Methotrexate

Pharmacologic Category

Antineoplastic Agent, Antimetabolite (Antifolate); Antirheumatic, Disease Modifying; Immunosuppressant Agent

Dosing: Adult

Note: Methotrexate doses between 100 to 500 mg/m² may require leucovorin calcium rescue. Doses >500 mg/m² require leucovorin calcium rescue (refer to Dosing – Adjustment for Toxicity for leucovorin calcium dosing). Doses ≥250 mg/m² (IV) are associated with moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting.

Acute lymphoblastic leukemia:

Meningeal leukemia prophylaxis or treatment: Intrathecal: Manufacturer's labeling: 12 mg (maximum 15 mg/dose) every 2 to 7 days; continue for 1 dose beyond cerebrospinal fluid (CSF) cell count normalization. Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer 1983; Kerr 2001).

CALGB 8811 regimen (Larson 1995; combination therapy):

Early intensification: Intrathecal: 15 mg day 1 of early intensification phase, repeat in 4 weeks.

CNS prophylaxis/interim maintenance phase:

Intrathecal: 15 mg day 1, 8, 15, 22, and 29.

Oral: 20 mg/m² days 36, 43, 50, 57, and 64.

Prolonged maintenance: Oral: 20 mg/m² days 1, 8, 15, and 22 every 4 weeks for 24 months from diagnosis.

Dose-intensive regimen (Kantarjian 2000; combination therapy):

IV: 200 mg/m² over 2 hours, followed by 800 mg/m² over 24 hours beginning day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD).

CNS prophylaxis: Intrathecal: 12 mg on day 2 of each cycle; duration depends on risk.

Maintenance: IV: 10 mg/m²/day for 5 days every month for 2 years (in combination with prednisone, vincristine, and mercaptopurine).

Acute promyelocytic leukemia maintenance phase (off-label use):

Oral: 15 mg/m² once weekly for 2 years (Ades 2008) or 20 mg/m² once weekly for 1 year (Powell 2010).

IM: 15 mg/m² once weekly for 2 years (Sanz 2004).

Bladder cancer (off-label use): IV:

Locally advanced or metastatic disease:

Dose-dense MVAC regimen: 30 mg/m² on day 1 every 14 days (in combination with vinblastine, doxorubicin, cisplatin, and growth factor support) until disease progression or unacceptable toxicity (Sternberg 2001; Sternberg 2006).

MVAC regimen: 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) for up to 6 cycles (von der Maase 2000) or 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) until disease progression or unacceptable toxicity (Sternberg 2001; Sternberg 2006) or 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, cisplatin, and filgrastim) for up to 6 cycles or until loss of clinical benefit (Bamias 2004).

Neoadjuvant treatment:

Note: Patients with non-organ confined disease at cystectomy who did not receive cisplatin-based neoadjuvant chemotherapy should be offered an adjuvant cisplatin-based chemotherapy regimen (AUA/ASCO/ASTRO/SUO [Chang 2017]).

Dose-dense MVAC regimen: 30 mg/m² on day 1 every 14 days (in combination with vinblastine, doxorubicin, cisplatin, and pegfilgrastim) for 3 or 4 cycles (Choueiri 2014; Plimack 2014).

MVAC regimen: 30 mg/m² on days 1, 15, and 22 every 28 days (in combination with vinblastine, doxorubicin, and cisplatin) for 3 cycles (Grossman 2003).

CMV regimen: 30 mg/m² on days 1 and 8 every 21 days (in combination with cisplatin, vinblastine, and leucovorin) for 3 cycles (Griffiths 2011).

Breast cancer: IV: CMF regimen: 40 mg/m² days 1 and 8 every 4 weeks (in combination with cyclophosphamide and fluorouracil) for 6 to 12 cycles (Bonadonna 1995; Levine 1998).

Crohn disease, corticosteroid dependent or remission maintenance (off-label use): IM, SubQ: 25 mg once weekly; may reduce dose to 15 mg once weekly if steroid-free remission maintained for 4 months (Lichtenstein 2018).

Dermatomyositis/polymyositis (off-label use): Note: Concomitant folic acid is recommended to reduce the side effects; leucovorin can be administered in patients who do not respond to folic acid (Briemberg 2003; Miller 2019).

Oral: Initial: 5 to 15 mg once weekly, usually given adjunctively with prednisone; may increase the dose slowly in 2.5 mg/week increments to 25 mg once weekly (McGrath 2018; Oddis 2016; Wiendl 2008). Some experts prefer to initiate therapy at 15 mg once weekly and if there is an inadequate response after 8 to 12 weeks, begin increasing the dose in 2.5 mg/week increments to 25 mg once weekly (Miller 2019). Note: Doses >25 mg/week have been used historically in refractory/resistant disease, but should be avoided due to the availability of alternative agents; do not exceed a maximum dose of 50 mg/week. If doses >25 mg/week are given, methotrexate should be administered parenterally (McGrath 2018; Miller 2019).

SubQ, IV, IM: The same oral weekly dose may be administered once weekly parenterally in patients unable to tolerate oral administration (subcutaneous administration is preferred, depending on clinical setting) (Miller 2019).

Gestational trophoblastic diseases, choriocarcinoma, chorioadenoma: 15 to 30 mg oral or IM daily for a 5-day course; may repeat for 3 to 5 courses (manufacturer's labeling) or

Gestational trophoblastic neoplasia, low-risk disease (off-label dosing): IV: 100 mg/m² over 30 minutes followed by 200 mg/m² over 12 hours (with leucovorin 24 hours after the start of methotrexate), administer a second course if hCG levels plateau for 3 consecutive weeks (Garrett 2002).

Gestational trophoblastic neoplasia, high-risk metastatic disease (off-label dosing): IV:

EMA-CO regimen: 100 mg/m² IV push followed by 200 mg/m² over 12 hours on day 1 (with leucovorin 24 hours after the start of methotrexate; in combination with dactinomycin, etoposide, vincristine, and cyclophosphamide) every 14 days and continuing for at least 2 cycles after hCG level is normal (Escobar 2003; Lurain 2006).

EMA-EP regimen:

Patients without brain metastases: 100 mg/m² IV push followed by 200 mg/m² over 12 hours on day 1 every 2 weeks (in combination with etoposide, leucovorin, dactinomycin, and cisplatin), continue for 2 cycles after hCG level is normal (Ghaemmaghami 2004).

Patients with brain metastases: 100 mg/m² IV push followed by 1,000 mg/m² over 12 hours on day 1 every 2 weeks (in combination with etoposide, leucovorin, dactinomycin, and cisplatin), continue for 4 cycles after hCG level is normal (Ghaemmaghami 2004).

EP-EMA regimen: EMA: 300 mg/m² over 12 hours on day 1 (in combination with etoposide, leucovorin, and dactinomycin); alternating weekly with EP (etoposide and cisplatin) (Newlands 2000).

Graft-versus-host disease, acute, prophylaxis (off-label use): IV: 15 mg/m² on day 1 and 10 mg/m² on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) (Chao 1993; Chao 2000; Ross 1999) or 15 mg/m² on day 1 and 10 mg/m² on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) (Chao 2000) or 15 mg/m² on day 1 and 10 mg/m² on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine, followed by leucovorin); may omit day 11 methotrexate for ≥ grade 2 toxicity (Ruutu 2013).

Granulomatosis with polyangiitis (Wegener granulomatosis) and microscopic polyangiitis (maintenance therapy after remission induction) (off-label use): Oral: Initial: 0.3 mg/kg/week (beginning 2 to 3 weeks after the last induction pulse); progressively increase by 2.5 mg each week up to 25 mg/week for 12 months followed by a 3-month taper (Pagnoux 2008) or Initial: 0.3 mg/kg/week (maximum: 15 mg/week), if tolerated, after 1 to 2 weeks, increase dose by 2.5 mg/week (up to 20 to 25 mg/week) for 2 years; if remission is sustained for 2 years, taper off by 2.5 mg each month until discontinued (Langford 2003).

Head and neck cancer, advanced: IV: 40 mg/m² once weekly until disease progression or unacceptable toxicity (Forastiere 1992; Guardiola 2004; Stewart 2009).

Lymphoma, non-Hodgkin: IV:

CODOX-M/IVAC regimen (Mead 2008): Cycles 1 and 3 of CODOX-M (CODOX-M alternates with IVAC).

Adults ≤65 years of age: IV: 300 mg/m² over 1 hour (on day 10) followed by 2,700 mg/m² over 23 hours (with leucovorin rescue).

Adults >65 years of age: IV: 100 mg/m² over 1 hour (on day 10) followed by 900 mg/m² over 23 hours (with leucovorin rescue).

Hyper-CVAD alternating with high-dose methotrexate/cytarabine regimen: IV: 1,000 mg/m² over 24 hours on day 1 during even courses (2, 4, 6, and 8) of 21-day treatment cycles (Thomas 2006) or 200 mg/m² bolus day 1 followed by 800 mg/m² over 24 hours during even courses (2, 4, 6, and 8) of 21-day treatment cycles (Khouri 1998) with leucovorin rescue.

Mycosis fungoides (cutaneous T-cell lymphoma): 5 to 50 mg once weekly or 15 to 37.5 mg twice weekly orally or IM for early stages (manufacturer's labeling) or 25 mg orally once weekly, may increase to 50 mg once weekly (Zackheim 2003).

Nonleukemic meningeal cancer (off-label use): Intrathecal: 12 mg/dose twice weekly for 4 weeks, then weekly for 4 doses, then monthly for 4 doses (Glantz 1998) or 10 mg twice weekly for 4 weeks, then weekly for 1 month, then every 2 weeks for 2 months (Glantz 1999) or 10 to 15 mg twice weekly for 4 weeks, then once weekly for 4 weeks, then a maintenance regimen of once a month (Chamberlain 2010).

Osteosarcoma: Adults ≤30 years of age: IV: MAP regimen: 12 g/m² (maximum: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 4, 5, 9, and 10, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 24, 25, 28, and 29 (in combination with doxorubicin and cisplatin) (Bielack 2015; Whelan 2015); other combinations, intervals, age ranges, and doses (8 to 14 g/m²/dose) have been described (with leucovorin rescue), refer to specific reference for details (Bacci 2000; Bacci 2003; Le Deley 2007; Meyers 1992; Meyers 2005; Weiner 1986; Winkler 1988).

Primary CNS lymphoma, newly diagnosed (off-label use): IV: 8 g/m² over 4 hours (followed by leucovorin rescue) every 14 days until complete response or a maximum of 8 cycles; if complete response, follow with 2 consolidation cycles at the same dose every 14 days (with leucovorin rescue), followed by 11 maintenance cycles of 8 g/m² every 28 days with leucovorin rescue (Batchelor 2003) or R-MPV regimen: 3.5 g/m² over 2 hours on day 2 every 2 weeks (in combination with rituximab, vincristine, procarbazine, and leucovorin [with intra-Ommaya methotrexate 12 mg between days 5 and 12 of each cycle if positive CSF cytology]) for 5 to 7 induction cycles followed by reduced-dose whole brain radiotherapy and then cytarabine (Morris 2013; Shah 2007) or autologous stem cell transplant (Omuro 2015) or R-MP regimen (patients ≥65 years of age): 3 g/m² over 4 hours on days 2, 16, and 30 of a 42-day cycle (in combination with rituximab, procarbazine, and leucovorin) for 3 cycles (Fritsch 2017) or MT-R regimen: 8 g/m² once every 2 weeks (adjusted for creatinine clearance [refer to protocol for details] and in combination with leucovorin, temozolomide, and rituximab) for 7 doses, then followed by high-dose consolidation chemotherapy (Rubenstein 2013) or 3.5 g/m² on weeks 1, 3, 5, 7, and 9 (in combination with leucovorin, temozolomide, and rituximab), followed by whole brain radiotherapy and then post-radiation temozolomide (Glass 2016).

Psoriasis: Note: Some experts recommend concomitant folic acid 1 to 5 mg daily to reduce hematologic, gastrointestinal, and hepatic adverse events related to methotrexate.

Oral: Initial: 2.5 to 5 mg/dose every 12 hours for 3 doses per week or

Oral, IM, IV, SubQ: Initial: 10 to 25 mg given once weekly; adjust dose gradually to optimal response; in general, doses >30 mg per week should not be exceeded.

Note: An initial test dose of 2.5 to 5 mg is recommended in patients with risk factors for hematologic toxicity or renal impairment (Kalb 2009).

Rheumatoid arthritis: Note: Some experts recommend concomitant folic acid at a dose of least 5 mg per week to reduce hematologic, gastrointestinal, and hepatic adverse events related to methotrexate.

Oral: Initial: 10 to 15 mg once weekly, increased by 5 mg every 2 to 4 weeks to a maximum of 20 to 30 mg once weekly has been recommended by some experts. Consider parenteral therapy with inadequate response or intolerance to oral therapy (Visser 2009).

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. 7.5 mg once weekly or 2.5 mg every 12 hours for 3 doses per week.

SubQ: Initial: 7.5 mg once weekly; adjust dose gradually based on response and toxicity or (off-label dosing): Initial: 15 mg once weekly; for inadequate response after 16 weeks, may increase to 20 mg once weekly (Braun 2008).

IM: 7.5 mg once weekly; adjust dose gradually based on response and toxicity.

Sarcoidosis, second-line therapy (off-label use) Oral: Initial: 5 to 15 mg once weekly; range: 5 to 20 mg/week; maximum: 20 mg/week (in combination with oral folic acid) (Judson 2012; WASGD [Cremers 2013]) or Initial: 10 mg once weekly; may increase to 15 mg once weekly (in combination with oral folic acid) (Vorselaars 2013) or Initial: 10 mg/week (as divided doses on 2 consecutive days with dosage adjustments as indicated [in combination with oral folic acid]) (Baughman 2000).

Soft tissue sarcoma (desmoid tumors, aggressive fibromatosis), advanced (off-label use): IV: 30 mg/m² every 7 to 10 days (dose usually rounded to 50 mg) in combination with vinblastine for 1 year (Azzarelli 2001).

Systemic lupus erythematosus, moderate-to-severe (off-label use): Oral: Initial: 7.5 mg once weekly; may increase by 2.5 mg increments weekly (maximum: 20 mg once weekly), in combination with prednisone (Fortin 2008).

Takayasu arteritis, refractory or relapsing disease (off-label use): Oral: Initial dose: 0.3 mg/kg/week (maximum: 15 mg per week), titrated by 2.5 mg increments every 1 to 2 weeks until reaching a maximum tolerated weekly dose of 25 mg (use in combination with a corticosteroid; Hoffman 1994).

Termination of intrauterine pregnancy (off-label use): IM: 50 mg/m² followed by vaginal misoprostol 3 to 7 days later in pregnancies ≤49 days' gestation (ACOG 143 2014; Creinin 1996).

Tubal ectopic pregnancy (off-label use): IM: Note: Regimens are named for the intended number of doses; actual number of doses given may be greater (Barnhart 2009).

Single-dose regimen: 50 mg/m² on day 1. Measure serum hCG levels on days 4 and 7; if hCG decrease is <15%, repeat dose (methotrexate 50 mg/m²) on day 7 (ACOG 193 2018; ASRM 2013; RCOG [Elson 2016]; Stovall 1993).

Two-dose regimen: 50 mg/m² on day 1. Measure serum hCG levels on day 4 and administer a second dose of methotrexate 50 mg/m². Measure serum hCG levels on day 7. If hCG decrease is <15%, administer a third dose of methotrexate 50 mg/m² and measure serum hCG again on day 11; if hCG decrease is <15% on day 11, administer a fourth dose of methotrexate 50 mg/m² and measure serum hCG levels on day 14 (ACOG 193 2018; Barnhart 2007).

Multidose regimen (in combination with leucovorin): 1 mg/kg on days 1, 3, 5, and 7 alternating with leucovorin calcium on days 2, 4, 6, and 8. Measure serum hCG on each day of methotrexate administration. If serum hCG decreases by >15% from previous measurement, discontinue methotrexate (total treatment may be between 1 and 4 doses). If serum hCG decreases by <15% from previous measurement, administer methotrexate (maximum 4 doses) (ACOG 193 2018; ASRM 2013; Sauer 1987; Stovall 1989).

Uveitis (off-label use): Oral: 7.5 to 20 mg once weekly either alone or in conjunction with other corticosteroids/immunosuppressants (Diaz-Llopis 2009; Galor 2008; Kaplan-Messas 2003; Munoz-Fernandez 2009).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing; adjust for renal impairment.

Breast cancer: Patients >60 years of age: CMF regimen: IV: 30 mg/m² days 1 and 8 every 4 weeks (in combination with cyclophosphamide and fluorouracil) for up to 12 cycles (Bonadonna 1995).

Meningeal leukemia: Intrathecal: Consider a dose reduction (CSF volume and turnover may decrease with age).

Non-Hodgkin lymphoma: CODOX-M/IVAC regimen (Mead 2008): Cycles 1 and 3 of CODOX-M (CODOX-M alternates with IVAC): IV: 100 mg over 1 hour (on day 10) followed by 900 mg over 23 hours (with leucovorin rescue).

Primary CNS lymphoma, newly diagnosed (off-label use): Patients ≥65 years of age: R-MP regimen: IV: 3 g/m² over 4 hours on days 2, 16, and 30 of a 42-day cycle (in combination with rituximab, procarbazine, and leucovorin) for 3 cycles (Fritsch 2017).

Rheumatoid arthritis/psoriasis: Oral: Initial: 5 to 7.5 mg per week.

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. Limited data are available describing methotrexate dosage adjustment in kidney impairment. The following general and regimen-specific dosage adjustments have been recommended:

General dosage adjustment recommendations:

Kintzel 1995:

CrCl >60 mL/minute: No dose adjustment necessary.

CrCl 46 to 60 mL/minute: Administer 65% of normal dose.

CrCl 31 to 45 mL/minute: Administer 50% of normal dose.

CrCl <30 mL/minute: Avoid use.

Aronoff 2007:

CrCl >50 mL/minute: No dose adjustment necessary.

CrCl 10 to 50 mL/minute: Administer 50% of dose.

CrCl <10 mL/minute: Avoid use.

Hemodialysis, intermittent (thrice weekly):

Cases of methotrexate toxicity (including death) have been reported in hemodialysis patients receiving methotrexate, even at low methotrexate doses. Avoid use (Al-Hasani 2011; Basile 2002).

Case reports describing methotrexate administration in cancer patients with close monitoring of methotrexate concentrations, leucovorin rescue, and frequent and/or extended dialysis using high-flux membranes to facilitate methotrexate removal have been published (Matzkies 2000; Murashima 2009; Mutsando 2012; Wall 1996; Yeung 2018).

Peritoneal dialysis: Cases of methotrexate toxicity (including death) have been reported in peritoneal dialysis patients receiving methotrexate, even at low doses. Avoid use (Al-Hasani 2011; Basile 2002; Diskin 2006).

CRRT: Administer 50% of methotrexate dose (Aronoff 2007).

Regimen-specific dosage adjustments:

Acute lymphoblastic lymphoma, dose-intensive (Hyper-CVAD) regimen (usual methotrexate dose: 200 mg/m² over 2 hours, followed by 800 mg/m² over 24 hours with leucovorin rescue [Kantarjian 2000]): IV:

SCr <1.5 mg/dL: No methotrexate dosage adjustment necessary.

SCr 1.5 to 2 mg/dL: Administer 75% of methotrexate dose.

SCr >2 mg/dL: Administer 50% of methotrexate dose.

Breast cancer, CMF regimen (usual methotrexate dose: 40 mg/m² days 1 and 8 every 4 weeks [in combination with cyclophosphamide and fluorouracil]); CrCl is calculated using the Cockcroft-Gault equation (Lichtman 2016).

Females ≥65 years of age: IV:

CrCl >80 mL/minute: No methotrexate dosage adjustment necessary.

CrCl 51 to 80 mL/minute: Reduce methotrexate dose to 30 mg/m².

CrCl 30 to 50 mL/minute: Reduce methotrexate dose to 20 mg/m².

CrCl <30 mL/minute: Avoid methotrexate use.

Primary CNS lymphoma, high dose methotrexate (usual methotrexate dose: 8 g/m² over 4 hours with leucovorin rescue [Gerber 2007]); CrCl is measured or can be calculated using the Cockcroft-Gault equation (Gerber 2007): IV:

CrCl ≥100 mL/minute: No methotrexate dosage adjustment necessary.

CrCl 50 to 99 mL/minute: Calculate dose using percentage reduction of CrCl below 100 mL/minute. Example: If CrCl is 80 mL/minute, adjust dose to 0.8 × 8 g/m² = 6.4 g/m².

CrCl <50 mL/minute: Avoid methotrexate use.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; use with caution in patients with impaired hepatic function or preexisting hepatic damage. The following adjustments have been recommended (Floyd 2006):

Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose

Bilirubin >5 mg/dL: Avoid use

Dosing: Obesity: Adult

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer (excludes leukemias): Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Dosing: Adjustment for Toxicity: Adult

Methotrexate toxicities:

Nonhematologic toxicity: Diarrhea, stomatitis, or vomiting which may lead to dehydration: Discontinue until recovery

Hematologic toxicity:

Psoriasis, rheumatoid arthritis: Significant blood count decrease: Discontinue immediately

Oncologic uses: Profound granulocytopenia and fever: Evaluate immediately; consider broad-spectrum parenteral antimicrobial coverage

Leucovorin calcium dosing (from methotrexate injection prescribing information; other leucovorin dosing/schedules may be specific to chemotherapy protocols):

Normal methotrexate elimination (serum methotrexate level ~10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and <0.2 micromolar at 72 hours): Leucovorin calcium 15 mg (oral, IM, or IV) every 6 hours for 60 hours (10 doses) beginning 24 hours after the start of methotrexate infusion

Delayed late methotrexate elimination (serum methotrexate level remaining >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours after administration): Continue leucovorin calcium 15 mg (oral, IM or IV) every 6 hours until methotrexate level is <0.05 micromolar

Delayed early methotrexate elimination and/or acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, or ≥5 micromolar at 48 hours, or a doubling of serum creatinine level at 24 hours after methotrexate administration): Leucovorin calcium 150 mg IV every 3 hours until methotrexate level is <1 micromolar, then 15 mg IV every 3 hours until methotrexate level <0.05 micromolar

Leucovorin nomogram dosing for high-dose methotrexate overexposure (generalized leucovorin dosing derived from reference nomogram figures, refer to each reference [Bleyer 1978; Bleyer 1981; Widemann 2006] or institution-specific nomogram for details):

At 24 hours:

For methotrexate levels of ≥100 micromolar at ~24 hours, leucovorin is initially dosed at 1,000 mg/m² IV every 6 hours

For methotrexate levels of ≥10 to <100 micromolar at 24 hours, leucovorin is initially dosed at 100 mg/m² IV every 3 or 6 hours

For methotrexate levels of ~1 to 10 micromolar at 24 hours, leucovorin is initially dosed at 10 mg/m² IV or orally every 3 or 6 hours

At 48 hours:

For methotrexate levels of ≥100 micromolar at 48 hours, leucovorin is dosed at 1,000 mg/m² IV every 6 hours

For methotrexate levels of ≥10 to <100 micromolar at 48 hours, leucovorin is dosed at 100 mg/m² IV every 3 hours

For methotrexate levels of ~1 to 10 micromolar at 48 hours, leucovorin is dosed at 100 mg/m² IV every 6 hours or 10 mg/m² IV or orally to 100 mg/m² IV every 3 hours

At 72 hours:

For methotrexate levels of ≥10 micromolar at 72 hours, leucovorin is dosed at 100 to 1,000 mg/m² IV every 3 to 6 hours

For methotrexate levels of ~1 to 10 micromolar at 72 hours, leucovorin is dosed at 10 mg/m² IV or orally to 100 mg/m² IV every 3 hours

For methotrexate levels of ~0.1 to 1 micromolar at 72 hours, leucovorin is dosed at 10 mg/m² IV or orally every 3 to 6 hours

If serum creatinine is increased more than 50% above baseline, increase the standard leucovorin dose to 100 mg/m² IV every 3 hours, then adjust according to methotrexate levels above.

Follow methotrexate levels daily, leucovorin may be discontinued when methotrexate level is <0.1 micromolar

Dosing: Chemotherapy Regimens

Bladder cancer:

CMV (Bladder)

Dose Dense MVAC (Bladder Cancer)

MVAC (Bladder)

Bone sarcoma (osteosarcoma): MAP (Osteosarcoma)

Breast cancer: CMF Oral (Breast)

Gestational trophoblastic tumor:

EMA/CO (Gestational Trophoblastic Tumor)

EMA-EP (Gestational Trophoblastic Tumor)

EP-EMA (Gestational Trophoblastic Tumor)

Leukemia, acute lymphocytic:

CALGB 8811 Regimen (ALL)

CALGB 9111 Regimen (ALL)

Hyper-CVAD + Imatinib

Hyper-CVAD (Leukemia, Acute Lymphocytic)

Linker Protocol (ALL)

MTX/6-MP/VP (Maintenance)

POMP

Leukemia, acute promyelocytic:

Tretinoin-Daunorubicin-Cytarabine Induction, Consolidation, Maintenance (APL)

Tretinoin-Idarubicin (APL)

Lymphoma, Hodgkin: VAMP (Hodgkin)

Lymphoma, non-Hodgkin (Burkitt):

CODOX-M/IVAC (NHL-Burkitt)

CODOX-M (NHL-Burkitt)

Hyper-CVAD Alternating With High-Dose Methotrexate-Cytarabine + Rituximab + CNS Prophylaxis (NHL-Burkitt)

Lymphoma, non-Hodgkin (Mantle Cell): Rituximab-Hyper-CVAD (NHL-Mantle Cell)

Soft tissue sarcoma: Methotrexate-Vinblastine (Soft Tissue Sarcoma)

Dosing: Pediatric

Note: Methotrexate doses between 100 to 500 mg/m² may require leucovorin calcium rescue. Methotrexate doses >500 mg/m² require leucovorin calcium rescue.

Note: Dosing may be presented as mg/m² or mg/kg; verify dosage unit for calculations; extra precautions should be taken. Frequency of dosing is indication specific (generally weekly or daily); patient harm may occur if administered incorrectly; extra precautions should be taken to verify appropriate frequency. For oncology uses, regimens with corresponding dosing and frequency are highly variable and subject to frequent changes; typical dose ranges presented; specific protocols should be consulted.

Acute lymphoblastic leukemia (ALL) of infancy: Limited data available: Note: Intrathecal therapy is also administered (refer to specific reference for intrathecal dosing used within protocol); other combination chemotherapy variable based on protocol, and phase of treatment; refer to specific protocol: Intensification and Consolidation: Infant (<1 year of age) at diagnosis: IV: 4,000 to 5,000 mg/m² over 24 hours every 7 days for 2 doses; specific days depends on protocol phase (Dreyer 2015; Pieters 2007)

Acute lymphoblastic leukemia (ALL): Note: Intrathecal therapy is also administered (refer to specific reference for intrathecal dosing used within protocol): Limited data available; multiple regimens reported; methotrexate is part of a combination regimen; refer to specific protocols:

Interim maintenance:

High-dose methotrexate: Children and Adolescents IV: 500 mg/m² over 30 minutes followed by 4,500 mg/m² over 23.5 hours (to complete a total dose of 5,000 mg/m² over 24 hours on days 1, 15, 29, and 43 (with leucovorin rescue) (Larsen 2016; Seibel 2008; Winter 2015)

Escalating-dose methotrexate: Children and Adolescents: IV: Initial dose: 100 mg/m² then escalate dose by 50 mg/m² every 10 days for 5 doses total (Larsen 2016; Seibel 2008; Winter 2015)

Maintenance: Children and Adolescents: Oral: 20 mg/m² once weekly (Larsen 2016; Seibel 2008; Winter 2015)

CNS prophylaxis intrathecal therapy: Infants, Children, and Adolescents: Intrathecal: Age-based dosing: Days of administration vary based on risk status and protocol; refer to institutional protocols or reference for details (Larsen 2016; Lin 2008; Matloub 2006):

<1 year: 6 mg

1 to <2 years: 8 mg

2 to <3 years: 10 mg

3 to ≤8 years: 12 mg

>8 years: 15 mg

CNS tumors, malignant (medulloblastoma, PNET, ependymoma, brainstem glioma): Limited data available: Head Start II Protocol (Chi 2004): Children <10 years: IV: 400 mg/kg on Day 4 with leucovorin rescue until level less than 0.1 micromolar (µM) every 21 days for 5 cycles (in combination with cisplatin, vincristine, etoposide, and cyclophosphamide; then followed by an auto-transplant)

Crohn disease: Limited data available: Children and Adolescents: Oral, SubQ: Note: Should be used in patients intolerant or unresponsive to purine analog therapy (eg, azathioprine, mercaptopurine); use in combination with folic acid supplementation

BSA-directed dosing: 15 mg/m² once weekly; maximum dose: 25 mg (Mack 1998; Rufo 2012; Sandhu 2010; Turner 2007)

Fixed-dosing (Kliegman 2011; Mack 1998; Turner 2007; Weiss 2009)

20 to 29 kg: 10 mg once weekly

30 to 39 kg: 15 mg once weekly

40 to 49 kg: 20 mg once weekly

≥50 kg: 25 mg once weekly

Dermatomyositis: Limited data available: Children and Adolescents:

IM or SubQ: 15 to 20 mg/m² once a week in combination with corticosteroids and with either folic acid or folinic acid supplementation (Ruperto 2016)

IM or SubQ (preferred): Initial: 15 to 20 mg/m² or 1 mg/kg (whichever is less) once weekly; maximum dose: 40 mg; used in combination with corticosteroids (Huber 2010; Ramanan 2005, Ruperto 2016)

Oral (not preferred): Initial: 15 mg/m² or 1 mg/kg (whichever is less) once weekly; maximum dose: 40 mg; used in combination with corticosteroids (Huber 2010; Ramanan 2005)

Graft-versus-host disease, acute (aGVHD) prophylaxis: Limited data available: Children and Adolescents: IV: 15 mg/m²/dose on day 1 and 10 mg/m²/dose on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) (Chao 1993; Chao 2000; Ross 1999) or 15 mg/m²/dose on day 1 and 10 mg/m²/dose on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) (Chao 2000). Leucovorin rescue may be administered according to protocol.

Juvenile idiopathic arthritis (JIA); polyarticular:

BSA-directed dosing: Children and Adolescents 2 to 16 years: Oral, IM, SubQ: Initial: 10 mg/m² once weekly, adjust gradually up to 20 to 30 mg/m² once weekly; usual maximum dose: 25 mg; to reduce GI side effects, consider parenteral administration (IM, SubQ) of higher doses (20 to 30 mg/m²)

Weight-directed dosing: Children and Adolescents: Oral, SubQ: Initial: 0.5 mg/kg once weekly; maximum initial dose: 15 mg; if symptoms worsen or unchanged after 4 weeks, may increase to SubQ: 1 mg/kg; maximum dose: 30 mg (Dewitt 2012)

Meningeal leukemia, prophylaxis or treatment: Note: Frequency and duration of treatment based on protocol; treatment dosing may be a frequency of every 2 to 7 days (based on protocol); for treatment, often used combination with cytarabine and hydrocortisone (triple intrathecal therapy); refer to institutional protocols or references for details. Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer 1983; Kerr 2001): Infants, Children, and Adolescents: Intrathecal:

<1 year: 6 mg/dose

1 to <2 years: 8 mg/dose

2 to <3 years: 10 mg/dose

3 to <9 years: 12 mg/dose

≥9 years: 15 mg/dose (Larsen 2016)

Non-Hodgkin Lymphoma, B-cell:

Intermediate risk: Limited data available (Goldman 2013; Goldman 2014): Note: Some regimens may include periodic intrathecal methotrexate doses; refer to institution specific protocols or references cited, only intravenous dosing provided. Induction 1 and 2 (COPADM regimen) and Consolidation 1 and 2 (CYM regimen): Children and Adolescents: IV: 3,000 mg/m² over 3 hours with leucovorin rescue, combination chemotherapy varied with protocol phase

High risk: Limited data available (Cairo 2007): Note: Some regimens may include periodic intrathecal methotrexate doses; refer to institution specific protocols or references cited, only intravenous dosing provided. Infants ≥6 months, Children, and Adolescents: IV: 8,000 mg/m² over 4 hours once followed by leucovorin rescue; specific day of therapy and combination chemotherapy depends on protocol phase and clinical factors (eg, CNS positive)

Non-Hodgkin Lymphoma, T-cell (Anaplastic Large Cell Lymphoma [ALCL]): Limited data available (Reiter 1994; Seideman 2001): NHL-BFM90 protocol: Note: Both intravenous and intrathecal methotrexate dosing were part of protocol; use extra precaution ensuring route and dose. Infants, Children, and Adolescents:

Course B:

IV: 500 mg/m² over 24 hours; administer 10% of dose over the first 30 minutes and remaining 90% of dose over 23.5 hours on Day 1 (in combination with dexamethasone, cyclophosphamide, doxorubicin, and triple intrathecal therapy)

Intrathecal: On Day 1; administer 2 hours after the start of the methotrexate IV infusion

<1 year: 6 mg/dose

1 to <2 years: 8 mg/dose

2 to 3 years: 10 mg/dose

≥3 years: 12 mg/dose

Course BB:

IV: 5,000 mg/m² over 24 hours; administer 10% of dose over the first 30 minutes and remaining 90% of dose over 23.5 hours on Day 1 (in combination with dexamethasone, cyclophosphamide, vincristine, doxorubicin, and triple intrathecal therapy)

Intrathecal: On Day 1 administer 2 hours after the start of the methotrexate IV infusion; also administered on Day 5. Note: In patients with overt CNS disease and an implantable intraventricular device, presented doses were reduced by 50% (Seideman 2001).

<1 year: 3 mg/dose

1 to <2 years: 4 mg/dose

2 to <3 years: 5 mg/dose

≥3 years: 6 mg

Osteosarcoma: Limited data available: High-dose methotrexate: Children and Adolescents: IV: 12 g/m² (maximum dose: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 3, 4, 8, and 9, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 25, 26, 30, and 31 (in combination with doxorubicin and cisplatin) (Meyers 2005); other frequency and duration have also been reported (Ferrari 2005)

Psoriasis, severe; recalcitrant to topical therapy: Limited data available: Children and Adolescents: Oral, SubQ: Usual reported range: 0.2 to 0.4 mg/kg once weekly; reported treatment duration is highly variable: 6 to 178 weeks (Dadlani 2005; deJager 2010)

Scleroderma, localized (juvenile): Limited data available: Infants, Children, and Adolescents: Oral, SubQ (preferred): 1 mg/kg once weekly; maximum dose: 25 mg; alone or in combinations with corticosteroids; duration of therapy: 12 months (Li 2012)

Uveitis, recalcitrant: Limited data available: Children and Adolescents:

BSA-directed dosing: Oral, SubQ: Most frequently reported: 15 mg/m² once weekly, usual range: 10 to 25 mg/m² (Foeldvari 2005; Simonini 2013); the SubQ route may be preferred for patients with GI symptoms, poor bioavailability or doses >15 mg/m² (Simonini 2010)

Weight-directed dosing: SubQ: 0.5 to 1 mg/kg once weekly; maximum dose: 25 mg (Weiss 1998)

Dosing adjustment for toxicity: Infants, Children, and Adolescents:

Nonhematologic toxicity: Diarrhea, stomatitis, or vomiting which may lead to dehydration: Discontinue until recovery

Hematologic toxicity:

Psoriasis, arthritis (JIA): Significant blood count decrease: Discontinue immediately.

Oncologic uses: Profound granulocytopenia and fever: Evaluate immediately; consider broad-spectrum parenteral antimicrobial coverage

Dosing: Renal Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling. The following adjustments have been recommended:

Infants, Children, and Adolescents:

Oncology doses/uses: Refer to specific protocols for adjustments; the higher oncology doses may require more aggressive dosing adjustments than those recommended.

Nononcology doses/uses: The following have been recommended (Aronoff 2007):

CrCl >50 mL/minute/1.73 m²: No adjustment necessary

CrCl 10 to 50 mL/minute/1.73 m²: Administer 50% of dose

CrCl <10 mL/minute/1.73 m²: Administer 30% of dose

Hemodialysis: Administer 30% of dose

Peritoneal dialysis (PD): Administer 30% of dose

Continuous renal replacement therapy (CRRT): Administer 50% of dose

Dosing: Hepatic Impairment: Pediatric

All patients: There are no dosage adjustments provided in the manufacturer's labeling; use with caution in patients with impaired hepatic function or preexisting hepatic dysfunction. In pediatric oncology patients, refer to specific protocols for adjustments; the higher oncology doses may require more aggressive dosing adjustments. The following adjustments have been recommended in adults (Floyd 2006):

Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose

Bilirubin >5 mg/dL: Avoid use

Calculations

• Body Surface Area (Du Bois Method)
• Body Surface Area (Gehan & George Method)
• Body Surface Area (Mosteller Method)
• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate by Schwartz
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Oncology uses: Acute lymphoblastic leukemia (ALL) maintenance treatment, ALL meningeal leukemia (preservative-free only; prophylaxis and treatment); treatment of trophoblastic neoplasms (gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole), breast cancer, head and neck cancer (epidermoid), cutaneous T-Cell lymphoma (advanced mycosis fungoides), lung cancer (squamous cell and small cell), advanced non-Hodgkin lymphomas (NHL), osteosarcoma (preservative-free only).

Nononcology uses: Treatment of psoriasis (severe, recalcitrant, disabling) that is unresponsive to other therapies; severe, active rheumatoid arthritis (RA) that is unresponsive to or intolerant of first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs); active polyarticular-course juvenile idiopathic arthritis (pJIA) that is unresponsive to or intolerant of first-line therapy including full dose NSAIDs.

Limitations of use: Otrexup and Rasuvo are not indicated for the treatment of neoplastic diseases.

Guideline recommendations: Rheumatoid arthritis: Treatment initiation with a disease-modifying antirheumatic drug (DMARD) is recommended in DMARD-naïve patients with either early rheumatoid arthritis (RA) (disease duration <6 months) or established RA (disease duration ≥6 months). Methotrexate is the preferred initial DMARD for most early or established RA patients (Singh [ACR 2016]).

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Acute promyelocytic leukemia maintenanceLevel of Evidence [A]

Data from studies of combination chemotherapy in adult patients with acute promyelocytic leukemia support the use of methotrexate as part of the maintenance phase of treatment ^Ref.

Bladder cancerLevel of Evidence [A, G]

Data from a multicenter, randomized, phase III study support the use of methotrexate (in combination with cisplatin, vinblastine, and leucovorin rescue [CMV regimen]) for the neoadjuvant treatment of muscle-invasive bladder cancer ^Ref. Also, data from multiple studies support the use of methotrexate (in combination with vinblastine, doxorubicin, and cisplatin [MVAC regimen or dose-dense MVAC]) in the treatment of advanced bladder cancer ^Ref.

Based on the Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: American Urological Association/American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Urologic Oncology Guideline, methotrexate in combination with vinblastine, doxorubicin, and cisplatin (MVAC regimen) or in combination with cisplatin and vinblastine (CMV regimen) is recommended as neoadjuvant therapy in the management of nonmetastatic, muscle-invasive bladder cancer. Adjuvant therapy (following radical cystectomy) with a cisplatin-containing regimen (such as MVAC, dose-dense MVAC, or CMV) should be offered to patients with high risk pathological features who did not receive neoadjuvant chemotherapy.

Crohn disease (corticosteroid-dependent or remission maintenance)Level of Evidence [A, G]

Data from a double-blind, placebo-controlled, multicenter trial and a systematic review of 5 randomized controlled trials support the use of methotrexate in the maintenance of remission in Crohn disease ^Ref.

Based on the American College of Gastroenterology guidelines for the management of Crohn disease in adults and the American Gastroenterological Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti-TNF-a Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn disease, methotrexate is effective and recommended for patients with steroid-dependent Crohn disease and for maintenance of remission.

Dermatomyositis/polymyositisLevel of Evidence [C]

Data from a retrospective cohort study and a retrospective chart review in patients with polymyositis or dermatomyositis suggest a benefit with methotrexate for this condition ^Ref.

Clinical experience also suggests the utility of methotrexate in the treatment of dermatomyositis/polymyositis, typically as a glucocorticoid-sparing agent to reduce the cumulative dose of glucocorticoid required ^Ref.

Graft-versus-host disease, acute (prophylaxis)Level of Evidence [A, G]

Data from a randomized study support the use of methotrexate (in combination with cyclosporine and prednisone) to prevent acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation ^Ref. This combination was more effective than using cyclosporine and prednisone alone. Subsequently, data from a follow-up, prospective, randomized study demonstrated that the addition of prednisone did not have an impact on the incidence of acute or chronic GVHD; however, the addition of prednisone was associated with a somewhat lower incidence of early posttransplant complications ^Ref. Further data suggest that the combination of cyclosporine and prednisone with or without methotrexate results in comparable chronic GVHD-free survival ^Ref.

Based on the Prophylaxis and Treatment of GVHD: European Society for Blood and Marrow Transplantation-European Leukemia Net Working Group Recommendations for a Standardized Practice, methotrexate as combination therapy given to prevent aGVHD is effective and recommended in the management of this condition ^Ref.

Granulomatosis with polyangiitis (Wegener granulomatosis) and microscopic polyangiitis (maintenance therapy)Level of Evidence [B]

Data from an open-label randomized multicenter study comparing methotrexate to azathioprine support the use of oral methotrexate as maintenance therapy (once remission induction was achieved) in the management of granulomatosis with polyangiitis and microscopic polyangiitis ^Ref. Another open-label prospective study also supports the use of oral methotrexate as maintenance therapy for managing granulomatosis with polyangiitis and microscopic polyangiitis following remission induction ^Ref.

Nonleukemic meningeal cancerLevel of Evidence [B]

Data from a limited number of patients studied suggested that intrathecal methotrexate and high dose intravenous methotrexate are comparable in the treatment of nonleukemic meningeal cancer ^Ref. Additional data from a randomized, controlled study support the use of intrathecal methotrexate in the treatment of nonleukemic meningeal cancer ^Ref.

Primary CNS lymphoma, newly diagnosedLevel of Evidence [B]

Data from two multicenter phase II trials support the use of methotrexate (in combination with rituximab, leucovorin, procarbazine, and vincristine [R-MPV], followed by radiotherapy and cytarabine, and intrathecal/intra-Ommaya methotrexate if indicated) for the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) ^Ref. Data from a single center study also support the use of R-MPV, followed by consolidation high-dose chemotherapy and autologous stem cell transplant in newly diagnosed PCNSL ^Ref. Data from a multicenter, phase II study in immunocompetent patients with newly diagnosed primary CNS lymphoma support the use of high dose methotrexate (with deferred whole-brain radiotherapy) in the treatment of CNS lymphoma ^Ref. Data from a multicenter, single-arm, phase II trial suggest that methotrexate (in combination with rituximab and procarbazine) may be an efficacious regimen in newly diagnosed PCNSL patients ≥65 years of age ^Ref. Data from a small phase II study support the use of methotrexate (in combination with leucovorin, temozolomide, and rituximab and followed by high-dose consolidation chemotherapy) for the treatment of newly diagnosed primary CNS lymphoma ^Ref. Data from the phase II portion of a phase I-II study also support the use of methotrexate (in combination with leucovorin, temozolomide, and rituximab and followed by whole brain radiation therapy and subsequent temozolomide) for the treatment of newly diagnosed primary CNS lymphoma ^Ref.

Sarcoidosis, second-line therapyLevel of Evidence [B, G]

Data from a small randomized study, a retrospective study, and a consensus study support the use of methotrexate as second-line therapy for sarcoidosis ^Ref. Clinical experience also suggests the utility of methotrexate as an alternative agent or as steroid-sparing therapy in the management of pulmonary sarcoidosis ^Ref.

Based on recommendations from the World Association of Sarcoidosis and Granulomatous Disorders for the use of methotrexate in sarcoidosis, oral methotrexate is a second-line therapy option in patients with steroid-refractory sarcoidosis, in patients with intolerance to steroid therapy, or as steroid-sparing therapy.

Soft tissue sarcoma (desmoid tumors, aggressive fibromatosis), advancedLevel of Evidence [B]

Data from a phase II study in patients with primary or recurrent, advanced, inoperable aggressive fibromatosis support the use of methotrexate (in combination with vinblastine) for the treatment of advanced soft tissue sarcoma (desmoid tumors, aggressive fibromatosis) ^Ref. Methotrexate (in combination with vinblastine) was found to prolong stable disease in a subset of patients with this condition.

Systemic lupus erythematosus, moderate-to-severeLevel of Evidence [A]

Data from a randomized, double-blind, placebo-controlled study in patients with systemic lupus erythematosus (SLE) support the use of methotrexate in the treatment of moderate-to-severe SLE. In patients with this condition, the use of methotrexate conferred a significant advantage in patients with moderate SLE by lowering prednisone dose and slightly reducing disease activity ^Ref.

Takayasu arteritis, refractory or relapsing diseaseLevel of Evidence [C]

Data from a limited number of patients in an open-label pilot study suggest that methotrexate may be beneficial for the treatment of refractory or relapsing Takayasu arteritis ^Ref.

Termination of intrauterine pregnancyLevel of Evidence [B, G]

Evidence from a large prospective multicenter non-controlled trial showed safety and efficacy of methotrexate followed by misoprostol for termination of intrauterine pregnancy in pregnancies ≤49 days gestation ^Ref. Clinical experience also suggests the utility of methotrexate (followed by misoprostol) in the termination of intrauterine pregnancy ^Ref.

Based on the American College of Obstetricians and Gynecologists (ACOG) guidelines for the Medical Management of First Trimester Abortion, methotrexate (followed by misoprostol) may be given for medical termination of intrauterine pregnancy with a gestational age up to 49 days ^Ref. This combination is rarely used in the United States, but may be considered for use in regions where mifepristone regimens are not available or inappropriate ^Ref.

Tubal ectopic pregnancyLevel of Evidence [B, G]

Evidence from multiple case series ^Ref, prospective non-randomized trials ^Ref, and a prospective randomized study ^Ref supports the use of methotrexate for the medical management of tubal ectopic pregnancy in appropriately selected patients.

Based on the ACOG Practice Bulletin: Tubal Ectopic Pregnancy ^Ref and the American Society for Reproductive Medicine: Medical Treatment of Ectopic Pregnancy: A Committee Opinion ^Ref, methotrexate is effective and recommended in the management of tubal ectopic pregnancy. Treatment may be appropriate in hemodynamically stable females with a nonruptured tubal ectopic pregnancy and who do not have absolute contraindications to methotrexate administration specific to this indication ^Ref. Absolute contraindications include: Anemia (moderate to severe), breastfeeding, hemodynamic instability, hepatic dysfunction (clinically important), hypersensitivity to methotrexate, immunodeficiency, intrauterine pregnancy, leukopenia (moderate to severe), peptic ulcer disease (active), pulmonary disease (active), renal dysfunction (clinically important), ruptured ectopic pregnancy, or thrombocytopenia (moderate to severe). Relative contraindications include: Embryonic cardiac activity, high initial hCG concentration (>5,000 mIU/mL per ASRM), ectopic pregnancy >4 cm, refusal to accept blood transfusion, or not available for follow-up ^Ref.

UveitisLevel of Evidence [C]

Results from noncontrolled studies demonstrate that methotrexate is generally effective in treating uveitis ^Ref. However, no controlled clinical trials have been performed. An expert review panel recommends methotrexate as second-line therapy for the treatment of uveitis in adults ^Ref.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Ankylosing Spondylitis:

ACR/SAA/SPARTAN, "2019 Update of the Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis," August 2019

Crohn Disease:

ACG, “Management of Crohn's Disease in Adults,” March 2018

AGA, “Use of Thiopurines, Methotrexate, and Anti-TNF-alfa Biologic Drugs for Remission Induction and Maintenance in Inflammatory Crohn’s Disease,” 2013

Drug-Induced Liver Injury:

ACG, “2014 ACG Guideline for Idiosyncratic Drug-induced Liver Injury,” July 2014

Juvenile Idiopathic Arthritis:

ACR, “2013 Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis,” 2013

Neurocysticercosis:

IDSA/ASTMH, "Diagnosis and Treatment of Neurocysticercosis," 2018

Obesity:

ASCO, "Clinical Practice Guideline for Appropriate Dosing for Obese Patients with Cancer," 2012

Oncology:

American Urological Association (AUA)/American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO), "Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline," 2017

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Acute Lymphoblastic Leukemia

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Acute Myeloid Leukemia

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Bladder Cancer

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Bone Cancer

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Breast Cancer

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Central Nervous System Cancers

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Gestational Trophoblastic Neoplasia

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Head and Neck Cancers

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Non-Hodgkin’s Lymphomas

National Comprehensive Cancer Network® (NCCN), "Clinical Practice Guidelines in Oncology™," Soft Tissue Sarcoma

Oncology Antiemesis:

ASCO, "Clinical Practice Guideline Update," 2017

MASCC/ESMO, “Antiemetic Guidelines,” Updated 2016

Pediatric Oncology Group of Ontario, "Classification of the acute emetogenicity of chemotherapy in pediatric patients," 2019

Pediatric Oncology Group of Ontario, "Guideline for the Classification of Acute Emetogenic Potential of Antineoplastic Medication in Pediatric Cancer Patients," 2011

Pediatric Oncology Group of Ontario, "Guideline for the Prevention of Acute Nausea and Vomiting Due to Antineoplastic Medication in Pediatric Cancer Patients," 2013

Pediatric Oncology Group of Ontario, "Guideline for the Prevention of Acute Chemotherapy-Induced Nausea and Vomiting in Pediatric Cancer Patients: A Focused Update," 2017

Polymyalgia Rheumatica:

EULAR/ACR, “2015 Recommendations for the Management of Polymyalgia Rheumatica,” 2015

Psoriatic Arthritis:

ACR/NPF, "Guideline for the Treatment of Psoriatic Arthritis," November 2018

Rheumatoid Arthritis:

ACR, "2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis,” 2016

Administration: IM

May be administered IM.

When administered IM for indications that may terminate a pregnancy, also consult local policies or regulations related to administration.

Administration: IV

Doses ≥250 mg/m² (IV) are associated with moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting.

May be administered IV; IV administration may be as slow push (10 mg/minute), bolus infusion, or 24-hour continuous infusion (route and rate of administration depends on indication and/or protocol; refer to specific references). Must use preservative-free formulation for high dose methotrexate.

Specific dosing schemes vary, but high dose should be followed by leucovorin calcium rescue to prevent toxicity.

Administration: Oral

Oral administration is often preferred when low doses are being administered.

Oral solution: Ensure accuracy when dispensing and administering to prevent dosing errors. A calibrated oral syringe/dosing cup that can measure and deliver the prescribed dose accurately should be used; do not use a household teaspoon or tablespoon to measure dose.

Administration: Subcutaneous

May be administered SubQ (depending on indication and product).

Otrexup and Rasuvo are autoinjectors for once weekly subcutaneous use in the abdomen or thigh; patient may self-administer after appropriate training on preparation and administration, and with appropriate follow-up monitoring. All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.

Administration: Intrathecal

May be administered intrathecally; must use preservative-free formulation for intrathecal administration.

Administration: Pediatric

Oral: Often preferred when low doses are being administered; administer on an empty stomach (at least 1 hour before or 2 hours after food or drink except water). Oral solution (Xatmep) contains 2.5 mg/mL concentrated solution; administer with an accurate measuring device (eg, calibrated oral syringe); do not use a household teaspoon (overdosage may occur).

Parenteral:

IM: May be administered at concentration ≤25 mg/mL; autoinjectors should not be used for IM administration.

IV:

IV push: May be administered as slow IV push at a concentration ≤25 mg/mL; some have suggested a rate of ≤10 mg/minute (Gahart 2014)

Bolus IV infusion, or 24-hour continuous infusion: Route and rate of administration depend upon indication and/or protocol; refer to specific references. For high-dose infusion, preservative-free formulation must be used [US Boxed Warning]. Specific dosing schemes vary, but high dose must be followed by leucovorin calcium to prevent toxicity.

SubQ: May be administered SubQ (dependent upon indication and product).

Otrexup and Rasuvo are for once weekly subcutaneous use in the abdomen or thigh; do not inject within 2 inches of the navel or in areas where the skin is tender, bruised, red, scaly, hard or has scars or stretch marks. Patient may self-administer after appropriate training on preparation and administration and with appropriate follow-up monitoring. All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects.

Intrathecal: May be administered intrathecally; must use preservative-free formulation for intrathecal administration.

Dietary Considerations

Some products may contain sodium.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules. Double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection are recommended for administration of an oral liquid/feeding tube administration. For injection preparation, NIOSH recommends double gloving, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs). Double gloving, a gown, and (if dosage form allows) CSTDs are required during injection administration (NIOSH 2016).

Storage/Stability

Injection: Note: Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

IV: Store intact vials and autoinjectors between 20°C and 25°C (68°F and 77°F); excursions may be permitted between 15°C and 30°C (59°F and 86°F). Protect from light. Solution diluted in D5W or NS is stable for 24 hours at room temperature (21°C to 25°C).

Intrathecal: Intrathecal dilutions are preservative free and should be used as soon as possible after preparation. After preparation, store intrathecal medications (until use) in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.

Oral:

Tablets: Store between 20°C and 25°C (68°F and 77°F). Protect from light.

Oral solution: Store at 2°C to 8°C (36°F to 46°F) in a tightly closed container. Patients may store either refrigerated (2°C to 8°C [36°F to 46°F]) or for up to 60 days at room temperature (20°C to 25°C [68°F to 77°F]). Excursions permitted to 15°C to 30°C (59°F to 86°F). Avoid freezing and excessive heat.

Preparation for Administration: Adult

Use preservative-free preparations for intrathecal or high-dose methotrexate administration.

IV: Dilute powder with D5W or NS to a concentration of ≤25 mg/mL (20 mg and 50 mg vials) and 50 mg/mL (1 g vial). May further dilute in D5W or NS.

Intrathecal: Prepare intrathecal solutions with preservative-free NS, lactated Ringer's, or Elliot's B solution to a final volume of up to 12 mL (volume generally based on institution or practitioner preference). Intrathecal methotrexate concentrations may be institution specific or based on practitioner preference, generally ranging from a final concentration of 1 mg/mL (per prescribing information; Grossman 1993; Lin 2008) up to ~2 to 4 mg/mL (de Lemos 2009; Glantz 1999). For triple intrathecal therapy (methotrexate 12 mg/hydrocortisone 24 mg/cytarabine 36 mg), preparation to final volume of 12 mL is reported (Lin 2008). Intrathecal medications should NOT be prepared during the preparation of any other agents.

Preparation for Administration: Pediatric

Parenteral: Use preservative-free preparations for intrathecal or high-dose methotrexate administration.

IV:

Powder for injection: Reconstitute 1 g vial with 19.4 mL of sterile preservative-free D5W or NS to a concentration of 50 mg/mL; further dilute in D5W or NS; for high doses, dilution of reconstituted solution in D5W is recommended by the manufacturer; maximum concentration: 25 mg/mL (Gahart 2014)

Solution for injection (25 mg/mL): May further dilute in D5W or NS

Intrathecal: Prepare intrathecal solutions with preservative-free NS to a final volume of up to 12 mL (volume generally based on institution or practitioner preference). Intrathecal methotrexate concentrations may be institution specific or based on practitioner preference, generally ranging from a final concentration of 1 mg/mL (per prescribing information; Grossman 1993; Lin 2008) up to ~2 to 4 mg/mL (deLemos 2009; Glantz 1999). For triple intrathecal therapy (methotrexate 12 mg/hydrocortisone 24 mg/cytarabine 36 mg), preparation to final volume of 12 mL is reported (Lin 2008). Intrathecal medications should NOT be prepared during the preparation of any other agents.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat cancer.

• It is used to treat some types of arthritis

• It is used to treat psoriasis.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Hair loss

• Nausea

• Vomiting

• Lack of appetite

• Abdominal pain

• Loss of strength and energy

• Common cold symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea, or lack of appetite; or feel sluggish

• Infection

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop

• Pancreas problem like pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting

• Kidney problems like not able to pass urine, blood in urine, change in amount of urine passed, weight gain

• Liver problems like dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes

• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.

• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight.

• DVT like swelling, warmth, numbness, change in color, or pain in the extremities

• Pinpoint red spots on skin

• Severe dizziness

• Passing out

• Seizures

• Confusion

• Fatigue

• Vision changes

• Bone pain

• Headache

• Neck rigidity

• Burning or numbness feeling

• Muscle weakness

• Trouble moving

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Administration issues:

Other safety concerns:

International issues:

Contraindications

Known hypersensitivity to methotrexate or any component of the formulation; breastfeeding (product-specific; refer to manufacturer's labeling).

Additional contraindications for patients with psoriasis, rheumatoid arthritis or polyarticular-course juvenile idiopathic arthritis: Pregnancy, alcoholism, alcoholic liver disease or other chronic liver disease, immunodeficiency syndromes (overt or laboratory evidence); preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia).

Canadian labeling: Additional contraindications (not in the US labeling): Severe renal impairment (including end-stage renal disease with or without dialysis); females of childbearing potential (until pregnancy is excluded); concomitant use with nitrous oxide anesthesia.

Warnings/Precautions

Concerns related to adverse effects:

• Acute renal failure: May cause renal damage leading to acute renal failure, especially with high-dose methotrexate; monitor renal function and methotrexate levels closely, maintain adequate hydration and urinary alkalinization. Use with caution in osteosarcoma patients treated with high-dose methotrexate in combination with nephrotoxic chemotherapy (eg, cisplatin).

• Bone marrow suppression: [US Boxed Warning]: Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs); anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia may occur. Monitor blood counts. Use with caution in patients with preexisting bone marrow suppression. Discontinue treatment (immediately) in rheumatoid arthritis (RA) or psoriasis if a significant decrease in hematologic components is noted.

• CNS effects: May cause neurotoxicity. Leukoencephalopathy has been reported (case reports), usually in patients who have received cranial irradiation and IV methotrexate. Chronic leukoencephalopathy has been reported with high-dose methotrexate (with leucovorin rescue and even without cranial irradiation) and with intrathecal methotrexate; discontinuing methotrexate does not always result in complete recovery; may be progressive and fatal. Serious neurotoxicity, including generalized and focal seizures has occurred (usually in pediatric ALL patients receiving intermediate-dose (1 g/m² IV methotrexate); leukoencephalopathy and/or microangiopathic calcifications were noted on diagnostic imaging studies in symptomatic patients. A transient acute stroke-like encephalopathy has been observed, usually with high-dose regimens; manifestations may include confusion, hemiparesis, transient blindness, seizure, and coma. Chemical arachnoiditis (headache, back pain, nuchal rigidity, fever) and myelopathy may result from intrathecal administration. May cause dizziness and fatigue; may affect the ability to drive or operate heavy machinery.

• Dermatologic toxicity: [US Boxed Warning]: Severe, occasionally fatal skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. Severe dermatologic reactions have included toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme; discontinue methotrexate if severe reactions occur. Radiation recall dermatitis and sunburn may be precipitated by methotrexate administration. Psoriatic lesions may be worsened by concomitant exposure to ultraviolet radiation.

• Gastrointestinal toxicity: [US Boxed Warning]: Gastrointestinal toxicity may occur (may be unexpectedly severe, usually occurs with high doses along with concomitant use of some NSAIDs); diarrhea and ulcerative stomatitis may require treatment interruption; otherwise hemorrhagic enteritis and death from intestinal perforation may occur. Diarrhea or stomatitis may also require discontinuation. Use with caution in patients with peptic ulcer disease or ulcerative colitis; the risk of GI adverse effects may be increased. In pediatrics, doses ≥12 g/m² (IV) are associated with a high emetic potential, while a 5 g/m² (IV) dose is associated with a moderate emetic potential (Dupuis 2011; Paw Cho Sing 2019); doses ≥250 mg/m² (IV) in adults are associated with moderate emetic potential. Antiemetics may be recommended to prevent nausea and vomiting.

• Hepatotoxicity: [US Boxed Warning]: Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions often are not preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. Risk is related to cumulative dose (≥1.5 g) and prolonged exposure. Monitor closely (with liver function tests, including serum albumin) for liver toxicities. Liver enzyme elevations may be noted, but may not be predictive of hepatic disease in long term treatment for psoriasis (but generally is predictive in RA treatment). Discontinue methotrexate with moderate to severe change in liver biopsy. Risk factors for hepatotoxicity include history of above moderate ethanol consumption, persistent abnormal liver chemistries, history of chronic liver disease (including hepatitis B or C), family history of inheritable liver disease, diabetes, obesity, hyperlipidemia, lack of folate supplementation during methotrexate therapy, cumulative methotrexate dose exceeding 1.5 g, continuous daily methotrexate dosing, history of significant exposure to hepatotoxic drugs, and advanced age. Use with caution with preexisting liver impairment; may require dosage reduction. Use with caution when used with other hepatotoxic agents (azathioprine, retinoids, sulfasalazine).

• Hypersensitivity: Anaphylaxis may occur; if anaphylaxis or other serious hypersensitivity reaction occurs, discontinue methotrexate immediately and institute appropriate management.

• Infections: [US Boxed Warning]: Immune suppression may lead to potentially fatal opportunistic infections, including Pneumocystis jirovecii pneumonia (PCP). Methotrexate use increases the risk for developing life-threatening or fatal bacterial, fungal, or viral infections, including invasive fungal infections, hepatitis B reactivation, tuberculosis (primary infection or reactivation), disseminated herpes zoster infection and/or cytomegalovirus infection. Use methotrexate with extreme caution in patients with an active infection (contraindicated in patients with immunodeficiency syndrome). Monitor for signs/symptoms of infection during and after treatment; manage promptly if infections occurs. Dose reduction or discontinuation may be necessary for serious infection.

• Pneumonitis: [US Boxed Warning]: Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. Pulmonary symptoms may occur at any time during therapy and at any dosage; monitor closely for pulmonary symptoms, particularly dry, nonproductive cough. Other potential symptoms include fever, dyspnea, hypoxemia, or pulmonary infiltrate.

• Secondary malignancy: [US Boxed Warning]: Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted. Other secondary tumors have been reported.

• Tumor lysis syndrome: [US Boxed Warning]: Tumor lysis syndrome may occur in patients with high tumor burden; appropriate supportive and pharmacologic measures may prevent or alleviate tumor lysis syndrome.

Disease-related concerns:

• Ascites/pleural effusions: [US Boxed Warning]: Elimination is reduced in patients with ascites and/or pleural effusions; resulting in prolonged half-life and toxicity; may require dose reduction or discontinuation. Monitor closely for toxicity.

• Hepatic impairment: Use with caution in patients with preexisting liver impairment.

• Peptic ulcer disease: Use with caution in patients with peptic ulcer disease; diarrhea and stomatitis may occur.

• Renal impairment: [US Boxed Warning]: Methotrexate elimination is reduced in patients with renal impairment; monitor closely for toxicity; may require dose reduction or, in some cases, discontinuation of methotrexate administration.

• Ulcerative colitis: Use with caution in patients with ulcerative colitis; diarrhea and stomatitis may occur.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Hepatotoxic agents: Use caution when used with other hepatotoxic agents (azathioprine, retinoids, sulfasalazine).

• Mercaptopurine: Methotrexate may increase the levels and effects of mercaptopurine; may require dosage adjustments.

• Nephrotoxic chemotherapy: Use with caution in osteosarcoma patients treated with high-dose methotrexate in combination with nephrotoxic chemotherapy (eg, cisplatin).

• NSAIDs: Do not administer NSAIDs prior to or during high dose methotrexate therapy; may increase and prolong serum methotrexate levels. Doses used for psoriasis may still lead to unexpected toxicities; use with caution when administering NSAIDs or salicylates with lower doses of methotrexate for RA.

• Proton pump inhibitors: Concomitant use of proton pump inhibitors with methotrexate (primarily high-dose methotrexate) may elevate and prolong serum methotrexate levels and metabolite (hydroxymethotrexate) levels (based on case reports and pharmacokinetic studies). May lead to toxicities; use with caution.

• Vaccines: Immunization may be ineffective during methotrexate treatment. Immunization with live vaccines is not recommended; cases of disseminated vaccinia infections due to live vaccines have been reported.

• Vitamins: Vitamins containing folate may decrease response to systemic methotrexate; folate deficiency may increase methotrexate toxicity.

Special populations:

• Elderly: Use caution and monitor closely in elderly patients; increased risk of toxicity.

• Pregnancy: [US Boxed Warning]: Methotrexate can cause embryo-fetal toxicity, including fetal death. Use in RA, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy. Consider the benefits and risks of methotrexate and risks to the fetus when prescribing methotrexate to a pregnant patient with a neoplastic disease. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females and males of reproductive potential to use effective contraception during and after treatment with methotrexate.

• Radiotherapy recipients: [US Boxed Warning]: Concomitant methotrexate administration with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

• Intrathecal and high-dose therapy: [US Boxed Warning]: Use only preservative-free methotrexate formulations and diluents for intrathecal and high-dose therapy. Do NOT use formulations or diluents containing preservatives for intrathecal and high-dose therapy because they contain benzyl alcohol.

Other warnings/precautions:

• Administration schedules: Errors have occurred (some resulting in death) when methotrexate was administered as a “daily” dose instead of a “weekly” dose intended for some indications. The ISMP Targeted Medication Safety Best Practices for Hospitals recommends hospitals use a weekly dosage regimen default for oral methotrexate orders in electronic order entry systems, with a hard stop verification required of appropriate oncology indication for daily orders; manual systems should require clarification of an oncology indication prior to dispensing oral methotrexate for daily administration. Provide patient and/or caregiver education for patients discharged on weekly oral methotrexate; education should include written leaflets that contain clear instructions about the weekly dosing schedule and explain the danger of taking extra doses (ISMP 2018).

• Appropriate use: [US Boxed Warning]: Because of the possibility of serious toxic reactions (which can be fatal), methotrexate should be used only in life threatening neoplastic diseases or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician's care throughout therapy. The use of methotrexate high-dose regimens recommended for osteosarcoma requires meticulous care. High-dose regimens of methotrexate injection for other neoplastic diseases are investigational, and a therapeutic advantage has not been established.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of a physician experienced in the use of antimetabolite therapy.

• Intrathecal safety: When used for intrathecal administration, should not be prepared during the preparation of any other agents. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications intended for administration into the central nervous system (Jacobson 2009).

• Methotrexate overexposure: Glucarpidase is an enzyme that rapidly hydrolyzes extracellular methotrexate into inactive metabolites, allowing for a rapid reduction of methotrexate concentrations. Glucarpidase may be used for methotrexate overexposure; it is approved for the treatment of toxic plasma methotrexate concentrations (>1 micromole/L) in patients with delayed clearance due to renal impairment. Refer to Glucarpidase monograph.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Toxicity to methotrexate or any immunosuppressive is increased in the elderly. Must monitor carefully. For rheumatoid arthritis and psoriasis, immunosuppressive therapy should only be used when disease is active and less toxic, traditional therapy is ineffective. Recommended doses should be reduced when initiating therapy in the elderly due to possible decreased metabolism, reduced renal function, and presence of interacting diseases and drugs. Adjust dose as needed for renal function (CrCl).

Pregnancy Risk Factor

X (psoriasis, rheumatoid arthritis)

Pregnancy Considerations

Methotrexate crosses the placenta (Schleuning 1987).

[US Boxed Warning]: Methotrexate can cause embryo-fetal toxicity, including fetal death. Following exposure during the first trimester, methotrexate may increase the risk of spontaneous abortion, skull anomalies, facial dysmorphism, CNS, limb and cardiac abnormalities; intellectual impairment may also occur. Intrauterine growth restriction and functional abnormalities may occur following second or third trimester exposure.

[US Boxed Warning]: Consider the benefits and risks of methotrexate and risks to the fetus when prescribing methotrexate to a pregnant patient with a neoplastic disease. Methotrexate is approved for the treatment of trophoblastic neoplasms (gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole). Methotrexate is recommended for the medical management of ectopic pregnancy in appropriately selected patients (ACOG 193 2018; ASRM 2013). Methotrexate has been used for the medical termination of intrauterine pregnancy with a gestational age up to 49 days (ACOG 143 2014).

[US Boxed Warning]: Use in rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy. It is currently recommended that females with inflammatory bowel disease, rheumatoid arthritis, or psoriasis discontinue methotrexate 3 months prior to a planned pregnancy (Flint 2016; Mahadevan 2019; Nguyen 2016; Rademaker 2018).

[US Boxed Warning]: Verify the pregnancy status of females of reproductive potential prior to initiating therapy.Advise females and males of reproductive potential to use effective contraception during and after treatment with methotrexate. Effective contraception is recommended for females during therapy and for ≥6 months. Effective contraception is recommended for males during therapy and for ≥3 months after the final dose of methotrexate.

The use of methotrexate may impair fertility and cause menstrual irregularities or oligospermia during treatment and following therapy. It is not known if infertility may be reversed in all affected males or females. Low-dose methotrexate, when used for rheumatoid arthritis, inflammatory bowel disease or psoriasis, is considered compatible for use in male patients planning to father a child (Flint 2016; Lamb 2019; Rademaker 2018).

Breast-Feeding Considerations

Methotrexate and 7-hydroxymethotrexate are present in breast milk (Baker 2018).

Information related to the use of methotrexate in breastfeeding females is limited (Baker 2018; Delaney 2017; Johns 1972; Tanaka 2009; Thorne 2014).

Methotrexate has the potential to cause serious adverse reactions in the breastfed infant. Recommendations for use women who wish to breastfeed vary. Breastfeeding is not recommended or is contraindicated by some manufacturers during treatment. Available guidelines state methotrexate is contraindicated when used for the treatment of tubal ectopic pregnancy (ACOG193 2018; ASRM 2013) and is not recommended during treatment for inflammatory bowel disease (Mahadevan 2019, Nguyen 2016), rheumatoid arthritis (Flint 2016), or psoriasis (Rademaker 2018). When high doses are used for chemotherapy, it is recommended to discard breast milk for at least 1 week following the last dose of methotrexate (Pistilli 2013). Although lower doses (such as those used for arthritis) may have lower risk to the breastfed infant, use of alternative medications is recommended in breastfeeding females (Ito 2000).

Lexicomp Pregnancy & Lactation, In-Depth

• Methotrexate

Briggs' Drugs in Pregnancy & Lactation

• Methotrexate

Adverse Reactions

Note: Adverse reactions vary by route and dosage. Frequency not always defined.

Cardiovascular: Arterial thrombosis, cerebral thrombosis, chest pain, deep vein thrombosis, hypotension, pericardial effusion, pericarditis, plaque erosion (psoriasis), pulmonary embolism, retinal thrombosis, thrombophlebitis, vasculitis

Central nervous system: Dizziness (≤3%), headache (pJIA 1%), abnormal cranial sensation, brain disease, chemical arachnoiditis (intrathecal; acute), chills, cognitive dysfunction (has been reported at low dosage), drowsiness, fatigue, leukoencephalopathy (intravenous administration after craniospinal irradiation or repeated high-dose therapy; may be chronic), malaise, mood changes (has been reported at low dosage), neurological signs and symptoms (at high dosages; including confusion, hemiparesis, transient blindness, seizures, and coma), severe neurotoxicity (reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate), speech disturbance

Dermatologic: Alopecia (≤10%), burning sensation of skin (psoriasis 3% to 10%), skin photosensitivity (3% to 10%), skin rash (≤3%), dermatitis (rheumatoid arthritis 1% to 3%), pruritus (rheumatoid arthritis 1% to 3%), acne vulgaris, dermal ulcer, diaphoresis, ecchymoses, erythema multiforme, erythematous rash, exfoliative dermatitis, furunculosis, hyperpigmentation, hypopigmentation, skin abnormalities related to radiation recall, skin necrosis, Stevens-Johnson syndrome, telangiectasia, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Decreased libido, decreased serum albumin, diabetes mellitus, gynecomastia, menstrual disease

Gastrointestinal: Diarrhea (≤11%), nausea and vomiting (≤11%), stomatitis (2% to 10%), abdominal distress, anorexia, aphthous stomatitis, enteritis, gastrointestinal hemorrhage, gingivitis, hematemesis, intestinal perforation, melena, pancreatitis

Genitourinary: Azotemia, cystitis, defective oogenesis, defective spermatogenesis, dysuria, hematuria, impotence, infertility, oligospermia, proteinuria, severe renal disease, vaginal discharge

Hematologic & oncologic: Thrombocytopenia (rheumatoid arthritis 3% to 10%; platelet count <100,000/mm³), leukopenia (1% to 3%; WBC <3000/mm³), pancytopenia (rheumatoid arthritis 1% to 3%), agranulocytosis, anemia, aplastic anemia, bone marrow depression (nadir: 7-10 days), decreased hematocrit, eosinophilia, gastric ulcer, hypogammaglobulinemia, lymphadenopathy, lymphoma, lymphoproliferative disorder, neutropenia, non-Hodgkin’s lymphoma (in patients receiving low-dose oral methotrexate), tumor lysis syndrome

Hepatic: Increased liver enzymes (14% to 15%), cirrhosis (chronic therapy), hepatic failure, hepatic fibrosis (chronic therapy), hepatitis (acute), hepatotoxicity

Hypersensitivity: Anaphylactoid reaction

Infection: Cryptococcosis, cytomegalovirus disease (including cytomegaloviral pneumonia, sepsis, nocardiosis), herpes simplex infection, herpes zoster, histoplasmosis, infection, vaccinia (disseminated; following smallpox immunization)

Neuromuscular & skeletal: Arthralgia, myalgia, myelopathy (subacute), osteonecrosis (with radiotherapy), osteoporosis

Ophthalmic: Blurred vision, conjunctivitis, eye pain, visual disturbance

Otic: Tinnitus

Renal: Renal failure

Respiratory: Interstitial pneumonitis (rheumatoid arthritis 1%), chronic obstructive pulmonary disease, cough, epistaxis, pharyngitis, pneumonia (including Pneumocystis jirovecii), pulmonary alveolitis, pulmonary disease, pulmonary fibrosis, respiratory failure, upper respiratory tract infection

Miscellaneous: Fever, nodule, tissue necrosis

<1%, postmarketing, and/or case reports: Acute respiratory distress (Morgan 2011), bone fracture (stress), cerebrovascular accident (Morgan 2011), mesenteric ischemia (acute; Morgan 2011)

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Methotrexate/Trimetrexate Allergy

Oncology: Emetic Potential

Pediatrics:

Intrathecal methotrexate: Moderate (30% to 90%)

IV:

≥12 g/m²/dose: High (>90%)

5 g/m²/dose: Moderate (30% to 90%)

38 to 83 mg/m²/dose: Low (10% to 30%)

Oral or SubQ: ≤10 mg/m²/dose: Minimal (<10%)

Adults:

IV:

≥250 mg/m²: Moderate (30% to 90%)

>50 to <250 mg/m²: Low (10% to 30%)

≤50 mg/m²: Minimal (<10%)

Oral: Minimal (<10%)

Metabolism/Transport Effects

Substrate of BCRP/ABCG2, OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1

Drug Interactions Open Interactions

Acitretin: May enhance the hepatotoxic effect of Methotrexate. Risk X: Avoid combination

Alcohol (Ethyl): May enhance the hepatotoxic effect of Methotrexate. Management: Limit alcohol consumption in patients taking methotrexate. The use of methotrexate for the treatment of psoriasis or rheumatoid arthritis is contraindicated in patients with alcoholism or alcoholic liver disease. Risk D: Consider therapy modification

Alitretinoin (Systemic): May enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Risk D: Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

Bile Acid Sequestrants: May decrease the absorption of Methotrexate. Risk C: Monitor therapy

Cephalothin: May diminish the therapeutic effect of Methotrexate. Risk C: Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Risk C: Monitor therapy

CycloSPORINE (Systemic): May increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE (Systemic). This may result in nephrotoxicity. Risk D: Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy

Dexketoprofen: May increase the serum concentration of Methotrexate. Management: Concurrent use of dexketoprofen with methotrexate doses of 15 mg/week or more is inadvisable. Use with lower methotrexate doses should only be performed with caution and increased monitoring. Risk D: Consider therapy modification

Dichlorphenamide: May increase the serum concentration of Methotrexate. Risk X: Avoid combination

Diethylamine Salicylate: May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Methotrexate. Methotrexate may enhance the adverse/toxic effect of Dipyrone. Specifically, the risk for agranulocytosis and pancytopenia may be increased. Risk X: Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Risk D: Consider therapy modification

Foscarnet: May enhance the nephrotoxic effect of Methotrexate. Risk X: Avoid combination

Fosphenytoin-Phenytoin: Methotrexate may decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug. Risk C: Monitor therapy

Gemfibrozil: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions. Risk C: Monitor therapy

Ibrutinib: May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk X: Avoid combination

Leflunomide: Methotrexate may enhance the adverse/toxic effect of Leflunomide. Particular concerns are an increased risk of pancytopenia and/or hepatotoxicity. Risk C: Monitor therapy

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

LevETIRAcetam: May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Loop Diuretics: Methotrexate may diminish the therapeutic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Methotrexate. Methotrexate may increase the serum concentration of Loop Diuretics. Management: Monitor for increased methotrexate and/or loop diuretic levels/toxicity with concomitant use of these agents and monitor for decreased therapeutic effects of loop diuretics. Methotrexate and/or loop diuretic dose reductions may be necessary. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Mercaptopurine: Methotrexate may increase the serum concentration of Mercaptopurine. Conversely, intracellular concentrations of thioguanine nucleotides may be decreased with the combination. Risk C: Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Mipomersen: May enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Nitisinone: May increase the serum concentration of OAT1/3 Substrates. Risk C: Monitor therapy

Nitrous Oxide: May enhance the adverse/toxic effect of Methotrexate. Risk X: Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate. Risk D: Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Penicillins: May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Pretomanid: May increase the serum concentration of OAT1/3 Substrates. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Methotrexate. Management: Avoid concomitant use of probenecid and methotrexate if possible. If used together, consider lower methotrexate doses and monitor for evidence of methotrexate toxicity. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Proton Pump Inhibitors: May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

Pyrimethamine: May enhance the adverse/toxic effect of Methotrexate. Risk C: Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification

Salicylates: May increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider therapy modification

Sapropterin: Methotrexate may decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Risk C: Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

SulfaSALAzine: May enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy

Sulfonamide Antibiotics: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and therapeutic doses of sulfonamides (eg, trimethoprim/sulfamethoxazole). Patients receiving prophylactic doses of trimethoprim/sulfamethoxazole and methotrexate should be carefully monitored. Risk D: Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination

Tegafur: Methotrexate may enhance the adverse/toxic effect of Tegafur. Risk C: Monitor therapy

Teriflunomide: May increase the serum concentration of OAT1/3 Substrates. Risk C: Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Risk C: Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Risk C: Monitor therapy

Theophylline Derivatives: Methotrexate may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Tofacitinib: Methotrexate may enhance the immunosuppressive effect of Tofacitinib. Management: Avoid the use of tofacinib in combination with potent immunosuppressive methotrexate-containing regimens. Risk C: Monitor therapy

Tolvaptan: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. Management: Avoid concomitant use of OATP1B1/1B3 substrates in patients receiving the Jynarque brand of tolvaptant. Concentrations and effects of the OATP1B1/1B3 substrate would be expected to increase with combined use. Risk D: Consider therapy modification

Tolvaptan: May increase the serum concentration of OAT1/3 Substrates. Management: Avoid concomitant use of OAT1/3 substrates in patients receiving the Jynarque brand of tolvaptan. Concentrations and effects of the OAT1/3 substrate would be expected to increase with combined use. Risk D: Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Trimethoprim: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (e.g., bone marrow suppression). Risk D: Consider therapy modification

Upadacitinib: Methotrexate may enhance the immunosuppressive effect of Upadacitinib. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Risk D: Consider therapy modification

Vaccines (Live): Methotrexate may enhance the adverse/toxic effect of Vaccines (Live). Methotrexate may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose methotrexate (0.4 mg/kg/week or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns. Higher doses of methotrexate should be avoided. Risk D: Consider therapy modification

Food Interactions

Methotrexate peak serum levels may be decreased if taken with food. Milk-rich foods may decrease methotrexate absorption. Management: Administer without regard to food.

Genes of Interest

• Methylenetetrahydrofolate Reductase

Monitoring Parameters

Evaluate pregnancy status prior to use in females of reproductive potential.

Oncologic uses: Baseline and frequently during treatment: CBC with differential and platelets, serum creatinine, BUN, LFTs; methotrexate levels and urine pH (with high-dose methotrexate); closely monitor fluid and electrolyte status in patients with impaired methotrexate elimination; chest x-ray (baseline); pulmonary function test (if methotrexate-induced lung disease suspected); monitor carefully for toxicities (due to impaired elimination) in patients with ascites, pleural effusion, decreased folate stores, renal impairment, and/or hepatic impairment

Psoriasis (Kalb 2009; Menter 2009):

CBC with differential and platelets (baseline, 7 to 14 days after initiating therapy or dosage increase, every 2 to 4 weeks for first few months, then every 1 to 3 months depending on leukocyte count and stability of patient) monitor more closely in patients with risk factors for hematologic toxicity (eg, renal insufficiency, advanced age, hypoalbuminemia); BUN and serum creatinine (baseline and every 2 to 3 months) calculate glomerular filtration rate if at risk for renal dysfunction; consider PPD for latent TB screening (baseline); LFTs (baseline, monthly for first 6 months, then every 1 to 2 months; more frequently if at risk for hepatotoxicity or if clinically indicated; liver function tests should be performed at least 5 days after the last dose); chest x-ray (baseline if underlying lung disease); pulmonary function test (if methotrexate-induced lung disease suspected)

Liver biopsy for patients with risk factors for hepatotoxicity: Baseline or after 2 to 6 months of therapy and with each 1 to 1.5 g cumulative dose interval

Liver biopsy for patients without risk factors for hepatotoxicity: If persistent elevations in 5 of 9 AST levels during a 12-month period, or decline of serum albumin below the normal range with normal nutritional status. Consider biopsy after cumulative dose of 3.5 to 4 g and after each additional 1.5 g.

Rheumatoid arthritis:

CBC with differential and platelets, serum creatinine, and LFTs: Baseline and every 2 to 4 weeks for 3 months after initiation or following dose increases, then every 8 to 12 weeks during 3 to 6 months of treatment, followed by every 12 weeks beyond 6 months of treatment; monitor more frequently if clinically indicated (Singh [ACR 2016]).

Chest x-ray (within 1 year prior to initiation), Hepatitis B and C serology (if at high risk); tuberculosis testing annually for patients who live, travel or work in areas with likely TB exposure (Kremer 1994).

Liver biopsy: Baseline (consider only for patients with persistent abnormal baseline LFTs, history of alcoholism, or chronic hepatitis B or C) or during treatment if persistent LFT elevations (6 of 12 tests abnormal over 1 year or 5 of 9 results when LFTs performed at 6-week intervals) (Kremer 1994).

Polyarticular-course juvenile idiopathic arthritis: Complete blood counts (at least monthly), renal function (every 1 to 2 months), liver function (every 1 to 2 months). Increase monitoring frequency during initial dosing, dose changes, or during periods of increased risk of elevated methotrexate blood levels (eg, dehydration). Monitor pulmonary function tests if methotrexate-induced lung disease is suspected, especially if baseline values are available.

Crohn disease (off-label use; Lichtenstein 2009): CBC with differential and platelets (baseline and periodic) and liver function tests (baseline and every 1 to 2 months); baseline liver biopsy (in patients with abnormal baseline LFTs or with chronic liver disease); liver biopsy at 1 year if (over a 1-year span) AST consistently elevated or serum albumin consistently decreased; chest x-ray (baseline)

Tubal ectopic pregnancy (off-label use):

Prior to therapy, serial hCG measurements 2 to 7 days apart along with other procedures to exclude the presence of a viable intrauterine pregnancy (ACOG 193 2018; RCOG [Elson 2016]). CBC with differential, liver function tests, serum creatinine, blood type and Rh (ASRM 2013). Evaluate for medical conditions considered absolute contraindications for methotrexate treatment of ectopic pregnancy (ACOG 193 2018).

Single-dose regimen: Post treatment serum hCG levels on days 4 and 7, if decrease is >15%, continue to measure serum hCG weekly until reaching a non-pregnant level. Consider surgical management if serum hCG does not decrease after two doses. If hCG levels plateau or increase during follow-up period, consider methotrexate for treatment of persistent ectopic pregnancy or surgical management (ACOG 193 2018).

Two-dose regimen: Post treatment serum hCG levels on days 4 and 7, if decrease is >15%, continue to measure serum hCG weekly until reaching a non-pregnant level. Consider surgical management if serum hCG does not decrease after four doses. If hCG levels plateau or increase during follow-up period, consider methotrexate for treatment of persistent ectopic pregnancy or surgical management (ACOG 193 2018).

Multidose regimen (in combination with leucovorin): Measure serum hCG on days of methotrexate administration. Once decrease is >15%, continue to measure serum hCG weekly until reaching a non-pregnant level. Consider surgical management if serum hCG does not decrease after four doses. If hCG levels plateau or increase during follow-up period, consider methotrexate for treatment of persistent ectopic pregnancy or surgical management (ACOG 193 2018).

Reference Range

Therapeutic levels: Variable; Toxic concentration: Variable; therapeutic range is dependent upon therapeutic approach.

High-dose regimens produce drug levels that are between 0.1 to 1 micromole/L 24 to 72 hours after drug infusion

Toxic: Low-dose therapy: >0.2 micromole/L; high-dose therapy: >1 micromole/L

Advanced Practitioners Physical Assessment/Monitoring

Obtain CBC with differential and platelets, serum creatinine, BUN, liver function tests (bilirubin, alkaline phosphatase, and transaminase), pulmonary function tests (if drug-induced lung disease suspected), and chest x-ray. Obtain methotrexate levels and urine pH with high doses. Dosage in the obese should be based on the actual body weight. Assess other medicines patient is taking; alternate therapy or dosage adjustment may be needed. Assess closely for toxicity in patients with ascites, pleural effusion, decreased folate stores, liver impairment, or renal impairment.

Nursing Physical Assessment/Monitoring

Check ordered labs and report any abnormalities. Monitor for and educate patient to report signs of pneumonitis (dry, nonproductive cough), gastrointestinal toxicities (blood in stool or vomit, black, tarry stools, mucositis, or mouth ulcers), dermatological effects (radiation recall and photosensitivity), signs of renal failure (decreased urine output, or dark, tea-colored urine), and signs of liver failure (lethargy, decreased appetite, right upper quadrant pain, or yellowing of skin or eyes).. Instruct patient on importance of limited alcohol intake during treatment.

Product Availability

RediTrex (methotrexate injection): FDA approved November 2019; anticipated availability is currently unknown. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Generic: 250 mg/10 mL (10 mL); 50 mg/2 mL (2 mL)

Solution, Injection [preservative free]:

Generic: 1 g/40 mL (40 mL); 100 mg/4 mL (4 mL [DSC]); 200 mg/8 mL (8 mL [DSC]); 250 mg/10 mL (10 mL); 50 mg/2 mL (2 mL)

Solution, Oral:

Xatmep: 2.5 mg/mL (60 mL, 120 mL) [contains methylparaben sodium, propylparaben sodium]

Solution Auto-injector, Subcutaneous [preservative free]:

Otrexup: 7.5 mg/0.4 mL (0.4 mL [DSC]); 10 mg/0.4 mL (0.4 mL); 12.5 mg/0.4 mL (0.4 mL); 15 mg/0.4 mL (0.4 mL); 17.5 mg/0.4 mL (0.4 mL); 20 mg/0.4 mL (0.4 mL); 22.5 mg/0.4 mL (0.4 mL); 25 mg/0.4mL (0.4 mL)

Rasuvo: 7.5 mg/0.15 mL (0.15 mL); 10 mg/0.2 mL (0.2 mL); 12.5 mg/0.25 mL (0.25 mL); 15 mg/0.3 mL (0.3 mL); 17.5 mg/0.35 mL (0.35 mL); 20 mg/0.4 mL (0.4 mL); 22.5 mg/0.45 mL (0.45 mL); 25 mg/0.5 mL (0.5 mL); 27.5 mg/0.55 mL (0.55 mL [DSC]); 30 mg/0.6 mL (0.6 mL)

Solution Reconstituted, Injection [preservative free]:

Generic: 1 g (1 ea)

Tablet, Oral:

Rheumatrex: 2.5 mg [DSC]

Trexall: 5 mg, 7.5 mg, 10 mg, 15 mg [scored]

Generic: 2.5 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Generic: 5 mg/2 mL (2 mL); 10 mg/mL (2 mL); 25 mg/mL (2 mL, 10 mL, 20 mL, 40 mL, 100 mL, 200 mL)

Solution Prefilled Syringe, Injection:

Metoject: 7.5 mg/0.75 mL (0.75 mL); 10 mg/mL (1 mL); 15 mg/1.5 mL ([DSC]); 25 mg/2.5 mL ([DSC])

Generic: 7.5 mg/0.3 mL (0.3 mL); 10 mg/0.4 mL (0.4 mL); 15 mg/0.6 mL (0.6 mL); 20 mg/0.8 mL (0.8 mL); 25 mg/mL (1 mL)

Solution Prefilled Syringe, Subcutaneous:

Metoject: 10 mg/0.2 mL (0.2 mL); 12.5 mg/0.25 mL (0.25 mL); 15 mg/0.3 mL (0.3 mL); 17.5 mg/0.35 mL (0.35 mL); 20 mg/0.4 mL (0.4 mL); 22.5 mg/0.45 mL (0.45 mL); 25 mg/0.5 mL (0.5 mL)

Tablet, Oral:

Generic: 2.5 mg, 10 mg

Anatomic Therapeutic Chemical (ATC) Classification

• L01BA01
• L04AX03

Generic Available (US)

May be product dependent

Pricing: US

Solution (Methotrexate Sodium (PF) Injection)

1 g/40mL (per mL): $1.00 - $1.20

50 mg/2 mL (per mL): $2.02 - $6.21

250 mg/10 mL (per mL): $1.08 - $1.38

Solution (Methotrexate Sodium Injection)

50 mg/2 mL (per mL): $4.30

250 mg/10 mL (per mL): $4.03

Solution (Xatmep Oral)

2.5 mg/mL (per mL): $19.92

Solution (reconstituted) (Methotrexate Sodium Injection)

1 g (per each): $76.32

Solution Auto-injector (Otrexup Subcutaneous)

10 mg/0.4 mL (per 0.4 mL): $194.94

12.5 mg/0.4 mL (per 0.4 mL): $194.94

15 mg/0.4 mL (per 0.4 mL): $194.94

17.5 mg/0.4 mL (per 0.4 mL): $194.94

20 mg/0.4 mL (per 0.4 mL): $194.94

22.5 mg/0.4 mL (per 0.4 mL): $194.94

25 mg/0.4 mL (per 0.4 mL): $194.94

Solution Auto-injector (Rasuvo Subcutaneous)

7.5 mg/0.15 mL (per 0.15 mL): $147.90

10 mg/0.2 mL (per 0.2 mL): $147.90

12.5 mg/0.25 mL (per 0.25 mL): $147.90

15 mg/0.3 mL (per 0.3 mL): $147.90

17.5 mg/0.35ml (per 0.35 mL): $147.90

20 mg/0.4 mL (per 0.4 mL): $147.90

22.5 mg/0.45ml (per 0.45 mL): $147.90

25 mg/0.5 mL (per 0.5 mL): $147.90

30 mg/0.6 mL (per 0.6 mL): $147.90

Tablets (Methotrexate Oral)

2.5 mg (per each): $3.56 - $6.24

Tablets (Methotrexate Sodium Oral)

2.5 mg (per each): $4.05

Tablets (Trexall Oral)

5 mg (per each): $19.32

7.5 mg (per each): $28.98

10 mg (per each): $38.64

15 mg (per each): $57.97

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. Methotrexate irreversibly binds to and inhibits dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis, thus interfering with DNA synthesis, repair, and cellular replication. Methotrexate is cell cycle specific for the S phase of the cycle. Actively proliferative tissues are more susceptible to the effects of methotrexate.

The mechanism in the treatment of rheumatoid arthritis and polyarticular-course juvenile idiopathic arthritis is unknown, but may affect immune function. In psoriasis, methotrexate is thought to target rapidly proliferating epithelial cells in the skin.

In Crohn disease, it may have immune modulator and anti-inflammatory activity.

Pharmacodynamics/Kinetics

Onset of action: Antirheumatic: 3 to 6 weeks; additional improvement may continue longer than 12 weeks

Absorption:

Oral: Highly variable; dose dependent; decreased absorption at higher doses (pediatric patients: >40 mg/m²; adult patients: >80 mg/m²); possibly due to saturation effect

IM injection: Complete

Distribution: Penetrates slowly into third space fluids (eg, pleural effusions, ascites), exits slowly from these compartments (slower than from plasma); sustained concentrations retained in kidney and liver

V_d: IV: 0.18 L/kg (initial); 0.4 to 0.8 L/kg (steady state)

Protein binding: ~50%

Metabolism: Partially metabolized by intestinal flora (after oral administration) to DAMPA by carboxypeptidase; hepatic aldehyde oxidase converts methotrexate to 7-hydroxy methotrexate; polyglutamates are produced intracellularly and are just as potent as methotrexate; their production is dose- and duration-dependent and they are slowly eliminated by the cell once formed. Polyglutamated forms can be converted back to methotrexate.

Bioavailability: Oral: Children: Highly variable: 23% to 95%; Adults: Low doses (≤30 mg/m²): ~60%; in general, bioavailability is dose dependent and decreases as the dose increases (especially at doses >80 mg/m² [>40 mg/m² in pediatric patients])

Half-life elimination:

Children: ALL: 0.7 to 5.8 hours (dose range: 6.3 to 30 mg/m²); pJIA: 0.9 to 2.3 hours (dose range: 3.75 to 26.2 mg/m²)

Adults: Low dose: 3 to 10 hours; High dose: 8 to 15 hours

Time to peak, serum: Oral: Children: 0.7 to 4 hours (reported for a 15 mg/m² dose); Adults: 0.75 to 6 hours; IM: Children and Adults: 30 to 60 minutes

Excretion: Dose and route dependent; IV: Urine (80% to 90% as unchanged drug; 5% to 7% as 7-hydroxy methotrexate); feces (<10%)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: An increase in serum levels occurs because of decreased elimination in patients with renal function impairment.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Ulcerative stomatitis, gingivitis, glossitis, and mucositis (dose dependent; appears 3-7 days post-therapy and resolves within 2 weeks). Dental professionals should note before prescribing NSAIDS that concurrent administration with methotrexate may cause severe bone marrow suppression, aplastic anemia, and GI toxicity (see Warnings/Precautions). Although the risk is lower at the methotrexate dosages used for rheumatoid conditions/psoriasis, the addition of an NSAID or salicylate may still lead to unexpected toxicities; caution is warranted.

Effects on Bleeding

Suppression of hematopoiesis may cause myelosuppression including thrombocytopenia. Medical consult recommended.

Related Information

• Common Toxicity Criteria
• Management of Chemotherapy-Induced Nausea and Vomiting in Adults
• Narrow Therapeutic Index Drugs
• Prevention of Chemotherapy-Induced Nausea and Vomiting in Children
• Safe Handling of Hazardous Drugs

Index Terms

Amethopterin; Methotrexate Sodium; Methotrexatum; MTX (error-prone abbreviation)

FDA Approval Date

March 03, 1982

References

Adès L, Sanz MA, Chevret S, et al, “Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL): A Comparison of French-Belgian-Swiss and PETHEMA Results,” Blood, 2008, 111(3):1078-84.[PubMed 17975017]

Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319.[PubMed 11487763]

Alfadhli AA, McDonald JW, and Feagan BG, “Methotrexate for Induction of Remission in Refractory Crohn's Disease,” Cochrane Database Syst Rev, 2005, 25(1):CD003459.[PubMed 15674908]

Al-Hasani H, Roussou E. Methotrexate for rheumatoid arthritis patients who are on hemodialysis. Rheumatol Int. 2011;31(12):1545-1547. doi: 10.1007/s00296-011-2041-5.[PubMed 21833520]

American College of Obstetricians and Gynecologists (ACOG). Practice bulletin no. 143: medical management of first-trimester abortion. Obstet Gynecol. 2014;123(3):676-692. doi: 10.1097/01.AOG.0000444454.67279.7d.[PubMed 24553166]

American College of Obstetricians and Gynecologists (ACOG). Practice bulletin no. 193: tubal ectopic pregnancy. Obstet Gynecol. 2018;131(3):e91-e103. doi: 10.1097/AOG.0000000000002560.[PubMed 29470343]

American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002;46(2):328–346.[PubMed 11840435]

APO-Methotrexate (methotrexate) [product monograph]. Toronto, Ontario, Canada: Apotex Inc; August 2019.

Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 101.

Asselin BL, Devidas M, Wang C, et al. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood. 2011;118(4):874-883. doi: 10.1182/blood-2010-06-292615.[PubMed 21474675]

Azzarelli A, Gronchi A, Bertulli R, et al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer. 2001;92(5):1259-1264.[PubMed 11571741]

Bacci G, Briccoli A, Rocca M, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003;14(7):1126-1134.[PubMed 12853357]

Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000;18(24):4016-4027. doi: 10.1200/JCO.2000.18.24.4016.[PubMed 11118462]

Baker T, Datta P, Rewers-Felkins K, Hale TW. High-dose methotrexate treatment in a breastfeeding mother with placenta accreta: a case report. Breastfeed Med. 2018;13(6):450-452. doi: 10.1089/bfm.2018.0078.[PubMed 29985651]

Bamias A, Aravantinos G, Deliveliotis C, et al; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group [published correction appears in J Clin Oncol. 2004;22(9):1771]. J Clin Oncol. 2004;22(2):220-228. doi: 10.1200/JCO.2004.02.152.[PubMed 14665607]

Barnhart KT. Clinical practice. Ectopic pregnancy. N Engl J Med. 2009;361(4):379-87. doi: 10.1056/NEJMcp0810384.[PubMed 19625718]

Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol. 2003;101(4):778-784.[PubMed 12681886]

Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of "2-dose" regimen of methotrexate to treat ectopic pregnancy. Fertil Steril. 2007;87(2):250-256. doi: 10.1016/j.fertnstert.2006.06.054.[PubMed 17097649]

Bartz D, Goldberg A. Medication abortion. Clin Obstet Gynecol. 2009;52(2):140-150. doi: 10.1097/GRF.0b013e3181a2b026.[PubMed 19407520]

Basile C, Montanaro A, Semeraro A. Should low-dose methotrexate therapy be prescribed to dialysis patients? Nephrol Dial Transplant. 2002;17(3):530-531. doi: 10.1093/ndt/17.3.530.[PubMed 11865117]

Batchelor T, Carson K, O'Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21(6):1044-1049. doi: 10.1200/JCO.2003.03.036.[PubMed 12637469]

Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17(1):60-66.[PubMed 10746262]

Bernstein SH, Epner E, Unger JM, et al. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Ann Oncol. 2013;24(6):1587-1593. doi: 10.1093/annonc/mdt070.[PubMed 23504948]

Bezabeh S, Mackey AC, Kluetz P, Jappar D, Korvick J. Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors. Oncologist. 2012;17(4):550-554.[PubMed 22477728]

Bielack SS, Smeland S, Whelan JS, et al. Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. J Clin Oncol. 2015;33(20):2279-2287.[PubMed 26033801]

Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978;41(1):36-51.[PubMed 342086]

Bleyer WA. Therapeutic monitoring of methotrexate and other antineoplastic drugs. In: Baer DM, Dita WR, eds. Interpretations in Therapeutic Drug Monitoring. Chicago, IL: American Society of Clinical Pathology; 1981:169-181.

Bleyer WA, Coccia PF, Sather HN, et al. Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncol. 1983;1(5):317-325. doi: 10.1200/JCO.1983.1.5.317.[PubMed 6366138]

Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332(14):901-906. doi: 10.1056/NEJM199504063321401.[PubMed 7877646]

Braun J, Kästner P, Flaxenberg P, et al; MC-MTX.6/RH Study Group. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;58(1):73-81. doi: 10.1002/art.23144.[PubMed 18163521]

Briemberg HR, Amato AA. Dermatomyositis and polymyositis. Curr Treat Options Neurol. 2003;5(5):349-356.[PubMed 12895397]

Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood. 2007;109(7):2736-2743.[PubMed 17138821]

Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm[PubMed 6810084]

Chamberlain MC. Leptomeningeal metastasis. Curr Opin Oncol. 2010;22(6):627-635. doi: 10.1097/CCO.0b013e32833de986.[PubMed 20689429]

Chang SS, Bochner BH, Chou R, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017;198(3):552-559.[PubMed 28456635]

Chao NJ, Schmidt GM, Niland JC, et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med. 1993;329(17):1225-1230. doi: 10.1056/NEJM199310213291703.[PubMed 8413388]

Chao NJ, Snyder DS, Jain M, et al. Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: results of a prospective double-blind randomized trial. Biol Blood Marrow Transplant. 2000;6(3):254-261.[PubMed 10871150]

Chi SN, Gardner SL, Levy AS, et al. Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol. 2004;22(24):4881-4887.[PubMed 15611503]

Choueiri TK, Jacobus S, Bellmunt J, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014;32(18):1889-1894.[PubMed 24821883]

Costescu D, Guilbert E, Bernardin J, et al; Society of Obstetricians and Gynecologists of Canada. Medical abortion. J Obstet Gynaecol Can. 2016;38(4):366-389. doi: 10.1016/j.jogc.2016.01.002.[PubMed 27208607]

Creinin MD, Vittinghoff E, Keder L, Darney PD, Tiller G. Methotrexate and misoprostol for early abortion: a multicenter trial. I. Safety and efficacy. Contraception. 1996;53(6):321-327.[PubMed 8773418]

Cremers JP, Drent M, Bast A, et al. Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide. Curr Opin Pulm Med. 2013;19(5):545-561. doi: 10.1097/MCP.0b013e3283642a7a.[PubMed 23880702]

Csordas K, Hegyi M, Eipel OT, Muller J, Erdelyo DJ, Kovacs GT. Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia. Anticancer Drugs. 2013;24(2):189-197. doi: 10.1097/CAD.0b013e32835b8662.[PubMed 23187460]

Dadlani C, Orlow SJ. Treatment of children and adolescents with methotrexate, cyclosporine, and etanercept: review of the dermatologic and rheumatologic literature. J Am Acad Dermatol. 2005;52:316-340.[PubMed 15692480]

Dassopoulos T, Sultan S, Falck-Ytter YT, Inadomi JM, Hanauer SB. American Gastroenterological Association Institute technical review on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. 2013;145(6):1464-1478. doi: 10.1053/j.gastro.2013.10.046.[PubMed 24267475 ]

Delaney S, Colantonio D, Ito S. 57th Annual Teratology Society Meeting. Methotrexate in breast milk. Birth Defects Res. 2017;109(9):579-718. doi: 10.1002/bdr2.1061.[PubMed 28503765]

de Lemos ML, Monfared S, Denyssevych T, et al. Evaluation of osmolality and pH of various concentrations of methotrexate, cytarabine, and thiotepa prepared in normal saline, sterile water for injection, and lactated Ringer's solution for intrathecal administration. J Oncol Pharm Pract. 2009;15(1):45-52. doi: 10.1177/1078155208096902.[PubMed 18772215]

deJager MEA, deJong EMGJ, van de Kerkhof PCM, et al. Efficacy and safety of treatments for childhood psoriasis: a systematic literature review. J Am Acad Dermatol. 2010;62:1013-1030.[PubMed 19900732]

DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2012;64(7):1001-1010.[PubMed 22290637]

Díaz-Llopis M, Gallego-Pinazo R, García-Delpech S, Salom-Alonso D. General principles for the treatment of non-infectious uveitis. Inflamm Allergy Drug Targets. 2009;8(4):260-265.[PubMed 19754409]

Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB. Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease. Am J Med Sci. 2006;332(3):156-158. doi: 10.1097/00000441-200609000-00013.[PubMed 16969149]

Dreyer ZE, Hilden JM, Jones TL, et al. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015;62(3):419-426.[PubMed 25399948]

Duffner PK, Armstrong FD, Chen L, et al. Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group. J Pediatr Hematol Oncol. 2014;36(1):8-15. doi: 10.1097/MPH.0000000000000000.[PubMed 24345882]

Dupuis LL, Boodhan S, Sung L, et al; Pediatric Oncology Group of Ontario. Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2011;57(2):191-198.[PubMed 21465637]

Egan LJ, Sandborn WJ, Tremaine WJ, et al. A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther. 1999;13(12):1597-1604.[PubMed 10594394]

Elson CJ, Salim R, Potdar N, Chetty M, Ross JA, Kirk EJ on behalf of the Royal College of Obstetricians and Gynaecologists (RCOG). Diagnosis and Management of Ectopic Pregnancy: Green-top Guideline No. 21 [published correction appears in BJOG. 2017;124(13):e314]. BJOG. 2016;123(13):e15-e55. doi: 10.1111/1471-0528.14189.[PubMed 27813249]

Escobar PF, Lurain JR, Singh DK, Bozorgi K, Fishman DA. Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy. Gynecol Oncol. 2003;91(3):552-557.[PubMed 14675675]

Evans WE, Pratt CB, Taylor RH, et al, “Pharmacokinetic Monitoring of High-Dose Methotrexate: Early Recognition of High-Risk Patients,” Cancer Chemother Pharmacol, 1979, 3:161-6.[PubMed 316744]

Feagan BG, Fedorak RN, Irvine EJ, et al, “A Comparison of Methotrexate With Placebo for the Maintenance of Remission in Crohn's Disease. North American Crohn's Study Group Investigators,” N Engl J Med, 2000, 342(22):1627-32.[PubMed 10833208]

Feldman BM, Rider LG, Reed AM, et al. Juvenile Dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet. 2008;371(9631):2201-2212.[PubMed 18586175]

Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999; 94(4):1192-1200.[PubMed 10438706]

Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol. 2005;23(34):8845-8852.[PubMed 16246977]

Flint J, Panchal S, Hurrell A, et al; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding - Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2016;55(9):1693-1697. doi: 10.1093/rheumatology/kev404.[PubMed 26750124]

Floyd J, Mirza I, Sachs B, et al, “Hepatotoxicity of Chemotherapy,” Semin Oncol, 2006, 33(1):50-67.[PubMed 16473644]

Floyd JD, Nguyen DT, Lobins RL, et al, “Cardiotoxicity of Cancer Therapy,” J Clin Oncol, 2005, 23(30):7685-96.[PubMed 16234530]

Foeldvari I, Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2005;32(2):362-365.[PubMed 15693100]

Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992;10(8):1245-1251.[PubMed 1634913]

Fortin PR, Abrahamowicz M, Ferland D, et al. Steroid-sparing effects of methotrexate in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2008;59(12):1796-1804.[PubMed 19035431]

Fritsch K, Kasenda B, Schorb E, et al. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017;31(4):846-852. doi: 10.1038/leu.2016.334.[PubMed 27843136]

Gahart BL and Nazareno AR, 2014 Intravenous Medications: A Handbook for Nurses and Health Professionals, 30th ed, St Louis, MO: Elsevier/Mosby, 2014, 780-785.

Galor A, Jabs DA, Leder HA, et al. Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology. 2008;115(10):1826-1832.[PubMed 18579209]

Gangaputra S, Newcomb CW, Liesegang TL, et al; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009;116(11):2188-2198.e1.[PubMed 19748676]

Garrett AP, Garner EO, Goldstein DP, Berkowitz RS. Methotrexate infusion and folinic acid as primary therapy for nonmetastatic and low-risk metastatic gestational trophoblastic tumors. 15 years of experience. J Reprod Med. 2002;47(5):355-362.[PubMed 12063874]

Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2006;24(28):4570-4574.[PubMed 17008697]

Gerber DE, Grossman SA, Batchelor T, Ye X. Calculated versus measured creatinine clearance for dosing methotrexate in the treatment of primary central nervous system lymphoma. Cancer Chemother Pharmacol. 2007;59(6):817-823. doi: 10.1007/s00280-006-0339-x.[PubMed 16972068]

Ghaemmaghami F, Modares M, Arab M, et al. EMA-EP regimen, as firstline multiple agent chemotherapy in high-risk GTT patients (stage II-IV). Int J Gynecol Cancer. 2004;14(2):360-365. doi: 10.1111/j.1048-891X.2004.014222.x.[PubMed 15086738]

Glantz MJ, Cole BF, Recht L, Akerley W, et al, “High-Dose Intravenous Methotrexate for Patients With Nonleukemic Leptomeningeal Cancer: Is Intrathecal Chemotherapy Necessary?” J Clin Oncol, 1998;16(4):1561-1567.[PubMed 9552066]

Glantz MJ, Jaeckle KA, Chamberlain MC, et al, “A Randomized Controlled Trial Comparing Intrathecal Sustained-Release Cytarabine (DepoCyt) to Intrathecal Methotrexate in Patients With Neoplastic Meningitis from Solid Tumors,” Clin Cancer Res, 1999, 5(11):3394-402.[PubMed 10589750]

Glass J, Won M, Schultz CJ, et al. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227. J Clin Oncol. 2016;34(14):1620-1625. doi: 10.1200/JCO.2015.64.8634.[PubMed 27022122]

Goldman S, Smith L, Anderson JR, et al. Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children's Oncology Group report. Leukemia. 2013;27(5):1174-1177.[PubMed 22940833]

Goldman S, Smith L, Galardy P, et al. Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children's Oncology Group Report. Br J Haematol. 2014;167(3):394-401.[PubMed 25066629]

Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical Chemotherapy Compared With Immediate Surgery and Adjuvant Chemotherapy for Nonmetastatic Osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol. 2003;21(8):1574-1580.[PubMed 12697883]

Grem JL, King SA, Wittes RE, et al, “The Role of Methotrexate in Osteosarcoma,” J Natl Cancer Inst, 1988, 80(9):626-55.[PubMed 3286880]

Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171-2177.[PubMed 21502557]

Griggs JJ, Mangu PB, Anderson H, et al, “Appropriate Chemotherapy Dosing For Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline,” J Clin Oncol, 2012, 30(13):1553-61.[PubMed 22473167]

Grossman SA, Finkelstein DM, Ruckeschel JC, et al, “Randomized Prospective Comparison of Intraventricular Methotrexate and Thiotepa in Patients With Previously Untreated Neoplastic Meningitis. Eastern Cooperative Oncology Group,” J Clin Oncol, 1993, 11(3):561-9.[PubMed 8445432]

Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866.[PubMed 12944571]

Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer. 2004;40(14):2071-2076.[PubMed 15341981]

“Guidelines for Referral and Management of Systemic Lupus Erythematosus in Adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines,” Arthritis Rheum, 1999, 42(9):1785-96.[PubMed 10513791]

Hoang-Xuan K, Taillandier L, Chinot O, et al, “Chemotherapy Alone as Initial Treatment for Primary CNS Lymphoma in Patients Older Than 60 Years: A Multicenter Phase II Study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group,” J Clin Oncol, 2003, 21(14):2726-31.[PubMed 12860951]

Hoffman GS, Leavitt RY, Kerr GS, et al, "Treatment of Glucocorticoid-Resistant or Relapsing Takayasu Arteritis With Methotrexate," Arthritis Rheum, 1994, 37(4):578-82.[PubMed 7908520]

Huber AM, Giannini EH, Bowyer SL, et al. Protocols for the initial treatment of moderately severe juvenile dermatomyositis: results of a Children's Arthritis and Rheumatology Research Alliance Consensus Conference. Arthritis Care Res (Hoboken). 2010;62(2):219-225.[PubMed 20191521]

Illerhaus G, Marks R, Ihorst G, et al. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006;24(24):3865-3870.[PubMed 16864853]

"Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278.[PubMed 9024461]

Institute for Safe Medication Practices. 2018-2019 Targeted Medication Safety Best Practices for Hospitals. Available at https://www.ismp.org/sites/default/files/attachments/2019-01/TMSBP-for-Hospitalsv2.pdgf. Accessed April 22, 2019.

Ito S. Drug therapy for breast-feeding women [published correction appears in N Engl J Med 2000;343(18):1348]. N Engl J Med. 2000;343(2):118-126. doi: 10.1056/NEJM200007133430208.[PubMed 10891521]

Jacobson JO, Polovich M, McNiff KK, et al; American Society of Clinical Oncology; Oncology Nursing Society. American Society Of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards. J Clin Oncol. 2009;27(32):5469-5475. doi: 10.1200/JCO.2009.25.1264.[PubMed 19786650]

Janus N, Thariat J, Boulanger H, Deray G, Launay-Vacher V. Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol. 2010;21(7):1395-1403. doi: 10.1093/annonc/mdp598.[PubMed 20118214]

Joffe MM, Love LA, Leff RL, et al. Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy. Am J Med. 1993;94(4):379-387.[PubMed 8386437]

Johns DG, Rutherford LD, Leighton PC, Vogel CL. Secretion of methotrexate into human milk. Am J Obstet Gynecol. 1972;112(7):978-980.[PubMed 5042796]

Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med. 1983;309(18):1094-1104. doi: 10.1056/NEJM198311033091805.[PubMed 6353235]

Jones HE, O'Connell White K, Norman WV, Guilbert E, Lichtenberg ES, Paul M. First trimester medication abortion practice in the United States and Canada. PLoS One. 2017;12(10):e0186487. doi: 10.1371/journal.pone.0186487.[PubMed 29023594]

Judson MA. The treatment of pulmonary sarcoidosis. Respir Med. 2012;106(10):1351-1361. doi: 10.1016/j.rmed.2012.01.013.[PubMed 22495110]

Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol. 2009;60(5):824-837. doi: 10.1016/j.jaad.2008.11.906.[PubMed 19389524]

Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18(3): 547-561.[PubMed 10653870]

Kaplan-Messas A, Barkana Y, Avni I, Neumann R. Methotrexate as a first-line corticosteroid-sparing therapy in a cohort of uveitis and scleritis. Ocul Immunol Inflamm. 2003;11(2):131-139.[PubMed 14533032]

Kerr JZ, Berg S, Blaney SM. Intrathecal chemotherapy. Crit Rev Oncol Hematol. 2001;37(3):227-236.[PubMed 11248578]

Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD and High-Dose Methotrexate/Cytarabine Followed by Stem-Cell Transplantation: An Active Regimen for Aggressive Mantle-Cell Lymphoma. J Clin Oncol. 1998;16(12):3803-3809. doi: 10.1200/JCO.1998.16.12.3803.[PubMed 9850025]

Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev. 1995;21(1):33-64.[PubMed 7859226]

Kliegman RM, Stanton BF, St. Gemell JW, et al, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Saunders Elsevier; 2011.

Kremer JM, Alarcón GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum. 1994;37(3):316-328.[PubMed 8129787]

Lacasce A, Howard O, Lib S, et al. Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Leuk Lymphoma. 2004;45(4):761-767. doi: 10.1080/1042819031000141301.[PubMed 15160953]

Lamb CA, Kennedy NA, Raine T, et al; IBD guidelines eDelphi consensus group. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(suppl 3):s1-s106. doi: 10.1136/gutjnl-2019-318484.[PubMed 31562236]

Langford CA, Talar-Williams C, Barron KS, Sneller MC. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse. Am J Med. 2003;114(6):463-469.[PubMed 12727579]

Larsen EC, Devidas M, Chen S, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group Study AALL0232. J Clin Oncol. 2016;34(20):2380-2388.[PubMed 27114587]

Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995;85(8):2025-2037.[PubMed 7718875 ]

Lauer SJ, Camitta BM, Leventhal BG, et al. Intensive alternating drug pairs for treatment of high-risk childhood acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study. Cancer. 1993;71(9):2854-2861.[PubMed 8467463]

Le Deley MC, Guinebretière JM, Gentet JC, et al. SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007;43(4):752-761.[PubMed 17267204]

Lee SL, Neskey D, Mouzakes J. Potential predisposition for nasal septal perforation with methotrexate use: report of 2 cases and literature review. Ear Nose Throat J. 2009;88(8):E12-E14.[PubMed 19688702]

Lehmann J, Franzaring L, Thuroff J, et al. Complete long-term survival data from a trial of adjuvant chemotherapy vs. control after radical cystectomy for locally advanced bladder cancer. BJU Int. 2006;97(1):42-47.[PubMed 16336326]

Levine MN, Bramwell VH, Pritchard KI, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998;16(8):2651-2658. doi: 10.1200/JCO.1998.16.8.2651.[PubMed 9704715]

Li SC, Torok KS, Pope E, et al. Development of consensus treatment plans for juvenile localized scleroderma: a roadmap toward comparative effectiveness studies in juvenile localized scleroderma. Arthrit Care Res. 2012;64(8):1175-1185.[PubMed 22505322]

Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn's disease in adults. Am J Gastroenterol. 2018;113(4):481-517. doi: 10.1038/ajg.2018.27.[PubMed 29610508]

Lichtman SM, Cirrincione CT, Hurria A, et al. Effect of pretreatment renal function on treatment and clinical outcomes in the adjuvant treatment of older women with breast cancer: alliance A171201, an Ancillary Study of CALGB/CTSU 49907. J Clin Oncol. 2016;34(7):699-705. doi: 10.1200/JCO.2015.62.6341.[PubMed 26755510]

Lin WY, Liu HC, Yeh TC, Wang LY, Liang DC. Triple intrathecal therapy without cranial irradiation for central nervous system preventive therapy in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2008;50(3):523-527. doi: 10.1002/pbc.21212.[PubMed 17455314]

Lopez-Oilvo MA, Tayar JH, Martinez-Lopez JA, et al, “Risk of Malignancies in Patients With Rheumatoid Arthritis Treated With Biologic Therapy: A Meta-Analysis,” JAMA, 2012, 308(9): 898-908.[PubMed 22948700]

Lurain JR, Singh DK, Schink JC. Primary treatment of metastatic high-risk gestational trophoblastic neoplasia with EMA-CO chemotherapy. J Reprod Med. 2006;51(10):767-772.[PubMed 17086804]

Mack DR, Young R, Kaufman SS, et al. Methotrexate in patients with Crohn’s disease after --mercaptopurine. J Pediatr. 1998;132:830-835.[PubMed 9602195]

Magrath I, Adde M, Shad A, et al. Adults and Children With Small Non-Cleaved-Cell Lymphoma Have a Similar Excellent Outcome When Treated With the Same Chemotherapy Regimen. J Clin Oncol. 1996;14(3):925-934.[PubMed 8622041]

Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group. Am J Obstet Gynecol. 2019;220(4):308-323. doi: 10.1016/j.ajog.2019.02.027.[PubMed 30948039]

Mahoney DH Jr, Shuster JJ, Nitschke R, et al. Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol. 2000;18(6):1285-1294.[PubMed 10715299]

Marina N, Gebhardt M, Teot L, et al. Biology and therapeutic advances for pediatric osteosarcomas. Oncologist. 2004;9(4):422-441.[PubMed 16266096]

Matloub Y, Lindemulder S, Gaynon PS, et al. Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group. Blood. 2006;108(4):1165-1173.[PubMed 16609069]

Matzkies FK, Tombach B, Dietrich M, et al. MVAC-therapy for advanced urothelial carcinoma in an anuric renal transplant recipient. Nephrol Dial Transplant. 2000;15(1):110-112. doi: 10.1093/ndt/15.1.110.[PubMed 10607779]

McGrath ER, Doughty CT, Amato AA. Autoimmune Myopathies: Updates on Evaluation and Treatment. Neurotherapeutics. 2018;15(4):976-994. doi: 10.1007/s13311-018-00676-2.[PubMed 30341597]

Mead GM, Barrans SL, Qian W, et al. A Prospective Clinicopathologic Study of Dose-Modified CODOX-M/IVAC in Patients With Sporadic Burkitt Lymphoma Defined Using Cytogenetic and Immunophenotypic Criteria (MRC/NCRI LY10 Trial). Blood.2008;112(6):2248-2260.[PubMed 18612102]

Mead GM, Sydes MR, Walewski J, et al. An International Evaluation of CODOX-M and CODOX-M Alternating With IVAC in Adult Burkitt's Lymphoma: Results of United Kingdom Lymphoma Group LY06 Study. Ann Oncol. 2002;13(8):1264-1274.[PubMed 12181251]

Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451-485. doi: 10.1016/j.jaad.2009.03.027.[PubMed 19493586]

Mergenthal MC, Senapati S, Zee J, et al. Medical management of ectopic pregnancy with single-dose and 2-dose methotrexate protocols: human chorionic gonadotropin trends and patient outcomes. Am J Obstet Gynecol. 2016;215(5):590.e1-590.e5. doi: 10.1016/j.ajog.2016.06.040.[PubMed 27371354]

Methotrexate injection [prescribing information]. Eatontown, NJ: West-Ward Pharmaceuticals; August 2019.

Methotrexate injection [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; July 2019.

Methotrexate tablets [prescribing information]. Morgantown WV: Mylan Pharmaceuticals Inc; May 2018.

Methotrexate tablets [prescribing information]. Kirkland, Quebec, Canada: Pfizer Canada ULC; September 2019.

Metoject solution for injection (methotrexate sodium) [product monograph]. Bolton, Ontario, Canada: Medexus Inc; December 2019.

Meyers PA, Heller G, Healey J, et al. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol. 1992;10(1):5-15.[PubMed 1370176]

Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005;23(9):2004-2011.[PubMed 15774791]

Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group. J Clin Oncol. 2008;26(4):633-638.[PubMed 18235123]

Miller ML. Initial treatment of dermatomyositis and polymyositis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 10, 2019.

Morgan C, Tillett T, Braybrooke J, Ajithkumar T. Management of uncommon chemotherapy-induced emergencies. Lancet Oncol. 2011;12(8):806-814. doi: 10.1016/S1470-2045(10)70208-4.[PubMed 21276754]

Morris PG, Correa DD, Yahalom J, et al. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol. 2013;31(31):3971-3979. doi: 10.1200/JCO.2013.50.4910.[PubMed 24101038]

Muñoz-Fernández S, García-Aparicio AM, Hidalgo MV, et al. Methotrexate: an option for preventing the recurrence of acute anterior uveitis. Eye (Lond). 2009;23(5):1130-1133.[PubMed 18688259]

Murashima M, Adamski J, Milone MC, Shaw L, Tsai DE, Bloom RD. Methotrexate clearance by high-flux hemodialysis and peritoneal dialysis: a case report. Am J Kidney Dis. 2009;53(5):871-874. doi: 10.1053/j.ajkd.2009.01.016.[PubMed 19339090]

Mutsando H, Fahim M, Gill DS, et al. High dose methotrexate and extended hours high-flux hemodialysis for the treatment of primary central nervous system lymphoma in a patient with end stage renal disease. Am J Blood Res. 2012;2(1):66-70.[PubMed 22432089]

Nash R, Antin J, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-vs-host disease after marrow transplantation from unrelated donors. Blood. 2000;96(6):2062-2068.[PubMed 10979948]

Nathan DM, Iser JH, and Gibson PR. A single center experience of methotrexate in the treatment of Crohn's disease and ulcerative colitis: a case for subcutaneous administration. Gastroenterol, 2008;23(6):954-958.[PubMed 17559377]

National Comprehensive Cancer Network (NCCN)®, "Clinical Practice Guidelines in Oncology™: Central Nervous System Cancers," Version 2.2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf.

Newlands ES, Mulholland PJ, Holden L, Seckl MJ, Rustin GJ. Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors. J Clin Oncol. 2000;18(4):854-859. doi: 10.1200/JCO.2000.18.4.854.[PubMed 10673528]

Newman ED and Scott DW, “The Use of Low-dose Oral Methotrexate in the Treatment of Polymyositis and Dermatomyositis,” J Clin Rheumatol, 1995, 1(2):99-102.[PubMed 19077954]

Nguyen GC, Seow CH, Maxwell C, et al; IBD in Pregnancy Consensus Group; Canadian Association of Gastroenterology. The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy. Gastroenterology. 2016;150(3):734-757.e1. doi: 10.1053/j.gastro.2015.12.003.[PubMed 26688268]

Oddis CV. Update on the pharmacological treatment of adult myositis. J Intern Med. 2016;280(1):63-74. doi: 10.1111/joim.12511.[PubMed 27098592]

Omuro A, Correa DD, DeAngelis LM, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015;125(9):1403-1410. doi: 10.1182/blood-2014-10-604561.[PubMed 25568347]

Ortega JJ, Madero L, Martín G, et al; PETHEMA Group. Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol. 2005;23(30):7632-7640.[PubMed 16234524]

Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. Am J Obstet Gynecol. 1986;154(6):1299-1306.[PubMed 2940870]

Otrexup (methotrexate injection) [prescribing information]. Ewing, NJ: Antares Pharma Inc; December 2019.

Otrexup PFS (methotrexate injection prefilled syringe) [prescribing information]. Ewing, NJ: Antares Pharma Inc; December 2019.

Pagnoux C, Mahr A, Hamidou MA, et al; French Vasculitis Study Group. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359(26):2790-2803. doi: 10.1056/NEJMoa0802311.[PubMed 19109574]

Patel V, Wang Y, MacDonald JK, et al. Methotrexate for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2014;(8):CD006884. doi: 10.1002/14651858.[PubMed 25157445]

Paw Cho Sing E, Robinson PD, Flank J, et al. Classification of the acute emetogenicity of chemotherapy in pediatric patients: A clinical practice guideline. Pediatr Blood Cancer. 2019;66(5):e27646. doi: 10.1002/pbc.27646.[PubMed 30729654]

Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370(9583):240-250.[PubMed 17658395]

Pistilli B, Bellettini G, Giovannetti E, et al. Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: how should we counsel cancer patients about breastfeeding? Cancer Treat Rev. 2013;39(3):207-211. doi: 10.1016/j.ctrv.2012.10.002.[PubMed 23199900]

Plimack ER, Hoffman-Censits JH, Viterbo R, et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014;32(18):1895-1901. doi: 10.1200/JCO.2013.53.2465.[PubMed 24821881]

Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, et al; European Organization for Research and Treatment of Cancer Lymphoma Group. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J Clin Oncol. 2003;21(24):4483-4488. doi: 10.1200/JCO.2003.03.108.[PubMed 14597741]

Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116(19):3751-3757. doi: 10.1182/blood-2010-02-269621.[PubMed 20705755]

Practice Committee of American Society for Reproductive Medicine (ASRM). Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril. 2013;100(3):638-644. doi: 10.1016/j.fertnstert.2013.06.013.[PubMed 23849842]

Rademaker M, Agnew K, Andrews M, et al. Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis Collaboration. Australas J Dermatol. 2018;59(2):86-100. doi: 10.1111/ajd.12641.[PubMed 28543445]

Ramanan AV, Campbell-Webster N, Ota S, et al. The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis Rheum. 2005;52(11):3570-3578.[PubMed 16255046]

Rasuvo (methotrexate) [prescribing information]. Chicago, IL: Medac Pharma Inc; March 2018.

Reiter A, Schrappe M, Tiemann M, et al. Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood. 1999;94(10):3294-3306.[PubMed 10552938]

Rizzieri DA, Johnson JL, Niedzwiecki D, et al. Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer. 2004;100(7):1438-1448.[PubMed 15042678]

Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):S119-S133.[PubMed 27664248]

Ross M, Schmidt GM, Niland JC, et al. Cyclosporine, Methotrexate, and Prednisone Compared With Cyclosporine and Prednisone for Prevention of Acute Graft-vs.-Host Disease: Effect on Chronic Graft-vs.-Host Disease and Long-Term Survival. Biol Blood Marrow Transplant. 1999;5(5):285-291.[PubMed 10534058]

Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31(25):3061-3068. doi: 10.1200/JCO.2012.46.9957.[PubMed 23569323]

Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr. 2012;55(1):93-108.[PubMed 22516861]

Ruperto N, Pistorio A, Oliveira S, et al. Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial. Lancet. 2016;387(10019):671-678.[PubMed 26645190]

Ruutu T, Gratwohl A, de Witte T, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2013;49(2):168-173.[PubMed 23892326]

Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008;59(6):762-784.[PubMed 18512708]

Sandhu BK, Fell JME, Beattie RM, et al. Guidelines for the management of inflammatory bowel disease in children in the United Kingdom. JPGN. 2010;50:S1-S13.[PubMed 20081543]

Sanz MA, Martin G, Gonzalez M, et al. Risk-Adapted Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid and Anthracycline Monochemotherapy: A Multicenter Study by the PETHEMA Group. Blood. 2004;103(4):1237-1243.[PubMed 14576047]

Sauer MV, Gorrill MJ, Rodi IA, et al. Nonsurgical management of unruptured ectopic pregnancy: an extended clinical trial. Fertil Steril. 1987;48(5):752-755.[PubMed 2444463]

Schleuning M, Clemm C. Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. N Engl J Med. 1987;317(26):1666-1667.[PubMed 3479687]

Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000;95(11):3310-3322.[PubMed 10828010]

Schutt AC, Bullington WM, Judson MA. Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study. Respir Med. 2010;104(5):717-723. doi: 10.1016/j.rmed.2009.12.009.[PubMed 20089389]

Schwartz S, Borner K, Muller K, et al, “Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients With Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy,” Oncologist, 2007 12(11):1299-308.[PubMed 18055849]

Seeber BE and Barnhart KT, “Suspected Ectopic Pregnancy,” Obstet Gynecol, 2006, 107(2 Pt 1):399-413.[PubMed 16449130]

Seibel NL, Steinherz PG, Sather HN, et al. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008;111(5):2548-2555.[PubMed 18039957]

Seidemann K, Tiemann M, Schrappe M, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood. 2001;97(12):3699-3706.[PubMed 11389005]

Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25(30):4730-4735.[PubMed 17947720]

Simonini G, Cantarini L, Bresci C, Lorusso M, Galeazzi M, Cimaz R. Current therapeutic approaches to autoimmune chronic uveitis in children. Autoimmun Rev. 2010;9(10):674-683.[PubMed 20553975]

Simonini G, Paudyal P, Jones GT, et al. Current evidence of methotrexate efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach. Rheumatol. 2013;52:825-831.[PubMed 22879466]

Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(1):1-26.[PubMed 26545940]

Song T, Kim MK, Kim ML, Jung YW, Yun BS, Seong SJ. Single-dose versus two-dose administration of methotrexate for the treatment of ectopic pregnancy: a randomized controlled trial. Hum Reprod. 2016;31(2):332-338. doi: 10.1093/humrep/dev312.[PubMed 26701971]

Sternberg CN, de Mulder P, Schornagel JH, et al; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50-54. doi: 10.1016/j.ejca.2005.08.032.[PubMed 6330205]

Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924. J Clin Oncol. 2001;19(10):2638-2646.[PubMed 11352955]

Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27(11):1864-1871.[PubMed 19289630]

Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol. 1993;168(6, pt 1):1759-1762; discussion 1762-5.[PubMed 8317518]

Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril. 1989;51(3):435-438.[PubMed 2784113]

Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol. 1991;77(5):754-757.[PubMed 2014091]

Stringer E, Bohnsack J, Bowyer SL, et al. Treatment approaches to juvenile dermatomyositis (JDM) across North America: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Treatment Survey. J Rheumatol. 2010;37(9):1953-1961.[PubMed 20595275]

Tanaka T, Walsh W, Verjee Z et al. Methotrexate use in a lactating woman with an ectopic pregnancy. Abstracts of the 49th Annual Meeting of the Teratology Society, 2009, Rio Grande, Puerto Rico. Birth Defects Res A Clin Mol Teratol. 2009; 85(5):494.[PubMed 19475580]

Terdiman JP, Gruss CB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. 2013;145(6):1459-1463.[PubMed 24267474]

Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106(7):1569-1580.[PubMed 16502413]

Thorne JC, Nadarajah T, Moretti M, Ito S. Methotrexate use in a breastfeeding patient with rheumatoid arthritis. J Rheumatol. 2014;41(11):2332. doi: 10.3899/jrheum.140263.[PubMed 25362724]

Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem. 1996;42(8, pt 2):1322-1329.[PubMed 8697606]

Trexall (methotrexate) [prescribing information]. North Wales, PA: Teva Pharmaceuticals; July 2016.

Turner D, Grossman AB, Rosh J, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease. Am J Gastroenterol. 2007;102(12):2804-1282.[PubMed 18042110]

Turner D, Levine A, Escher J, et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nutrit. 2012;55(3):340-361.[PubMed 22773060]

US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.

van Roon EN, van de Laar MA. Methotrexate Bioavailability. Clin Exp Rheumatol. 2010;28(suppl 61):27-32.[PubMed 21044430]

von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068-3077. doi: 10.1200/JCO.2000.18.17.3068.[PubMed 12860938]

von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602-4608.[PubMed 16034041]

Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144(3):805-812. doi: 10.1378/chest.12-1728.[PubMed 23538719]

Wall SM, Johansen MJ, Molony DA, DuBose TD Jr, Jaffe N, Madden T. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis. 1996;28(6):846-854. doi: 10.1016/s0272-6386(96)90384-4.[PubMed 8957036]

Weiner MA, Harris MB, Lewis M, et al. Neoadjuvant high-dose methotrexate, cisplatin, and doxorubicin for the management of patients with nonmetastatic osteosarcoma. Cancer Treat Rep. 1986; 70(12):1431-1432.[PubMed 3466693]

Weiss B, Lerner A, Shapiro R, et al. Methotrexate treatment in pediatric Crohn disease patients intolerant or resistant to purine analogues. J Pediatr Gastroenterol Nutr. 2009;48:526-530.[PubMed 19412004]

Weiss AH, Wallace CA, Sherry DD. Methotrexate for resistant chronic uveitis in children with juvenile rheumatoid arthritis. J Pediatr. 1998;133(2):266-268.[PubMed 9709718]

Whelan JS, Bielack SS, Marina N, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol. 2015;26(2):407-414.[PubMed 25421877]

Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist, 2006;11(6):694-703.[PubMed 16794248]

Widemann BC, Balis FM, Murphy RF, et al. Carboxypeptidase-G2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. J Clin Oncol. 1997;15(5):2125-2134.[PubMed 9164227]

Widemann BC, Balis FM, Shalabi A, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Natl Cancer Inst. 2004;96(20):1557-1559.[PubMed 15494606]

Wiendl H. Idiopathic inflammatory myopathies: current and future therapeutic options. Neurotherapeutics. 2008;5(4):548-557.[PubMed 19019306]

Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988;6(2):329-37.[PubMed 2448428]

Winter SS, Dunsmore KP, Devidas M, et al. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015;62(7):1176-1183.[PubMed 25755211]

Xatmep (methotrexate) [prescribing information]. Greenwood Village, CO: Silvergate Pharmaceuticals, Inc; December 2018.

Yeung J, Vaughan E, Chadban S, Saunders J, Thiagarajah N, Brown C. High-dose intravenous methotrexate with high-flux, extended-hours haemodialysis in treatment of primary central nervous system, post-transplant lymphoproliferative disorder and end-stage kidney disease: a case report. Nephrology (Carlton). 2018;23(11):1063-1064. doi: 10.1111/nep.13254.[PubMed 30362229]

Zackheim HS, Kashani-Sabet M, and McMillan A. Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol. 2003;49(5):87387-8.[PubMed 14576667]

Brand Names: International

Abitrexate (IL, SG, TH, TW, ZW); Alltrex (LK); Artrait (AR, PE); Atrexel (MX); Bertanel (ES); Biotrexate (IN); Brimexate (IT); Canceren (KR); Cytotrex (LK); Ebetrex (LV); Ebetrexat (AE, AT, BG, HR, LB); Ebetrexate (BE); Emthexat (SE); Emthexate (AT, BE, GR, ID, JO, KW, MY, NL, PH, PK, PT, TH, TR, TW); Emthexate PF (EG, KR); Emthrxate (SI); Hytas (BR); Imutrex (LK); Jylamvo (BE); Lantarel (DE); Ledertrexate (BE, FR, LU, MX, NZ, PT); Maxtrex (GB); Medsatrexate (MX); Meisusheng (CN); Merox-50 (ET); Metex (LV); Methoblastin (AU, NZ); Methocip (EG); Methofill (IE); Methotrexat (HR); Methotrexat Bigmar (CH); Methotrexat Ebewe (HU); Methotrexat Farmos (CH); Methotrexat Lachema (HU); Methotrexat Lederle (CH); Methotrexat Teva (CH); Methotrexate (AU, HK, ID, IL, MY, PH, TH, TW); Methotrexate Faulding (SE); Methotrexate Pharmacia (SE); Methotrexate Wyeth Lederle (SE); Methotrexate ”Lederle” (HU); Methotrexate[inj.] (HR, IT); Methotrexato (AR, EC); Methox (BD); Metodik (AR); Metoject (CZ, DK, ES, FR, HR, IE, IL, LB, RO, SK, UA); Metotreksat (HR); Metotressato Teva (IT); Metotrexato (CL); Metotrexato DBL (IT); Metrex (LK, PY); Mexat (CO); Midu (CN); Mtrex (BD); MTX (EG); MTX Hexal (LU); Neotrexate (IN); Novatrex (FR); Onkomet (TH); Otaxem (MX); P&U Methotrexate (ZA); Pterin (PH); Quinux (ES); Reumatrex (PE); Rheu-Trex (ID); Rheumatrex (JP); Sanotrexat (ID); Texate (MX); Trexan (EE, FI, HN, HU, LT, PL, RU, SG, TR, TW); Trexject (AU); Trexol (LK); Trexonate (BD); Trexxol (ET); Trixilem (CL, MX, TH); Unitrexates (VN); Xantromid (PY); Zexate (ET, PH, UY, VE, VN, ZW)

Last Updated 3/7/20