexate decreases effects of zoster vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

Serious - Use Alternative (71)

• adenovirus types 4 and 7 live, oral

  methotrexate decreases effects of adenovirus types 4 and 7 live, oral by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• anthrax vaccine

  methotrexate decreases effects of anthrax vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• aspirin

  aspirin increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• aspirin rectal

  aspirin rectal increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. The relative risk of interaction of different NSAIDs w/methotrexate is not established. Selective COX 2 inhibitors are believed to have minimal interaction. Greater risk in pts. with renal impairment. Greater toxicity with high dose methotrexate (e.g., anti neoplastic regimen).

• aspirin/citric acid/sodium bicarbonate

  aspirin/citric acid/sodium bicarbonate increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• axicabtagene ciloleucel

  methotrexate, axicabtagene ciloleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• bacitracin

  methotrexate and bacitracin both increase nephrotoxicity and/or ototoxicity. Avoid or Use Alternate Drug. Avoid concurrent use of bacitracin with other nephrotoxic drugs

• BCG intravesical live

  methotrexate decreases effects of BCG intravesical live by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• bremelanotide

  bremelanotide will decrease the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

• brexucabtagene autoleucel

  methotrexate, brexucabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• ceftobiprole medocaril sodium

  ceftobiprole medocaril sodium will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Ceftobiprole (an OATP1B1/1B3 inhibitor) may increase plasma concentrations of OATP1B1 and OATP1B3 substrates.

• celecoxib

  celecoxib 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. .

• choline magnesium trisalicylate

  choline magnesium trisalicylate increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. The relative risk of interaction of different NSAIDs w/methotrexate is not established. Selective COX 2 inhibitors are believed to have minimal interaction. Greater risk in pts. with renal impairment. Greater toxicity with high dose methotrexate (e.g., anti neoplastic regimen).

• ciltacabtagene autoleucel

  methotrexate, ciltacabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• darolutamide

  darolutamide will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Darolutamide is a BCRP inhibitor. Avoid coadministration with BCRP inhibitors. If use is unavoidable, closely monitor for adverse reactions and consider dose reduction of BCRP substrate drug (refer BCRP substrate prescribing information).

• deferiprone

  deferiprone, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; if an alternative is not possible, monitor absolute neutrophil count more frequently.

• diclofenac

  diclofenac 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. .

• diflunisal

  diflunisal 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. .

• divalproex sodium

  methotrexate will decrease the level or effect of divalproex sodium by unspecified interaction mechanism. Avoid or Use Alternate Drug. may potentially result in increased frequency of seizures or bipolar symptoms; monitor serum valproate concentrations and clinical response when adding or discontinuing methotrexate and adjust valproate dosage

• erdafitinib

  erdafitinib will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index.

• ethanol

  methotrexate, ethanol. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. 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.

• etodolac

  etodolac 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. .

• etrasimod

  etrasimod, methotrexate. Either increases effects of the other by Mechanism: aldehyde dehydrogenase inhibition. Avoid or Use Alternate Drug. Risk of additive immune system effects with etrasimod has not been studied in combination with antineoplastic, immune-modulating, or noncorticosteroid immunosuppressive therapies. Avoid coadministration during and in the weeks following administration of etrasimod.

• fenoprofen

  fenoprofen 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. .

• flurbiprofen

  flurbiprofen 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. .

• human papillomavirus vaccine, nonavalent

  methotrexate decreases effects of human papillomavirus vaccine, nonavalent by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines.

• human papillomavirus vaccine, quadrivalent

  methotrexate decreases effects of human papillomavirus vaccine, quadrivalent by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines.

• ibuprofen

  ibuprofen 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. .

• ibuprofen IV

  ibuprofen IV 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. .

• idecabtagene vicleucel

  methotrexate, idecabtagene vicleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• indomethacin

  indomethacin 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. .

• influenza virus vaccine quadrivalent, adjuvanted

  methotrexate decreases effects of influenza virus vaccine quadrivalent, adjuvanted by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive drugs may reduce the immune response to influenza vaccine.

• influenza virus vaccine trivalent, adjuvanted

  methotrexate decreases effects of influenza virus vaccine trivalent, adjuvanted by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive drugs may reduce the immune response to influenza vaccine.

• ketoprofen

  ketoprofen 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. .

• ketorolac

  ketorolac 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. .

• ketorolac intranasal

  ketorolac intranasal increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. The relative risk of interaction of different NSAIDs w/methotrexate is not established. Selective COX 2 inhibitors are believed to have minimal interaction. Greater risk in pts. with renal impairment. Greater toxicity with high dose methotrexate (e.g., anti neoplastic regimen).

• lasmiditan

  lasmiditan increases levels of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Comment: Lasmiditan inhibits BCRP in vitro. Avoid coadministration of lasmiditan with BCRP substrates.

• leniolisib

  leniolisib will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Leniolisib, a BCRP, OATP1B1, and OATP1B3 inhibitor, may increase systemic exposure of these substrates

• lisocabtagene maraleucel

  methotrexate, lisocabtagene maraleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• meclofenamate

  meclofenamate 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. .

• mefenamic acid

  mefenamic acid 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. .

• meloxicam

  meloxicam 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. .

• nabumetone

  nabumetone 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. .

• naproxen

  naproxen 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.

• oxaprozin

  oxaprozin 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. .

• pacritinib

  pacritinib will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Concomitant administration of pacritinib (BCRP inhibitor) with BCRP substrates may increase the plasma concentrations of these substrates.

• palifermin

  palifermin increases toxicity of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hrbefore, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

• pexidartinib

  methotrexate and pexidartinib both increase inhibition of GI absorption. Applies only to oral form of both agents. Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.

• piroxicam

  piroxicam 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. .

• pneumococcal vaccine 13-valent

  methotrexate decreases effects of pneumococcal vaccine 13-valent by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• pretomanid

  methotrexate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.

• probenecid

  probenecid increases levels of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Avoid or Use Alternate Drug. If combination must be used, decrease methotrexate dose; also, methotrexate increases uric acid production and risk for uric acid neuropathy.

• ropeginterferon alfa 2b

  ropeginterferon alfa 2b, methotrexate. Either increases levels of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression.

• salicylates (non-asa)

  salicylates (non-asa) increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• salsalate

  salsalate increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• sotorasib

  sotorasib will decrease the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.

• sparsentan

  sparsentan will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Sparsentan (a BCRP inhibitor) may increase exposure of sensitive BCRP substrates and the risk of these substrates toxicities.

• sulfadiazine

  sulfadiazine increases toxicity of methotrexate by plasma protein binding competition. Avoid or Use Alternate Drug.

• sulfamethoxazole

  sulfamethoxazole increases toxicity of methotrexate by plasma protein binding competition. Avoid or Use Alternate Drug. Methotrexate concentrations may be elevated, increasing the risk of toxicity (eg, bone marrow suppression).

• sulfasalazine

  sulfasalazine increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug.

• sulfisoxazole

  sulfisoxazole increases toxicity of methotrexate by plasma protein binding competition. Avoid or Use Alternate Drug.

• sulindac

  sulindac 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. .

• tepotinib

  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.

• tisagenlecleucel

  methotrexate, tisagenlecleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• tocilizumab

  tocilizumab and methotrexate both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• tofacitinib

  methotrexate, tofacitinib. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• tolmetin

  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 ali

  methotrexate and tongkat ali both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• tretinoin topical

  methotrexate, tretinoin topical. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Additive hepatotoxicity.

• trimethoprim

  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.

• trofinetide

  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.

Monitor Closely (152)

• acalabrutinib

  acalabrutinib increases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Acalabrutinib may increase exposure to coadministered BCRP substrates by inhibition of intestinal BCRP.
  
  acalabrutinib, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration may increase risk of myelosuppressive effects.

• activated charcoal

  activated charcoal will decrease the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Charcoal can reduce absorption of methotrexate and remove it from systemic circulation. Depending on the clinical situation, this will reduce the effectiveness or toxicity of methotrexate.

• aldesleukin

  aldesleukin increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. May increase myelosupression and hepatotoxicity.

• allopurinol

  allopurinol decreases effects of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of myelosuppression.

• aminohippurate sodium

  aminohippurate sodium will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• amoxicillin

  amoxicillin 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.

• ampicillin

  ampicillin 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.

• apalutamide

  apalutamide will decrease the level or effect of methotrexate by increasing elimination. Use Caution/Monitor. Apalutamide weakly induces BCRP and OATP1B1 and may decrease systemic exposure of drugs that are substrates of both BCRP and OATP1B1.

• aspirin rectal

  aspirin rectal will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• aspirin/citric acid/sodium bicarbonate

  aspirin/citric acid/sodium bicarbonate will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• astragalus

  methotrexate increases and astragalus decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• belatacept

  belatacept and methotrexate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor.

• berotralstat

  berotralstat will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.

• bosutinib

  bosutinib increases levels of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• caffeine

  caffeine decreases effects of methotrexate by pharmacodynamic antagonism. Use Caution/Monitor.

• carboplatin

  carboplatin and methotrexate both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• chlorpropamide

  chlorpropamide will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor. 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.

• cholera vaccine

  methotrexate decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.

• cholestyramine

  cholestyramine decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4-6 hours after the administration of cholestyramine.

• choline magnesium trisalicylate

  choline magnesium trisalicylate will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• cidofovir

  cidofovir and methotrexate both decrease immunosuppressive effects; risk of infection. Use Caution/Monitor. May increase myelosupression.

• ciprofloxacin

  ciprofloxacin will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Renal tubular transport of methotrexate may be inhibited by coadministration of ciprofloxacin, potentially leading to increased methotrexate plasma levels and toxicity.

• cisplatin

  cisplatin and methotrexate both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• crofelemer

  crofelemer increases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Crofelemer has the potential to inhibit transporters MRP2 and OATP1A2 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

• cyclosporine

  cyclosporine, methotrexate. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Close monitoring of cyclosporine and methotrexate concentrations, renal function, and liver enzymes is recommended during concurrent therapy. .

• danicopan

  danicopan will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Danicopan increases plasma concentrations of BCRP substrates; consider dose reduction of BCRP substrate according to its prescribing information.
  
  danicopan will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Danicopan increases plasma concentrations of P-gp substrates; consider dose reduction of P-gp substrates where minimal concentration changes may lead to serious adverse reactions.

• dapsone

  dapsone, methotrexate. Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of hematologic toxicity.

• demeclocycline

  demeclocycline increases levels of methotrexate by decreasing elimination. Use Caution/Monitor. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

• dengue vaccine

  methotrexate decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

• denosumab

  methotrexate, denosumab. Other (see comment). Use Caution/Monitor. Comment: Caution should be taken in patients on concomitant immunosuppressants or with impaired immune systems because of increased risk for serious infections.

• dexlansoprazole

  dexlansoprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• dicloxacillin

  dicloxacillin 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.

• digoxin

  methotrexate decreases levels of digoxin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Serum levels of digoxin may be reduced and actions may be decreased. Monitor patient for signs of reduction in pharmacologic effect of digoxin and increase digoxin dose if necessary. Serum level monitoring may facilitate tailoring dosage.

• diphtheria & tetanus toxoids

  methotrexate decreases effects of diphtheria & tetanus toxoids by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• diphtheria & tetanus toxoids/ acellular pertussis vaccine

  methotrexate decreases effects of diphtheria & tetanus toxoids/ acellular pertussis vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine

  methotrexate decreases effects of diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• doxycycline

  doxycycline increases levels of methotrexate by decreasing elimination. Use Caution/Monitor. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

• echinacea

  methotrexate increases and echinacea decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• elacestrant

  elacestrant will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Elacestrant (a BCRP inhibitor) may increase plasma concentrations of sensitive BCRP substrates, which may increase risk of adverse reactions related to these substrates. Refer to prescribing information for sensitive BCRP substrates for dosing recommendations.

• elagolix

  elagolix will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• eliglustat

  eliglustat increases levels of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.

• eltrombopag

  eltrombopag increases levels of methotrexate by decreasing metabolism. Use Caution/Monitor. OATP transporter protein inhibition.

• eluxadoline

  eluxadoline increases levels of methotrexate by decreasing metabolism. Use Caution/Monitor. Eluxadoline may increase the systemic exposure of coadministered BCRP substrates.

• elvitegravir/cobicistat/emtricitabine/tenofovir DF

  methotrexate and elvitegravir/cobicistat/emtricitabine/tenofovir DF both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• encorafenib

  encorafenib will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Encorafenib (a OATP1B1, OATP1B3, and BCRP inhibitor) may increase the concentration and toxicities of OATP1B1, OATP1B3, and BCRP substrates. Closely monitor for signs and symptoms of increased exposure and consider adjusting the dose of these substrates. Screen reader support enabled.

• esomeprazole

  esomeprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• ferric maltol

  ferric maltol, methotrexate. Either increases levels of the other by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Coadministration of ferric maltol with certain oral medications may decrease the bioavailability of either ferric maltol and some oral drugs. For oral drugs where reductions in bioavailability may cause clinically significant effects on its safety or efficacy, separate administration of ferric maltol from these drugs. Duration of separation may depend on the absorption of the medication concomitantly administered (eg, time to peak concentration, whether the drug is an immediate or extended release product).

• fingolimod

  methotrexate increases effects of fingolimod by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects. .

• food

  food decreases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Food may delay the absorption and reduce the peak concentration of methotrexate.

• fosphenytoin

  fosphenytoin increases toxicity of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs.

• fostamatinib

  fostamatinib will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Concomitant use of fostamatinib may increase concentrations of P-gp/BCRP substrate drugs. Monitor for toxicities of P-gp/BCRP substrate drug that may require dosage reduction when given concurrently with fostamatinib.

• fostemsavir

  fostemsavir will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits OATP1B1/3 and BCRP transporters. If possible, avoid coadministration or modify dose of OATP1B1/3 or BCRP substrates coadministered with fostemsavir.

• glecaprevir/pibrentasvir

  glecaprevir/pibrentasvir will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Glecaprevir/pibrentasvir may increase plasma concentration of OATP1B1/OATP1B3, P-gp and BCRP substrates.

• haemophilus influenzae type b vaccine

  methotrexate decreases effects of haemophilus influenzae type b vaccine by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Avoid vaccination during chemotherapy or radiation therapy if possible because antibody response might be suboptimal. Patients vaccinated within a 14-day period before starting or during immunosuppressive therapy should be revaccinated =3 months after therapy is discontinued if immune competence has been restored. .

• hepatitis A vaccine inactivated

  methotrexate decreases effects of hepatitis A vaccine inactivated by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• hepatitis a/b vaccine

  methotrexate decreases effects of hepatitis a/b vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• hepatitis b vaccine

  methotrexate decreases effects of hepatitis b vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• hydroxychloroquine sulfate

  hydroxychloroquine sulfate decreases levels of methotrexate by unknown mechanism. Use Caution/Monitor. Hydroxychloroquine may reduce the renal clearance of methotrexate; the exact mechanism of this interaction is unknown. .

• hydroxyurea

  methotrexate, hydroxyurea. Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of myelosuppression.

• ibuprofen IV

  ibuprofen IV will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• ifosfamide

  ifosfamide, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration with ifosfamide may increase the risk of immunosuppression and myelosuppression.

• influenza A (H5N1) vaccine

  methotrexate decreases effects of influenza A (H5N1) vaccine by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressive therapies may reduce immune response to H5N1 vaccine.

• influenza virus vaccine (H5N1), adjuvanted

  methotrexate decreases effects of influenza virus vaccine (H5N1), adjuvanted by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressive therapies may reduce immune response to H5N1 vaccine.

• influenza virus vaccine quadrivalent

  methotrexate decreases effects of influenza virus vaccine quadrivalent by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• influenza virus vaccine quadrivalent, cell-cultured

  methotrexate decreases effects of influenza virus vaccine quadrivalent, cell-cultured by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• influenza virus vaccine quadrivalent, recombinant

  methotrexate decreases effects of influenza virus vaccine quadrivalent, recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immune response to vaccine may be decreased in immunocompromised individuals.

• influenza virus vaccine trivalent

  methotrexate decreases effects of influenza virus vaccine trivalent by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• influenza virus vaccine trivalent, recombinant

  methotrexate decreases effects of influenza virus vaccine trivalent, recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immune response to vaccine may be decreased in immunocompromised individuals.

• ioversol

  ioversol and methotrexate both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• isavuconazonium sulfate

  methotrexate and isavuconazonium sulfate both decrease immunosuppressive effects; risk of infection. Use Caution/Monitor.

• isotretinoin

  methotrexate, isotretinoin. 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.

• istradefylline

  istradefylline will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of P-gp substrates in clinical trials. Consider dose reduction of sensitive P-gp substrates.

• Japanese encephalitis virus vaccine

  methotrexate decreases effects of Japanese encephalitis virus vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• ketorolac intranasal

  ketorolac intranasal will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• L-methylfolate

  methotrexate decreases effects of L-methylfolate by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Folic acid antagonists may interfere with folic acid utilization.

• lansoprazole

  lansoprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• leflunomide

  leflunomide increases levels of methotrexate by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Additive hepatotoxicity, pancytopenia. If leflunomide and methotrexate are given concomitantly, monitor liver toxicity with ALT, AST, and serum albumin testing. Also, monitor platelets, WBC count, hemoglobin, or hematocrit at baseline and monthly for 6 months following initiation and every 6-8 weeks thereafter.

• letermovir

  letermovir increases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Letermovir, an OATP1B1/3 inhibitor may increase plasma concentrations of coadministered OATP1B1/3 substrates.

• lomitapide

  lomitapide increases levels of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing dose when used concomitantly with lomitapide.

• lomustine

  lomustine, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration with lomustine may increase the risk of immunosuppression and myelosuppression.

• lonafarnib

  lonafarnib will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Lonafarnib is a weak P-gp inhibitor. Monitor for adverse reactions if coadministered with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. Reduce P-gp substrate dose if needed.

• maitake

  methotrexate increases and maitake decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• meclofenamate

  meclofenamate will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• meningococcal A C Y and W-135 polysaccharide vaccine combined

  methotrexate decreases effects of meningococcal A C Y and W-135 polysaccharide vaccine combined by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• meningococcal group B vaccine

  methotrexate decreases effects of meningococcal group B vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Individuals with altered immunocompetence may have reduced immune responses to the vaccine.

• methyclothiazide

  methyclothiazide will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• minocycline

  minocycline 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.

• mipomersen

  mipomersen, methotrexate. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.

• momelotinib

  momelotinib increases toxicity of methotrexate by plasma protein binding competition. Modify Therapy/Monitor Closely. Momelotinib (BCRP inhibitor) may increase exposure of BCRP substrates, which may increase the risk of BCRP substrate adverse reactions. Dose adjustment of other BCRP substrates may necessary.

• muromonab CD3

  methotrexate and muromonab CD3 both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• mycophenolate

  mycophenolate, methotrexate. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Infections may occur.

• nafcillin

  nafcillin 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.

• neomycin PO

  neomycin PO decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Neomycin may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

• ocrelizumab

  methotrexate and ocrelizumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Coadministration of ocrelizumab with immunosuppessants is expected to increase the risk of immunosuppression.

• ofatumumab SC

  ofatumumab SC, methotrexate. Either decreases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with coadministration. When switching from therapies with immune effects, take into account the duration and mechanism of action of these therapies when initiating ofatumumab SC.

• olaparib

  methotrexate and olaparib both increase pharmacodynamic synergism. Use Caution/Monitor. Coadministration with other other myelosuppressive anticancer agents, including DNA damaging agents, may potentiate and prolongate the myelosuppressive toxicity.

• omeprazole

  omeprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Temporary withdrawal of PPI may be considered in some patients.

• osimertinib

  osimertinib will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Osimertinib is an inhibitor of BCRP transport. Caution if coadministered with sensitive BCRP substrates.

• oteseconazole

  oteseconazole will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Otesezonale, a BCRP inhibitor, may increase the effects and risk of toxicities of BCRP substrates. Use lowest starting dose of BCRP substrate, or consider reducing BCRP substrate dose.

• oxaliplatin

  methotrexate and oxaliplatin both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.
  
  oxaliplatin, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• ozanimod

  ozanimod, methotrexate. Either increases effects of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Coadministration with immunosuppressive therapies may increase the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs in order to avoid unintended additive immunosuppressive effects.

• pantoprazole

  pantoprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• paromomycin

  paromomycin decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. 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

  pegaspargase decreases effects of methotrexate by pharmacodynamic antagonism. Use Caution/Monitor. It is recommended to give pegaspargase at least 10-14 days prior to methotrexate or shortly after methotrexate administration.

• phenytoin

  phenytoin increases toxicity of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as phenytoin.

• pirtobrutinib

  pirtobrutinib will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Pirtobrutinib (a BCRP inhibitor) may increase plasma concentrations of sensitive BCRP substrates, which may increase the risk of adverse reactions related to these substrates. Refer to prescribing information for sensitive BCRP substrates for dosing recommendations.

• pneumococcal vaccine polyvalent

  methotrexate decreases effects of pneumococcal vaccine polyvalent by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• poliovirus vaccine inactivated

  methotrexate decreases effects of poliovirus vaccine inactivated by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Avoid vaccination during chemotherapy or radiation therapy if possible because antibody response might be suboptimal. Patients vaccinated within a 14-day period before starting or during immunosuppressive therapy should be revaccinated =3 months after therapy is discontinued if immune competence has been restored. .

• ponatinib

  ponatinib increases levels of methotrexate by Other (see comment). Use Caution/Monitor.

• ponesimod

  ponesimod and methotrexate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• pretomanid

  pretomanid will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.

• probenecid

  probenecid will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Methotrexate plasma levels, therapeutic effects, and toxicity may be enhanced. Monitor methotrexate concentrations and adjust dose accordingly.

• procarbazine

  procarbazine, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of immunosupression.

• rabeprazole

  rabeprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• rabies vaccine

  methotrexate decreases effects of rabies vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• regorafenib

  regorafenib will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Regorafenib likely inhibits BCRP (ABCG2) transport. Coadministration with a BCRP substrate may increase systemic exposure to the substrate and related toxicity.

• rilonacept

  methotrexate and rilonacept both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• rolapitant

  rolapitant will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Oral rolapitant (BCRP inhibitor) may increase plasma concentrations of BCRP substrates and may result in potential adverse reactions. Monitor possible adverse reactions if concomitant use of BCRP substrates and rolapitant can not be avoided.

• rose hips

  rose hips will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• safinamide

  safinamide will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Safinamide and its major metabolite may inhibit intestinal BCRP. Monitor BCRP substrates for increased pharmacologic or adverse effects.

• sapropterin

  methotrexate decreases levels of sapropterin by Other (see comment). Use Caution/Monitor. Comment: Mechanism: Inhibition of dihydropteridine reductase (DHPR).

• sarecycline

  sarecycline will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.

• siponimod

  siponimod and methotrexate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• sipuleucel-T

  methotrexate decreases effects of sipuleucel-T by pharmacodynamic antagonism. Modify Therapy/Monitor Closely.

• sirolimus

  methotrexate and sirolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• sofosbuvir/velpatasvir

  sofosbuvir/velpatasvir will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Velpatasvir is an inhibitor of the drug transporter BCRP. Coadministration may increase systemic exposure of drugs that are BCRP substrates.

• stiripentol

  stiripentol will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.
  
  stiripentol will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Stiripentol is a BCRP transport inhibitor. Consider dosage reduction for BCRP substrates if adverse effects are experienced when coadministered.

• streptozocin

  methotrexate and streptozocin both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• tacrolimus

  methotrexate and tacrolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• tafamidis

  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 meglumine

  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.

• temsirolimus

  methotrexate and temsirolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• tetanus toxoid adsorbed or fluid

  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.

• tetracycline

  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.

• theophylline

  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.

• ticarcillin

  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.

• trastuzumab

  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 deruxtecan

  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. .

• tretinoin

  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.

• trimethoprim

  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.

• tucatinib

  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 vaccine

  methotrexate decreases effects of typhoid polysaccharide vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• ublituximab

  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 coadministered

• ustekinumab

  methotrexate and ustekinumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.
  
  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.

• vadadustat

  vadadustat will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Vadadustat may increase exposure of BCRP and OAT3 substrates. Monitor for signs of adverse effect of BCRP and OAT3 substrates and reduce substrate dose in accordance with their product labeling.

• valoctocogene roxaparvovec

  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.

• vancomycin

  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. .

• voclosporin

  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.

• warfarin

  methotrexate increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor.

• willow bark

  willow bark will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• zidovudine

  methotrexate, zidovudine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of myelosuppression.

• zoster vaccine recombinant

  methotrexate decreases effects of zoster vaccine recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressive therapies may reduce the effectiveness of zoster vaccine recombinant.

Minor (10)

• adalimumab

  methotrexate decreases levels of adalimumab by decreasing renal clearance. Minor/Significance Unknown. Methotrexate reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44%, respectively. Dosage adjustment is not needed.

• colestipol

  colestipol decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown. Patients should take other drugs at least 1 hour before or 4 hours after colestipol to avoid impeding their absorption.

• folic acid

  folic acid decreases effects of methotrexate by pharmacodynamic antagonism. Minor/Significance Unknown. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate.

• golimumab

  golimumab, methotrexate. Other (see comment). Minor/Significance Unknown. Comment: Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.

• hydrochlorothiazide

  hydrochlorothiazide increases toxicity of methotrexate by decreasing elimination. Minor/Significance Unknown. Increased myelosuppression.

• L-methylfolate

  L-methylfolate decreases levels of methotrexate by increasing metabolism. Minor/Significance Unknown. Folic acid antagonists may interfere with folic acid utilization.
  
  L-methylfolate decreases levels of methotrexate by pharmacodynamic antagonism. Minor/Significance Unknown.
  
  methotrexate decreases levels of L-methylfolate by altering metabolism. Minor/Significance Unknown.

• maitake

  maitake increases effects of methotrexate by pharmacodynamic synergism. Minor/Significance Unknown. Maitake mushroom has anti-tumor effects (animal/in vitro research).

• methyclothiazide

  methyclothiazide increases toxicity of methotrexate by decreasing elimination. Minor/Significance Unknown. Increased myelosuppression.

• rituximab-hyaluronidase

  methotrexate and rituximab-hyaluronidase both increase nephrotoxicity and/or ototoxicity. Minor/Significance Unknown.

• voclosporin

  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.

• acalabrutinib

  Monitor Closely (2)acalabrutinib increases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Acalabrutinib may increase exposure to coadministered BCRP substrates by inhibition of intestinal BCRP.
  
  acalabrutinib, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration may increase risk of myelosuppressive effects.

• acitretin

  Contraindicated (1)acitretin, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. Risk of additive hepatotoxicity.

• activated charcoal

  Monitor Closely (1)activated charcoal will decrease the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Charcoal can reduce absorption of methotrexate and remove it from systemic circulation. Depending on the clinical situation, this will reduce the effectiveness or toxicity of methotrexate.

• adalimumab

  Minor (1)methotrexate decreases levels of adalimumab by decreasing renal clearance. Minor/Significance Unknown. Methotrexate reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44%, respectively. Dosage adjustment is not needed.

• adenovirus types 4 and 7 live, oral

  Serious - Use Alternative (1)methotrexate decreases effects of adenovirus types 4 and 7 live, oral by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• aldesleukin

  Monitor Closely (1)aldesleukin increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. May increase myelosupression and hepatotoxicity.

• allopurinol

  Monitor Closely (1)allopurinol decreases effects of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of myelosuppression.

• aminohippurate sodium

  Monitor Closely (1)aminohippurate sodium will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• amoxicillin

  Monitor Closely (1)amoxicillin 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.

• ampicillin

  Monitor Closely (1)ampicillin 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.

• anthrax vaccine

  Serious - Use Alternative (1)methotrexate decreases effects of anthrax vaccine by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• apalutamide

  Monitor Closely (1)apalutamide will decrease the level or effect of methotrexate by increasing elimination. Use Caution/Monitor. Apalutamide weakly induces BCRP and OATP1B1 and may decrease systemic exposure of drugs that are substrates of both BCRP and OATP1B1.

• aspirin

  Serious - Use Alternative (1)aspirin increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• aspirin rectal

  Monitor Closely (1)aspirin rectal will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious - Use Alternative (1)aspirin rectal increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. The relative risk of interaction of different NSAIDs w/methotrexate is not established. Selective COX 2 inhibitors are believed to have minimal interaction. Greater risk in pts. with renal impairment. Greater toxicity with high dose methotrexate (e.g., anti neoplastic regimen).

• aspirin/citric acid/sodium bicarbonate

  Monitor Closely (1)aspirin/citric acid/sodium bicarbonate will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious - Use Alternative (1)aspirin/citric acid/sodium bicarbonate increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• astragalus

  Monitor Closely (1)methotrexate increases and astragalus decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• axicabtagene ciloleucel

  Serious - Use Alternative (1)methotrexate, axicabtagene ciloleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• bacitracin

  Serious - Use Alternative (1)methotrexate and bacitracin both increase nephrotoxicity and/or ototoxicity. Avoid or Use Alternate Drug. Avoid concurrent use of bacitracin with other nephrotoxic drugs

• BCG intravesical live

  Serious - Use Alternative (1)methotrexate decreases effects of BCG intravesical live by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• belatacept

  Monitor Closely (1)belatacept and methotrexate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor.

• berotralstat

  Monitor Closely (1)berotralstat will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.

• bosutinib

  Monitor Closely (1)bosutinib increases levels of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• bremelanotide

  Serious - Use Alternative (1)bremelanotide will decrease the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

• brexucabtagene autoleucel

  Serious - Use Alternative (1)methotrexate, brexucabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• caffeine

  Monitor Closely (1)caffeine decreases effects of methotrexate by pharmacodynamic antagonism. Use Caution/Monitor.

• carboplatin

  Monitor Closely (1)carboplatin and methotrexate both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• ceftobiprole medocaril sodium

  Serious - Use Alternative (1)ceftobiprole medocaril sodium will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Ceftobiprole (an OATP1B1/1B3 inhibitor) may increase plasma concentrations of OATP1B1 and OATP1B3 substrates.

• celecoxib

  Serious - Use Alternative (1)celecoxib 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. .

• chlorpropamide

  Monitor Closely (1)chlorpropamide will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor. 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.

• cholera vaccine

  Monitor Closely (1)methotrexate decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.

• cholestyramine

  Monitor Closely (1)cholestyramine decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4-6 hours after the administration of cholestyramine.

• choline magnesium trisalicylate

  Monitor Closely (1)choline magnesium trisalicylate will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious - Use Alternative (1)choline magnesium trisalicylate increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. The relative risk of interaction of different NSAIDs w/methotrexate is not established. Selective COX 2 inhibitors are believed to have minimal interaction. Greater risk in pts. with renal impairment. Greater toxicity with high dose methotrexate (e.g., anti neoplastic regimen).

• cidofovir

  Monitor Closely (1)cidofovir and methotrexate both decrease immunosuppressive effects; risk of infection. Use Caution/Monitor. May increase myelosupression.

• ciltacabtagene autoleucel

  Serious - Use Alternative (1)methotrexate, ciltacabtagene autoleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• ciprofloxacin

  Monitor Closely (1)ciprofloxacin will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Renal tubular transport of methotrexate may be inhibited by coadministration of ciprofloxacin, potentially leading to increased methotrexate plasma levels and toxicity.

• cisplatin

  Monitor Closely (1)cisplatin and methotrexate both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• colestipol

  Minor (1)colestipol decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown. Patients should take other drugs at least 1 hour before or 4 hours after colestipol to avoid impeding their absorption.

• crofelemer

  Monitor Closely (1)crofelemer increases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Crofelemer has the potential to inhibit transporters MRP2 and OATP1A2 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

• cyclosporine

  Monitor Closely (1)cyclosporine, methotrexate. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Close monitoring of cyclosporine and methotrexate concentrations, renal function, and liver enzymes is recommended during concurrent therapy. .

• danicopan

  Monitor Closely (2)danicopan will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Danicopan increases plasma concentrations of BCRP substrates; consider dose reduction of BCRP substrate according to its prescribing information.
  
  danicopan will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Danicopan increases plasma concentrations of P-gp substrates; consider dose reduction of P-gp substrates where minimal concentration changes may lead to serious adverse reactions.

• dapsone

  Monitor Closely (1)dapsone, methotrexate. Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of hematologic toxicity.

• darolutamide

  Serious - Use Alternative (1)darolutamide will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Darolutamide is a BCRP inhibitor. Avoid coadministration with BCRP inhibitors. If use is unavoidable, closely monitor for adverse reactions and consider dose reduction of BCRP substrate drug (refer BCRP substrate prescribing information).

• deferiprone

  Serious - Use Alternative (1)deferiprone, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis; if an alternative is not possible, monitor absolute neutrophil count more frequently.

• demeclocycline

  Monitor Closely (1)demeclocycline increases levels of methotrexate by decreasing elimination. Use Caution/Monitor. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

• dengue vaccine

  Monitor Closely (1)methotrexate decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

• denosumab

  Monitor Closely (1)methotrexate, denosumab. Other (see comment). Use Caution/Monitor. Comment: Caution should be taken in patients on concomitant immunosuppressants or with impaired immune systems because of increased risk for serious infections.

• dexlansoprazole

  Monitor Closely (1)dexlansoprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• diclofenac

  Serious - Use Alternative (1)diclofenac 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. .

• dicloxacillin

  Monitor Closely (1)dicloxacillin 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.

• diflunisal

  Serious - Use Alternative (1)diflunisal 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. .

• digoxin

  Monitor Closely (1)methotrexate decreases levels of digoxin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Serum levels of digoxin may be reduced and actions may be decreased. Monitor patient for signs of reduction in pharmacologic effect of digoxin and increase digoxin dose if necessary. Serum level monitoring may facilitate tailoring dosage.

• diphtheria & tetanus toxoids

  Monitor Closely (1)methotrexate decreases effects of diphtheria & tetanus toxoids by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• diphtheria & tetanus toxoids/ acellular pertussis vaccine

  Monitor Closely (1)methotrexate decreases effects of diphtheria & tetanus toxoids/ acellular pertussis vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine

  Monitor Closely (1)methotrexate decreases effects of diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• divalproex sodium

  Serious - Use Alternative (1)methotrexate will decrease the level or effect of divalproex sodium by unspecified interaction mechanism. Avoid or Use Alternate Drug. may potentially result in increased frequency of seizures or bipolar symptoms; monitor serum valproate concentrations and clinical response when adding or discontinuing methotrexate and adjust valproate dosage

• doxycycline

  Monitor Closely (1)doxycycline increases levels of methotrexate by decreasing elimination. Use Caution/Monitor. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

• echinacea

  Monitor Closely (1)methotrexate increases and echinacea decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.

• elacestrant

  Monitor Closely (1)elacestrant will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Elacestrant (a BCRP inhibitor) may increase plasma concentrations of sensitive BCRP substrates, which may increase risk of adverse reactions related to these substrates. Refer to prescribing information for sensitive BCRP substrates for dosing recommendations.

• elagolix

  Monitor Closely (1)elagolix will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• eliglustat

  Monitor Closely (1)eliglustat increases levels of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.

• eltrombopag

  Monitor Closely (1)eltrombopag increases levels of methotrexate by decreasing metabolism. Use Caution/Monitor. OATP transporter protein inhibition.

• eluxadoline

  Monitor Closely (1)eluxadoline increases levels of methotrexate by decreasing metabolism. Use Caution/Monitor. Eluxadoline may increase the systemic exposure of coadministered BCRP substrates.

• elvitegravir/cobicistat/emtricitabine/tenofovir DF

  Monitor Closely (1)methotrexate and elvitegravir/cobicistat/emtricitabine/tenofovir DF both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• encorafenib

  Monitor Closely (1)encorafenib will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Encorafenib (a OATP1B1, OATP1B3, and BCRP inhibitor) may increase the concentration and toxicities of OATP1B1, OATP1B3, and BCRP substrates. Closely monitor for signs and symptoms of increased exposure and consider adjusting the dose of these substrates. Screen reader support enabled.

• erdafitinib

  Serious - Use Alternative (1)erdafitinib will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index.

• esomeprazole

  Monitor Closely (1)esomeprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• ethanol

  Serious - Use Alternative (1)methotrexate, ethanol. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. 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.

• etodolac

  Serious - Use Alternative (1)etodolac 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. .

• etrasimod

  Serious - Use Alternative (1)etrasimod, methotrexate. Either increases effects of the other by Mechanism: aldehyde dehydrogenase inhibition. Avoid or Use Alternate Drug. Risk of additive immune system effects with etrasimod has not been studied in combination with antineoplastic, immune-modulating, or noncorticosteroid immunosuppressive therapies. Avoid coadministration during and in the weeks following administration of etrasimod.

• fenoprofen

  Serious - Use Alternative (1)fenoprofen 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. .

• ferric maltol

  Monitor Closely (1)ferric maltol, methotrexate. Either increases levels of the other by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Coadministration of ferric maltol with certain oral medications may decrease the bioavailability of either ferric maltol and some oral drugs. For oral drugs where reductions in bioavailability may cause clinically significant effects on its safety or efficacy, separate administration of ferric maltol from these drugs. Duration of separation may depend on the absorption of the medication concomitantly administered (eg, time to peak concentration, whether the drug is an immediate or extended release product).

• fingolimod

  Monitor Closely (1)methotrexate increases effects of fingolimod by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects. .

• flurbiprofen

  Serious - Use Alternative (1)flurbiprofen 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. .

• folic acid

  Minor (1)folic acid decreases effects of methotrexate by pharmacodynamic antagonism. Minor/Significance Unknown. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate.

• food

  Monitor Closely (1)food decreases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Food may delay the absorption and reduce the peak concentration of methotrexate.

• fosphenytoin

  Monitor Closely (1)fosphenytoin increases toxicity of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs.

• fostamatinib

  Monitor Closely (1)fostamatinib will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Concomitant use of fostamatinib may increase concentrations of P-gp/BCRP substrate drugs. Monitor for toxicities of P-gp/BCRP substrate drug that may require dosage reduction when given concurrently with fostamatinib.

• fostemsavir

  Monitor Closely (1)fostemsavir will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits OATP1B1/3 and BCRP transporters. If possible, avoid coadministration or modify dose of OATP1B1/3 or BCRP substrates coadministered with fostemsavir.

• glecaprevir/pibrentasvir

  Monitor Closely (1)glecaprevir/pibrentasvir will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Glecaprevir/pibrentasvir may increase plasma concentration of OATP1B1/OATP1B3, P-gp and BCRP substrates.

• golimumab

  Minor (1)golimumab, methotrexate. Other (see comment). Minor/Significance Unknown. Comment: Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.

• haemophilus influenzae type b vaccine

  Monitor Closely (1)methotrexate decreases effects of haemophilus influenzae type b vaccine by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Avoid vaccination during chemotherapy or radiation therapy if possible because antibody response might be suboptimal. Patients vaccinated within a 14-day period before starting or during immunosuppressive therapy should be revaccinated =3 months after therapy is discontinued if immune competence has been restored. .

• hepatitis A vaccine inactivated

  Monitor Closely (1)methotrexate decreases effects of hepatitis A vaccine inactivated by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• hepatitis a/b vaccine

  Monitor Closely (1)methotrexate decreases effects of hepatitis a/b vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• hepatitis b vaccine

  Monitor Closely (1)methotrexate decreases effects of hepatitis b vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• human papillomavirus vaccine, nonavalent

  Serious - Use Alternative (1)methotrexate decreases effects of human papillomavirus vaccine, nonavalent by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines.

• human papillomavirus vaccine, quadrivalent

  Serious - Use Alternative (1)methotrexate decreases effects of human papillomavirus vaccine, quadrivalent by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines.

• hydrochlorothiazide

  Minor (1)hydrochlorothiazide increases toxicity of methotrexate by decreasing elimination. Minor/Significance Unknown. Increased myelosuppression.

• hydroxychloroquine sulfate

  Monitor Closely (1)hydroxychloroquine sulfate decreases levels of methotrexate by unknown mechanism. Use Caution/Monitor. Hydroxychloroquine may reduce the renal clearance of methotrexate; the exact mechanism of this interaction is unknown. .

• hydroxyurea

  Monitor Closely (1)methotrexate, hydroxyurea. Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of myelosuppression.

• ibuprofen

  Serious - Use Alternative (1)ibuprofen 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. .

• ibuprofen IV

  Monitor Closely (1)ibuprofen IV will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious - Use Alternative (1)ibuprofen IV 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. .

• idecabtagene vicleucel

  Serious - Use Alternative (1)methotrexate, idecabtagene vicleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• ifosfamide

  Monitor Closely (1)ifosfamide, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration with ifosfamide may increase the risk of immunosuppression and myelosuppression.

• indomethacin

  Serious - Use Alternative (1)indomethacin 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. .

• influenza A (H5N1) vaccine

  Monitor Closely (1)methotrexate decreases effects of influenza A (H5N1) vaccine by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressive therapies may reduce immune response to H5N1 vaccine.

• influenza virus vaccine (H5N1), adjuvanted

  Monitor Closely (1)methotrexate decreases effects of influenza virus vaccine (H5N1), adjuvanted by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Immunosuppressive therapies may reduce immune response to H5N1 vaccine.

• influenza virus vaccine quadrivalent

  Monitor Closely (1)methotrexate decreases effects of influenza virus vaccine quadrivalent by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• influenza virus vaccine quadrivalent, adjuvanted

  Serious - Use Alternative (1)methotrexate decreases effects of influenza virus vaccine quadrivalent, adjuvanted by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive drugs may reduce the immune response to influenza vaccine.

• influenza virus vaccine quadrivalent, cell-cultured

  Monitor Closely (1)methotrexate decreases effects of influenza virus vaccine quadrivalent, cell-cultured by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• influenza virus vaccine quadrivalent, intranasal

  Contraindicated (1)methotrexate decreases effects of influenza virus vaccine quadrivalent, intranasal by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• influenza virus vaccine quadrivalent, recombinant

  Monitor Closely (1)methotrexate decreases effects of influenza virus vaccine quadrivalent, recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immune response to vaccine may be decreased in immunocompromised individuals.

• influenza virus vaccine trivalent

  Monitor Closely (1)methotrexate decreases effects of influenza virus vaccine trivalent by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• influenza virus vaccine trivalent, adjuvanted

  Serious - Use Alternative (1)methotrexate decreases effects of influenza virus vaccine trivalent, adjuvanted by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Immunosuppressive drugs may reduce the immune response to influenza vaccine.

• influenza virus vaccine trivalent, recombinant

  Monitor Closely (1)methotrexate decreases effects of influenza virus vaccine trivalent, recombinant by pharmacodynamic antagonism. Use Caution/Monitor. Immune response to vaccine may be decreased in immunocompromised individuals.

• ioversol

  Monitor Closely (1)ioversol and methotrexate both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• isavuconazonium sulfate

  Monitor Closely (1)methotrexate and isavuconazonium sulfate both decrease immunosuppressive effects; risk of infection. Use Caution/Monitor.

• isotretinoin

  Monitor Closely (1)methotrexate, isotretinoin. 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.

• istradefylline

  Monitor Closely (1)istradefylline will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of P-gp substrates in clinical trials. Consider dose reduction of sensitive P-gp substrates.

• Japanese encephalitis virus vaccine

  Monitor Closely (1)methotrexate decreases effects of Japanese encephalitis virus vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• ketoprofen

  Serious - Use Alternative (1)ketoprofen 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. .

• ketorolac

  Serious - Use Alternative (1)ketorolac 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. .

• ketorolac intranasal

  Monitor Closely (1)ketorolac intranasal will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious - Use Alternative (1)ketorolac intranasal increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. The relative risk of interaction of different NSAIDs w/methotrexate is not established. Selective COX 2 inhibitors are believed to have minimal interaction. Greater risk in pts. with renal impairment. Greater toxicity with high dose methotrexate (e.g., anti neoplastic regimen).

• L-methylfolate

  Monitor Closely (1)methotrexate decreases effects of L-methylfolate by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Folic acid antagonists may interfere with folic acid utilization.Minor (3)L-methylfolate decreases levels of methotrexate by increasing metabolism. Minor/Significance Unknown. Folic acid antagonists may interfere with folic acid utilization.
  
  L-methylfolate decreases levels of methotrexate by pharmacodynamic antagonism. Minor/Significance Unknown.
  
  methotrexate decreases levels of L-methylfolate by altering metabolism. Minor/Significance Unknown.

• lansoprazole

  Monitor Closely (1)lansoprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• lasmiditan

  Serious - Use Alternative (1)lasmiditan increases levels of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Comment: Lasmiditan inhibits BCRP in vitro. Avoid coadministration of lasmiditan with BCRP substrates.

• leflunomide

  Monitor Closely (1)leflunomide increases levels of methotrexate by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Additive hepatotoxicity, pancytopenia. If leflunomide and methotrexate are given concomitantly, monitor liver toxicity with ALT, AST, and serum albumin testing. Also, monitor platelets, WBC count, hemoglobin, or hematocrit at baseline and monthly for 6 months following initiation and every 6-8 weeks thereafter.

• leniolisib

  Serious - Use Alternative (1)leniolisib will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Leniolisib, a BCRP, OATP1B1, and OATP1B3 inhibitor, may increase systemic exposure of these substrates

• letermovir

  Monitor Closely (1)letermovir increases levels of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Letermovir, an OATP1B1/3 inhibitor may increase plasma concentrations of coadministered OATP1B1/3 substrates.

• lisocabtagene maraleucel

  Serious - Use Alternative (1)methotrexate, lisocabtagene maraleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• lomitapide

  Monitor Closely (1)lomitapide increases levels of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing dose when used concomitantly with lomitapide.

• lomustine

  Monitor Closely (1)lomustine, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration with lomustine may increase the risk of immunosuppression and myelosuppression.

• lonafarnib

  Monitor Closely (1)lonafarnib will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Lonafarnib is a weak P-gp inhibitor. Monitor for adverse reactions if coadministered with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. Reduce P-gp substrate dose if needed.

• maitake

  Monitor Closely (1)methotrexate increases and maitake decreases immunosuppressive effects; risk of infection. Effect of interaction is not clear, use caution. Use Caution/Monitor.Minor (1)maitake increases effects of methotrexate by pharmacodynamic synergism. Minor/Significance Unknown. Maitake mushroom has anti-tumor effects (animal/in vitro research).

• measles mumps and rubella vaccine, live

  Contraindicated (1)methotrexate decreases effects of measles mumps and rubella vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• measles, mumps, rubella and varicella vaccine, live

  Contraindicated (1)methotrexate decreases effects of measles, mumps, rubella and varicella vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• meclofenamate

  Monitor Closely (1)meclofenamate will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.Serious - Use Alternative (1)meclofenamate 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. .

• mefenamic acid

  Serious - Use Alternative (1)mefenamic acid 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. .

• meloxicam

  Serious - Use Alternative (1)meloxicam 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. .

• meningococcal A C Y and W-135 polysaccharide vaccine combined

  Monitor Closely (1)methotrexate decreases effects of meningococcal A C Y and W-135 polysaccharide vaccine combined by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• meningococcal group B vaccine

  Monitor Closely (1)methotrexate decreases effects of meningococcal group B vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Individuals with altered immunocompetence may have reduced immune responses to the vaccine.

• methyclothiazide

  Monitor Closely (1)methyclothiazide will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.Minor (1)methyclothiazide increases toxicity of methotrexate by decreasing elimination. Minor/Significance Unknown. Increased myelosuppression.

• minocycline

  Monitor Closely (1)minocycline 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.

• mipomersen

  Monitor Closely (1)mipomersen, methotrexate. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.

• momelotinib

  Monitor Closely (1)momelotinib increases toxicity of methotrexate by plasma protein binding competition. Modify Therapy/Monitor Closely. Momelotinib (BCRP inhibitor) may increase exposure of BCRP substrates, which may increase the risk of BCRP substrate adverse reactions. Dose adjustment of other BCRP substrates may necessary.

• muromonab CD3

  Monitor Closely (1)methotrexate and muromonab CD3 both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• mycophenolate

  Monitor Closely (1)mycophenolate, methotrexate. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Infections may occur.

• nabumetone

  Serious - Use Alternative (1)nabumetone 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. .

• nafcillin

  Monitor Closely (1)nafcillin 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.

• naproxen

  Serious - Use Alternative (1)naproxen 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.

• neomycin PO

  Monitor Closely (1)neomycin PO decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Neomycin may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

• ocrelizumab

  Monitor Closely (1)methotrexate and ocrelizumab both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Coadministration of ocrelizumab with immunosuppessants is expected to increase the risk of immunosuppression.

• ofatumumab SC

  Monitor Closely (1)ofatumumab SC, methotrexate. Either decreases toxicity of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with coadministration. When switching from therapies with immune effects, take into account the duration and mechanism of action of these therapies when initiating ofatumumab SC.

• olaparib

  Monitor Closely (1)methotrexate and olaparib both increase pharmacodynamic synergism. Use Caution/Monitor. Coadministration with other other myelosuppressive anticancer agents, including DNA damaging agents, may potentiate and prolongate the myelosuppressive toxicity.

• omeprazole

  Monitor Closely (1)omeprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Temporary withdrawal of PPI may be considered in some patients.

• osimertinib

  Monitor Closely (1)osimertinib will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Osimertinib is an inhibitor of BCRP transport. Caution if coadministered with sensitive BCRP substrates.

• oteseconazole

  Monitor Closely (1)oteseconazole will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Otesezonale, a BCRP inhibitor, may increase the effects and risk of toxicities of BCRP substrates. Use lowest starting dose of BCRP substrate, or consider reducing BCRP substrate dose.

• oxaliplatin

  Monitor Closely (2)methotrexate and oxaliplatin both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.
  
  oxaliplatin, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• oxaprozin

  Serious - Use Alternative (1)oxaprozin 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. .

• ozanimod

  Monitor Closely (1)ozanimod, methotrexate. Either increases effects of the other by immunosuppressive effects; risk of infection. Use Caution/Monitor. Coadministration with immunosuppressive therapies may increase the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs in order to avoid unintended additive immunosuppressive effects.

• pacritinib

  Serious - Use Alternative (1)pacritinib will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Concomitant administration of pacritinib (BCRP inhibitor) with BCRP substrates may increase the plasma concentrations of these substrates.

• palifermin

  Serious - Use Alternative (1)palifermin increases toxicity of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hrbefore, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

• pantoprazole

  Monitor Closely (1)pantoprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• paromomycin

  Monitor Closely (1)paromomycin decreases levels of methotrexate by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. 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

  Monitor Closely (1)pegaspargase decreases effects of methotrexate by pharmacodynamic antagonism. Use Caution/Monitor. It is recommended to give pegaspargase at least 10-14 days prior to methotrexate or shortly after methotrexate administration.

• pexidartinib

  Serious - Use Alternative (1)methotrexate and pexidartinib both increase inhibition of GI absorption. Applies only to oral form of both agents. Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.

• phenytoin

  Monitor Closely (1)phenytoin increases toxicity of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as phenytoin.

• piroxicam

  Serious - Use Alternative (1)piroxicam 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. .

• pirtobrutinib

  Monitor Closely (1)pirtobrutinib will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Pirtobrutinib (a BCRP inhibitor) may increase plasma concentrations of sensitive BCRP substrates, which may increase the risk of adverse reactions related to these substrates. Refer to prescribing information for sensitive BCRP substrates for dosing recommendations.

• pneumococcal vaccine 13-valent

  Serious - Use Alternative (1)methotrexate decreases effects of pneumococcal vaccine 13-valent by pharmacodynamic antagonism. Contraindicated. Immunosuppressants also increase risk of infection with concomitant live vaccines.

• pneumococcal vaccine polyvalent

  Monitor Closely (1)methotrexate decreases effects of pneumococcal vaccine polyvalent by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• poliovirus vaccine inactivated

  Monitor Closely (1)methotrexate decreases effects of poliovirus vaccine inactivated by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Avoid vaccination during chemotherapy or radiation therapy if possible because antibody response might be suboptimal. Patients vaccinated within a 14-day period before starting or during immunosuppressive therapy should be revaccinated =3 months after therapy is discontinued if immune competence has been restored. .

• ponatinib

  Monitor Closely (1)ponatinib increases levels of methotrexate by Other (see comment). Use Caution/Monitor.

• ponesimod

  Monitor Closely (1)ponesimod and methotrexate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• pretomanid

  Monitor Closely (1)pretomanid will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.Serious - Use Alternative (1)methotrexate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.

• probenecid

  Monitor Closely (1)probenecid will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Methotrexate plasma levels, therapeutic effects, and toxicity may be enhanced. Monitor methotrexate concentrations and adjust dose accordingly.Serious - Use Alternative (1)probenecid increases levels of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Avoid or Use Alternate Drug. If combination must be used, decrease methotrexate dose; also, methotrexate increases uric acid production and risk for uric acid neuropathy.

• procarbazine

  Monitor Closely (1)procarbazine, methotrexate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of immunosupression.

• rabeprazole

  Monitor Closely (1)rabeprazole increases levels of methotrexate by decreasing renal clearance. Use Caution/Monitor. Increased risk of toxicity with higher doses.

• rabies vaccine

  Monitor Closely (1)methotrexate decreases effects of rabies vaccine by pharmacodynamic antagonism. Use Caution/Monitor. Concomitant administration of methotrexate can decrease the immunological response of vaccines.

• regorafenib

  Monitor Closely (1)regorafenib will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Regorafenib likely inhibits BCRP (ABCG2) transport. Coadministration with a BCRP substrate may increase systemic exposure to the substrate and related toxicity.

• rilonacept

  Monitor Closely (1)methotrexate and rilonacept both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• rituximab-hyaluronidase

  Minor (1)methotrexate and rituximab-hyaluronidase both increase nephrotoxicity and/or ototoxicity. Minor/Significance Unknown.

• rolapitant

  Monitor Closely (1)rolapitant will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Oral rolapitant (BCRP inhibitor) may increase plasma concentrations of BCRP substrates and may result in potential adverse reactions. Monitor possible adverse reactions if concomitant use of BCRP substrates and rolapitant can not be avoided.

• ropeginterferon alfa 2b

  Serious - Use Alternative (1)ropeginterferon alfa 2b, methotrexate. Either increases levels of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression.

• rose hips

  Monitor Closely (1)rose hips will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

• rotavirus oral vaccine, live

  Contraindicated (1)methotrexate decreases effects of rotavirus oral vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• safinamide

  Monitor Closely (1)safinamide will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Safinamide and its major metabolite may inhibit intestinal BCRP. Monitor BCRP substrates for increased pharmacologic or adverse effects.

• salicylates (non-asa)

  Serious - Use Alternative (1)salicylates (non-asa) increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• salsalate

  Serious - Use Alternative (1)salsalate increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug. Caution should be exercised when salicylates are given in combination with methotrexate. 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.

• sapropterin

  Monitor Closely (1)methotrexate decreases levels of sapropterin by Other (see comment). Use Caution/Monitor. Comment: Mechanism: Inhibition of dihydropteridine reductase (DHPR).

• sarecycline

  Monitor Closely (1)sarecycline will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.

• siponimod

  Monitor Closely (1)siponimod and methotrexate both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• sipuleucel-T

  Monitor Closely (1)methotrexate decreases effects of sipuleucel-T by pharmacodynamic antagonism. Modify Therapy/Monitor Closely.

• sirolimus

  Monitor Closely (1)methotrexate and sirolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• smallpox (vaccinia) vaccine, live

  Contraindicated (1)methotrexate decreases effects of smallpox (vaccinia) vaccine, live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• sofosbuvir/velpatasvir

  Monitor Closely (1)sofosbuvir/velpatasvir will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Velpatasvir is an inhibitor of the drug transporter BCRP. Coadministration may increase systemic exposure of drugs that are BCRP substrates.

• sotorasib

  Serious - Use Alternative (1)sotorasib will decrease the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.

• sparsentan

  Serious - Use Alternative (1)sparsentan will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. Sparsentan (a BCRP inhibitor) may increase exposure of sensitive BCRP substrates and the risk of these substrates toxicities.

• stiripentol

  Monitor Closely (2)stiripentol will increase the level or effect of methotrexate by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.
  
  stiripentol will increase the level or effect of methotrexate by Other (see comment). Modify Therapy/Monitor Closely. Stiripentol is a BCRP transport inhibitor. Consider dosage reduction for BCRP substrates if adverse effects are experienced when coadministered.

• streptozocin

  Monitor Closely (1)methotrexate and streptozocin both increase nephrotoxicity and/or ototoxicity. Use Caution/Monitor.

• sulfadiazine

  Serious - Use Alternative (1)sulfadiazine increases toxicity of methotrexate by plasma protein binding competition. Avoid or Use Alternate Drug.

• sulfamethoxazole

  Serious - Use Alternative (1)sulfamethoxazole increases toxicity of methotrexate by plasma protein binding competition. Avoid or Use Alternate Drug. Methotrexate concentrations may be elevated, increasing the risk of toxicity (eg, bone marrow suppression).

• sulfasalazine

  Serious - Use Alternative (1)sulfasalazine increases levels of methotrexate by decreasing renal clearance. Avoid or Use Alternate Drug.

• sulfisoxazole

  Serious - Use Alternative (1)sulfisoxazole increases toxicity of methotrexate by plasma protein binding competition. Avoid or Use Alternate Drug.

• sulindac

  Serious - Use Alternative (1)sulindac 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. .

• tacrolimus

  Monitor Closely (1)methotrexate and tacrolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• tafamidis

  Monitor 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 meglumine

  Monitor 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.

• temsirolimus

  Monitor Closely (1)methotrexate and temsirolimus both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Combination may increase risk of myelosuppression.

• tepotinib

  Serious - 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 fluid

  Monitor 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.

• tetracycline

  Monitor 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.

• theophylline

  Monitor 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.

• ticarcillin

  Monitor 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.

• tisagenlecleucel

  Serious - Use Alternative (1)methotrexate, tisagenlecleucel. Either increases effects of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• tocilizumab

  Serious - Use Alternative (1)tocilizumab and methotrexate both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• tofacitinib

  Serious - Use Alternative (1)methotrexate, tofacitinib. Either increases toxicity of the other by immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• tolmetin

  Serious - 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 ali

  Serious - Use Alternative (1)methotrexate and tongkat ali both increase immunosuppressive effects; risk of infection. Avoid or Use Alternate Drug.

• trastuzumab

  Monitor 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 deruxtecan

  Monitor 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. .

• tretinoin

  Monitor 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 topical

  Serious - Use Alternative (1)methotrexate, tretinoin topical. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Additive hepatotoxicity.

• trimethoprim

  Monitor 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.

• trofinetide

  Serious - 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.

• tucatinib

  Monitor 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 vaccine

  Monitor 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 live

  Contraindicated (1)methotrexate decreases effects of typhoid vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• ublituximab

  Monitor 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 coadministered

• ustekinumab

  Monitor 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.

• vadadustat

  Monitor Closely (1)vadadustat will increase the level or effect of methotrexate by Other (see comment). Use Caution/Monitor. Vadadustat may increase exposure of BCRP and OAT3 substrates. Monitor for signs of adverse effect of BCRP and OAT3 substrates and reduce substrate dose in accordance with their product labeling.

• valoctocogene roxaparvovec

  Monitor 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.

• vancomycin

  Monitor 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 live

  Contraindicated (1)methotrexate decreases effects of varicella virus vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• voclosporin

  Monitor 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.

• warfarin

  Monitor Closely (1)methotrexate increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor.

• willow bark

  Monitor 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 vaccine

  Contraindicated (1)methotrexate decreases effects of yellow fever vaccine by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• zidovudine

  Monitor Closely (1)methotrexate, zidovudine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of myelosuppression.

• zoster vaccine live

  Contraindicated (1)methotrexate decreases effects of zoster vaccine live by pharmacodynamic antagonism. Contraindicated. Immunization with live virus vaccines is generally not recommended.

• zoster vaccine recombinant

  Monitor 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.