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Methotrexate: Drug information

Methotrexate: Drug information
(For additional information see "Methotrexate: Patient drug information" and see "Methotrexate: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning

Methotrexate Oral:

Adverse reactions:

Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, GI tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate.

Methotrexate can cause the following severe or fatal adverse reactions. Monitor closely and modify dose or discontinue methotrexate as appropriate. Bone marrow suppression, serious infections, renal toxicity and increased toxicity with renal impairment, GI toxicity, hepatic toxicity, pulmonary toxicity, hypersensitivity, and dermatologic reactions.

Hypersensitivity:

Methotrexate is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis.

Pregnancy:

Methotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.

Methotrexate Injection:

Intrathecal and high-dose therapy:

For intrathecal and high-dose therapy, use preservative-free formulation of methotrexate and diluents. Do NOT use formulations or diluents containing preservatives for intrathecal and high-dose therapy because they contain benzyl alcohol. Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free methotrexate injection for treatment of neonates or low-birth-weight infants and for intrathecal use. Do not use benzyl alcohol–containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available.

Hypersensitivity

Methotrexate is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis.

Appropriate use:

Serious adverse reactions, including deaths, have been reported with methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Closely monitor for adverse reactions of the bone marrow, GI tract, liver, lungs, skin, and kidneys. 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.

Pregnancy:

Methotrexate can cause embryo-fetal toxicity, including fetal death and/or congenital anomalies. Use in rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. 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.

Bone marrow suppression:

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).

Renal impairment:

Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.

Hepatotoxicity:

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 may not be 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.

Pneumonitis:

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.

GI toxicity:

Unexpectedly severe (sometimes fatal) GI toxicity has been reported with concomitant administration of methotrexate (usually in high dosage) along with some NSAIDs. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur.

Secondary malignancy:

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.

Tumor lysis syndrome:

Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Dermatologic toxicity:

Severe, occasionally fatal skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, IM, IV, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.

Opportunistic infections:

Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy.

Other serious reactions:

Other serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, GI tract, lungs, and skin. Withhold or discontinue methotrexate injection as appropriate.

Radiotherapy:

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Experienced physician (injection):

Methotrexate should be used only by health care providers whose knowledge and experience include the use of antimetabolite therapy.

Brand Names: US
  • Otrexup;
  • Rasuvo;
  • RediTrex;
  • Trexall;
  • Xatmep
Brand Names: Canada
  • ACH-Methotrexate;
  • JAMP-Methotrexate;
  • Metoject;
  • PMS-Methotrexate;
  • RATIO-Methotrexate Sodium [DSC]
Pharmacologic Category
  • Antineoplastic Agent, Antimetabolite (Antifolate);
  • Antirheumatic, Disease Modifying;
  • Immunosuppressant Agent
Dosing: Adult

Note: Safety: Fatal errors have occurred when methotrexate was administered as a daily dose instead of a weekly dose. Verify the indication before administration; oral methotrexate is typically only administered daily for an oncology-related indication (ISMP 2020). Patient should be under the care of a clinician experienced with using methotrexate.

Oncology uses :

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). Only preservative-free formulations should be used for intrathecal administration and for high-dose methotrexate regimens. Methotrexate doses ≥250 mg/m2 (IV) are associated with moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting.

Acute lymphoblastic leukemia

Acute lymphoblastic leukemia:

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

CALGB 8811 regimen (as a component of combination chemotherapy):

Early intensification: Intrathecal: 15 mg on day 1 of early intensification phase, repeat in 4 weeks (Larson 1995).

CNS prophylaxis/interim maintenance phase:

Intrathecal: 15 mg on days 1, 8, 15, 22, and 29 (Larson 1995).

Oral: 20 mg/m2 on days 36, 43, 50, 57, and 64 (Larson 1995).

Prolonged maintenance: Oral: 20 mg/m2 on days 1, 8, 15, and 22 every 4 weeks for 24 months from diagnosis (Larson 1995).

Dose-intensive regimen (as a component of combination chemotherapy):

IV: 200 mg/m2 over 2 hours, followed by 800 mg/m2 over 24 hours beginning on day 1, (followed by leucovorin rescue) of even numbered cycles (in combination with cytarabine; alternates with Hyper-CVAD) (Kantarjian 2000).

CNS prophylaxis: Intrathecal: 12 mg on day 2 of each cycle; duration depends on risk (Kantarjian 2000).

Maintenance: IV: 10 mg/m2/day for 5 days every month for 2 years (in combination with prednisone, vincristine, and mercaptopurine) (Kantarjian 2000).

Protocol 8787 regimen (as part of a multiphase, multiagent regimen): Patients <60 years of age:

CNS prophylaxis: Intrathecal: 12 mg at the start of induction, then 12 mg with first postremission chemotherapy, then 12 mg once weekly for 4 more doses, for a total of 6 doses (patients with CNS disease at diagnosis required a total of 10 doses) (Linker 2002).

Consolidation phases (1C, 2C, and 3C): IV: 220 mg/m2 bolus, followed by 60 mg/m2/hour for 36 hours beginning on days 1 and 15 (followed by leucovorin rescue) of each 28-day consolidation cycle (in combination with mercaptopurine) (Linker 2002).

Maintenance: Oral: 20 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (in combination with mercaptopurine) until in complete remission for 30 months (Linker 2002).

Acute promyelocytic leukemia maintenance phase

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

Oral: 15 mg/m2 once weekly for 2 years (Adès 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

Bladder cancer (off-label use):

Locally advanced or metastatic disease:

Dose-dense MVAC regimen: IV: 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: IV: 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: IV: 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: IV: 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: IV: 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

Breast cancer: CMF regimen: IV: 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).

Gestational trophoblastic neoplasia

Gestational trophoblastic neoplasia:

Gestational trophoblastic neoplasia, low-risk disease (off-label dosing):

8-day regimen: IM: 1 mg/kg every 48 hours (on days 1, 3, 5, and 7) for 4 doses (with leucovorin 30 hours after each methotrexate dose), repeat cycle every 14 days until hCG level is normal, followed by 2 to 3 more cycles as consolidation therapy (SOGC [Eiriksson 2021]).

5-day regimen: IV/IM: 0.4 mg/kg (maximum dose: 25 mg) once daily for 5 days, repeat every 14 days until hCG level is normal, followed by 2 to 3 more cycles as consolidation therapy (SOGC [Eiriksson 2021]).

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

EMA-CO regimen: IV: 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: IV: 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: IV: 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: IV: 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-vs-host disease, acute, prophylaxis

Graft-vs-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 (EBMT/ELN [Ruutu 2013]).

Head and neck cancer

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

Large granular lymphocyte leukemia, symptomatic

Large granular lymphocyte leukemia, symptomatic (off-label use): Oral: Initial: 5 to 7.5 mg once weekly (with or without prednisone), escalate up to 15 to 20 mg once weekly or 10 mg/m2/week over 1 to 3 months; methotrexate was administered in split doses in the morning and evening on one day per week (Loughran 1994) or 10 mg/m2/week (administered in divided doses in the morning and evening on one day per week), in combination with prednisone, followed by a prednisone taper after 30 days (Loughran 2015) or 10 mg/m2/week (administered in divided doses in the morning and evening on one day per week), with or without prednisone; discontinue treatment if no response after 4 months (Lamy 2011) or 7.5 mg/m2 once weekly (Bareau 2010).

Mycosis fungoides

Mycosis fungoides (cutaneous T-cell lymphoma): Oral or IM: 25 to 75 mg orally once weekly (as a single agent) or 10 mg/m2 orally twice weekly (as part of a combination regimen) or 5 to 50 mg IM once weekly (for early stage) or 15 to 37.5 mg IM twice weekly (if poor response to weekly therapy) (manufacturer's labeling) or 25 mg orally once weekly, may increase to 50 mg orally once weekly (Zackheim 2003).

Non-Hodgkin lymphoma

Non-Hodgkin lymphoma:

Burkitt lymphoma:

Modified CODOX-M/IVAC regimen ± rituximab (Barnes 2011; Lacasce 2004; 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).

High-dose methotrexate/cytarabine alternating with Hyper-CVAD: IV: 1,000 mg/m2 over 24 hours on day 1 during even courses (2, 4, 6, and 8) of 21-day treatment cycles (with leucovorin rescue) (Thomas 2006).

9251 regimen: IV: 150 mg/m2 over 30 minutes followed by 1,350 mg/m2 over 23.5 hours (with leucovorin rescue) on day 1 of cycles 2 through 7 (in combination with cyclophosphamide, prednisone, ifosfamide, mesna, vincristine, cytarabine, etoposide, dexamethasone, doxorubicin, and CNS prophylaxis) (Lee 2001; Rizzieri 2004).

Mantle cell lymphoma: High-dose methotrexate/cytarabine alternating with Hyper-CVAD (± rituximab): IV: 200 mg/m2 bolus on day 1 or day 2 followed by 800 mg/m2 over 24 hours during even courses (2, 4, 6, and 8) of 21-day treatment cycles (with leucovorin rescue) (Khouri 1998; Romaguera 2005).

Nonleukemic meningeal cancer

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

Osteosarcoma: Adults ≤30 years of age: MAP regimen: IV: 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

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).

Primary cutaneous anaplastic large cell lymphoma

Primary cutaneous anaplastic large cell lymphoma (off-label use): Oral: 15 to 25 mg once weekly (range: 10 to 60 mg once weekly); based on response, may increase dosing interval up to once every 2 weeks after the weekly dose has been optimized (Vonderheid 1996) or 5 to 50 mg once weekly (median dose: 20 to 25 mg once weekly) for up to 48 weeks or until disease progression or unacceptable toxicity (Prince 2017).

Soft tissue sarcoma

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).

Nononcology uses:

Note: During chronic therapy, treat with folic acid to reduce the risk of adverse effects; leucovorin may be considered in patients who do not respond to folic acid (Kremer 2021; Lucas 2019; McGrath 2018). In patients with inadequate response or intolerance to oral methotrexate therapy at doses ≥15 mg/week, may consider switching to parenteral administration (using a 1:1 dose conversion) or dividing the weekly oral dose (eg, in 2 to 3 divided doses administered every 12 hours over 12 to 24 hours) (Baughman 2000; Kremer 2021; Lucas 2019; Verstappen 2007; Visser 2009b).

Atopic dermatitis or eczema, moderate to severe

Atopic dermatitis or eczema, moderate to severe (alternative agent) (off-label use):

Oral, SUBQ, IM: Initial: 10 to 15 mg once weekly. Adjust dose by 2.5 to 5 mg/week every 2 to 4 weeks if needed based on response (usual dosage range: 7.5 to 25 mg/week) (AAD [Sidbury 2014]; Goujon 2018; Schram 2011). Consider discontinuation if no improvement after 12 to 16 weeks on dosages ≥15 mg/week (AAD [Sidbury 2014]).

Bullous pemphigoid

Bullous pemphigoid (alternative agent) (adjunctive agent) (off-label use):

Oral, IM, SUBQ: Initial: 5 mg once weekly; often given in combination with glucocorticoids. Increase dose as tolerated by 2.5 mg/week approximately every 4 weeks if needed (usual dosage range: 5 to 20 mg/week). Once disease control is achieved, gradually taper therapy (eg, every 2 to 4 weeks) to minimum effective dose (Heilborn 1999; Kjellman 2008; Murrell 2021; Paul 1994). Consider discontinuation if no improvement after 4 weeks on dosages ≥15 mg/week (Murrell 2021).

Crohn disease, moderate to severe

Crohn disease, moderate to severe (alternative agent) (adjunctive agent) (off-label use):

Note: For use as part of an appropriate combination regimen for induction of remission and as an alternative monotherapy for maintenance of remission (ACG [Lichtenstein 2018]; AGA [Feuerstein 2021]). Patient should be under the care of a clinician experienced with using methotrexate for this condition.

IM, SUBQ, Oral: Initial: 15 to 25 mg administered IM or SUBQ once weekly; an initial dose of 12.5 to 15 mg/week administered orally or parenterally may be used when adding to biologic therapy. For lower initial doses, may gradually increase dose (eg, by 5 mg/week every month) if needed (maximum: 25 mg/week). If remission is sustained after 4 months, may reduce dose to 15 mg/week administered orally or parenterally (ACG [Lichtenstein 2018]; AGA [Feuerstein 2021]; Hashash 2021).

Dermatomyositis, cutaneous

Dermatomyositis, cutaneous (alternative agent) (adjunctive agent) (off-label use):

Note: In patients with mild disease, may be used as combination therapy when response to initial systemic therapy (eg, with hydroxychloroquine) is inadequate, or as an alternative initial systemic therapy in patients who cannot take preferred agents. In patients with severe disease, may be used as initial systemic therapy with or without hydroxychloroquine (Vleugels 2021).

Oral, SUBQ, IM: Initial: 5 to 15 mg once weekly. May increase dose by 2.5 mg/week every 1 to 2 weeks up to a goal of 25 mg/week, or directly to 25 mg/week after 2 weeks on the initial dose, if needed based on response (Oddis 2016; Vleugels 2021).

Dermatomyositis/polymyositis

Dermatomyositis/Polymyositis (alternative agent) (adjunctive agent) (off-label use):

Note: For use as an adjunct to glucocorticoids, or as an alternative initial therapy in patients who cannot receive glucocorticoids (McGrath 2018; Targoff 2022).

Oral, SUBQ, IM: Initial: 7.5 to 15 mg once weekly; adjust dose by 2.5 mg/week every 2 to 4 weeks if needed based on response (usual dose: 15 to 25 mg once weekly) (McGrath 2018; Targoff 2022; Oddis 2016; Wiendl 2008).

Discoid lupus erythematosus and subacute cutaneous lupus erythematosus, refractory

Discoid lupus erythematosus and subacute cutaneous lupus erythematosus, refractory (adjunctive agent) (off-label use):

SUBQ (preferred), IM, Oral: 10 to 25 mg once weekly (EDF/EADV [Kuhn 2017]; Kuhn 2011; Wenzel 2005).

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (alternative agent) (off-label use):

Note: May be used as an alternative induction therapy in patients with mild disease, or as maintenance therapy (in combination with glucocorticoids); efficacy data are limited (EULAR [Mukhtyar 2009]; King 2021a; Metzler 2004).

Oral, SUBQ: Initial: 15 mg once weekly, then increase dose by 5 mg/week every 2 to 8 weeks up to 25 mg/week if tolerated. If remission is sustained after 12 to 18 months, may gradually taper dosage until discontinued (King 2021a; Metzler 2004).

Giant cell arteritis

Giant cell arteritis (alternative agent) (adjunctive agent) (off-label use):

Note: For use as an alternative to tocilizumab in patients who require glucocorticoid-sparing therapy; clinical experience suggests limited efficacy (Docken 2021; EULAR [Hellmich 2020]).

Oral, SUBQ: Initial: 10 to 15 mg once weekly (EULAR [Hellmich 2020]; Jover 2001; Mahr 2007). Adjust dose by 2.5 mg/week if needed based on response (usual dosage range: 7.5 to 15 mg/week); may discontinue therapy after 24 months if disease remission is achieved (Jover 2001; Leon 2017; Mahr 2007).

Granulomatosis with polyangiitis and microscopic polyangiitis

Granulomatosis with polyangiitis and microscopic polyangiitis (off-label use):

Note: For use as maintenance therapy (regardless of initial disease severity) to extend remission and prevent relapse; may also be used as induction therapy (in combination with glucocorticoids) only for patients with non–organ- and non–life-threatening disease (EULAR/ERA-EDTA [Yates 2016]).

Oral, SUBQ, IM: Initial: 15 to 20 mg once weekly, then increase dose by 2.5 to 5 mg/week every 2 to 8 weeks based on response up to 25 mg/week. If remission is sustained after 1 to 2 years, may gradually taper dosage (eg, reduce by 2.5 mg/week each month) until discontinued (EULAR/ERA-EDTA [Yates 2016]; Langford 2003; Merkel 2021b; Pagnoux 2008; WGET 2002).

Morphea or localized scleroderma

Morphea or localized scleroderma (off-label use):

Note: For use in patients with severe skin and/or musculoskeletal involvement, either as monotherapy or in combination with glucocorticoids (EDF [Knobler 2017]).

SUBQ, Oral: 12.5 to 25 mg once weekly. May gradually taper therapy after 6 to 12 months of disease inactivity (usual total duration: 1 to 2 years) (EDF [Knobler 2017]; Jacobe 2021; Kroft 2009). Note: May consider a second (or third) course of methotrexate in patients who experience disease relapse (Kroft 2009).

Psoriasis, moderate to severe

Psoriasis, moderate to severe:

Note: Patient should be under the care of a clinician experienced with using methotrexate for this condition.

Oral, IM, SUBQ: Initial: 10 to 15 mg once weekly. Adjust dose gradually (eg, every 4 to 8 weeks) if needed based on response (usual dosage range: 7.5 to 25 mg/week) (AAD/NPF [Menter 2020]; Feldman 2021).

Rheumatoid arthritis

Rheumatoid arthritis:

Note: Patient should be under the care of a clinician experienced with using methotrexate for this condition.

Oral, SUBQ, IM: Initial: 7.5 to 15 mg once weekly. Increase dose by 2.5 to 5 mg/week every 4 to 12 weeks if needed based on response (maximum: 25 mg/week); current guidelines suggest titrating to a target dose of ≥15 mg/week within 4 to 6 weeks of initiation. Once disease remission is achieved, may gradually reduce dose (eg, by 2.5 mg/week every 1 to 2 months) to 15 mg/week to limit adverse effects (ACR [Fraenkel 2021]; Braun 2008; Cohen 2021; EULAR [Smolen 2017]; Kremer 2021).

Sarcoidosis, pulmonary

Sarcoidosis, pulmonary (adjunctive agent) (off-label use):

Note: For use as an adjunctive agent in patients whose disease progresses despite glucocorticoids or in those who require glucocorticoid-sparing therapy (BTS [Thillai 2021]).

Oral, SUBQ, IM: Initial: 5 to 7.5 mg once weekly. Increase dose gradually (eg, by 2.5 mg/week every 2 weeks) if needed; usual dosage range: 10 to 15 mg/week (maximum: 20 mg/week) (Baughman 2000; BTS [Thillai 2021]; Judson 2012; King 2021b; WASGD [Cremers 2013]).

Scleritis, idiopathic, noninfectious

Scleritis, idiopathic, noninfectious (adjunctive agent) (off-label use):

Note: For use in patients with persistent or progressive disease or who require glucocorticoid-sparing therapy; in patients with necrotizing scleritis, alternative agents should be considered (Dana 2021; Rossi 2019).

SUBQ, Oral: Initial: 7.5 to 15 mg once weekly (in combination with glucocorticoids). Increase dose by 5 mg/week every week if needed based on response (maximum: 25 mg/week); may gradually taper and discontinue therapy if disease remission is maintained for 6 to 12 months after glucocorticoids are stopped (Dana 2021; Kaplan-Messas 2003; Rossi 2019).

Still disease, adult-onset, moderate to severe

Still disease, adult-onset, moderate to severe (adjunctive agent) (off-label use):

Note: For use as an adjunct to glucocorticoids in patients with moderate to severe, arthritis-predominant disease (Mandl 2021; Pay 2006).

Oral, SUBQ: Initial: 10 to 15 mg once weekly; increase dose by 2.5 mg/week every week if needed after the first 4 weeks based on response (maximum: 25 mg/week) (Franchini 2010; Mandl 2021). Once disease control is achieved for ≥3 months, gradually taper therapy (eg, by 2.5 to 5 mg/week every 2 to 3 months) to minimum effective dose; may discontinue therapy based on response (Mandl 2021).

Systemic lupus erythematosus

Systemic lupus erythematosus (adjunctive agent) (off-label use):

Note: For use in patients with arthritis-predominant disease who require glucocorticoid-sparing therapy, or in patients with persistent arthritis symptoms despite first-line therapy (EULAR [Fanouriakis 2019]; Ruiz-Irastorza 2020).

Oral, SUBQ: Initial: 5 to 15 mg once weekly. Increase dose gradually (eg, by 2.5 mg/week every 4 weeks) if needed based on response (maximum: 20 to 25 mg/week) (Fortin 2008; Ruiz-Irastorza 2020).

Systemic sclerosis or scleroderma

Systemic sclerosis or scleroderma (off-label use):

Note: For use in patients with diffuse skin involvement, or in patients with overlapping skin and musculoskeletal involvement; methotrexate should not be used in patients with pulmonary involvement (EDF [Knobler 2017]).

Oral, SUBQ: Initial: 10 mg once weekly; adjust dose by 2.5 mg/week every 4 weeks up to target dose of 15 to 25 mg/week (Denton 2021; Pope 2001).

Takayasu arteritis

Takayasu arteritis (off-label use): Oral, SUBQ: Initial: 15 mg once weekly in combination with a glucocorticoid. Increase dose by 2.5 to 5 mg/week every 1 to 2 weeks if needed based on response (maximum: 25 mg/week) (Hoffman 1994; Merkel 2021a; Spies 2010).

Termination of intrauterine pregnancy, first trimester

Termination of intrauterine pregnancy, first trimester (alternative agent) (off-label use):

Note: For use only as an alternative to mifepristone/misoprostol combination or misoprostol-only regimens in patients at ≤49 days of gestation (ACOG 2020; Creinin 1996). Do not administer folic acid (including folic acid-containing vitamins) during methotrexate therapy for this indication (Creinin 1996; SOGC [Costescu 2016]).

IM: 50 mg/m2 once, followed by vaginal misoprostol 3 to 7 days later (Creinin 1996); some experts do not exceed a methotrexate dose of 100 mg (Tulandi 2021).

Tubal ectopic pregnancy

Tubal ectopic pregnancy (off-label use):

Note: May be used as an alternative to surgery for selected patients who meet all the following criteria: no fetal cardiac activity, hemodynamic stability, serum beta-hCG ≤5,000 milli-international units/mL, and ability to comply with posttreatment follow-up. May be given as single-dose or multiple-dose protocol; some experts prefer the single-dose regimen (ACOG 2018; Tulandi 2021). Regimens are named for the minimum number of planned doses; actual number of doses given may be greater.

Single-dose regimen: Note: Do not administer folic acid during methotrexate therapy during this regimen (ACOG 2018).

IM: 50 mg/m2 on day 1; some experts do not exceed 100 mg. Measure serum hCG level on days 1, 4 and 7; if the hCG decrease from day 4 to 7 is <15%, administer a second 50 mg/m2 dose on day 7 and measure serum hCG level again on day 14; if the hCG decrease from day 7 to 14 is <15%, administer a third 50 mg/m2 dose (some experts do not exceed 100 mg/dose for each dose). Consider surgical management if hCG does not adequately decrease after 3 doses (ACOG 2018; ASRM 2013; RCOG [Elson 2016]; Stovall 1993; Tulandi 2021).

Two-dose regimen: Note: Do not administer folic acid during methotrexate therapy during this regimen (ACOG 2018).

IM: 50 mg/m2 on days 1 and 4; some experts do not exceed 100 mg/dose for each dose. Measure serum hCG level on days 1 and 7; if the hCG decrease from day 1 to 7 is <15%, administer a third 50 mg/m2 dose and measure serum hCG level again on day 11; if hCG decrease from day 7 to 11 is <15%, administer a fourth 50 mg/m2 dose and measure serum hCG level on day 14 (some experts do not exceed 100 mg/dose for each dose). Consider surgical management if hCG does not adequately decrease after 4 doses (ACOG 2018; Barnhart 2007; Tulandi 2021).

Multidose regimen (in combination with leucovorin): IM: 1 mg/kg on day 1; some experts do not exceed 100 mg. Measure hCG level on days 1, 3, 5, 7, and 14. Administer subsequent 1 mg/kg doses on days 3, 5, 7, and 14 only if there is a <15% decline in hCG from previous measurement; some experts do not exceed 100 mg/dose for each dose. Administer leucovorin on days 2, 4, 6, 8, and 15 only if methotrexate was given on the previous day. Consider surgical management if hCG does not adequately decrease after 5 doses (total treatment may be between 1 and 5 doses) (ACOG 2018; ASRM 2013; Sauer 1987; Stovall 1989; Tulandi 2021).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

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 patients with cancer 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

Hepatic impairment prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution and consider a reduced dose 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.

Hepatotoxicity during treatment: Withhold, consider a reduced dose, or discontinue methotrexate as appropriate.

Dosing: Pediatric

(For additional information see "Methotrexate: Pediatric drug information")

Note: Dosing may be presented as mg/m2 or mg/kg; verify dosage unit for calculations; maximum doses may be presented in mg or g; extra precautions should be taken. Frequency of dosing is indication specific (generally weekly or specific days within a protocol); 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. 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 (POGO [Dupuis 2011]; POGO [Paw Cho Sing 2019]); antiemetics may be recommended to prevent nausea and vomiting. Methotrexate doses between 100 to 500 mg/m2 may require leucovorin calcium rescue. Methotrexate doses >500 mg/m2 require leucovorin calcium rescue.

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); administer methotrexate 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/dose (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 (preferred): Initial: 15 to 20 mg/m2 or 1 mg/kg (whichever is less) once weekly; maximum dose: 40 mg/dose; used in combination with corticosteroids and with either folic acid or folinic acid supplementation (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/dose; 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:

Note: Therapy should be individualized based on disease severity and activity; when initiating therapy, a trial of at least 3 months is considered adequate; however, if there is no response or only minimal response after 6 to 8 weeks, changing therapy or adding additional therapy may be appropriate. Due to variable bioavailability of oral administration and GI side effects, some experts suggest subcutaneous administration over oral especially when doses are >10 mg/m2 (ACR/AF [Ringold 2019]). When switching between dosage forms and routes of administration, dosage adjustment may be needed.

BSA-directed dosing: Children and Adolescents: Oral, IM, SUBQ: Initial: 10 to 15 mg/m2 once weekly; adjust gradually up to 20 to 30 mg/m2 once weekly; maximum dose: 25 mg/dose. To reduce GI side effects and improve bioavailability and efficacy, consider parenteral administration (IM, SUBQ) of doses >10 mg/m2 (ACR/AF [Ringold 2019]; CARRA [Ringold 2014]; manufacturer's labeling).

Weight-directed dosing: Children and Adolescents: Oral, SUBQ: Initial: 0.5 mg/kg once weekly; maximum initial dose: 15 mg/dose; if symptoms worsen or unchanged after 4 weeks, may increase to SUBQ: 1 mg/kg; maximum dose: 25 mg/dose (CARRA [Ringold 2014]).

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; maximum reported dose: 25 mg/dose; 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/dose; alone or in combination 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; a maximum dose of 25 mg/dose was reported in other pediatric uveitis trials (Simonini 2010; Weiss 1998).

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

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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: Kidney 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

Dosing: Older Adult

Refer to adult dosing; adjust for renal impairment.

Breast cancer: Patients >60 years of age: CMF regimen: IV: 30 mg/m2 on 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: Cycles 1 and 3 of CODOX-M: IV: 100 mg/m2 over 1 hour on day 10 followed by 900 mg/m2 over 23 hours (with leucovorin rescue); CODOX-M cycles alternate with IVAC (Meade 2008).

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/week.

Dosing: Obesity: Adult

ASCO guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2: 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 patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing with subsequent cycles, if cause of toxicity (eg, hepatic or renal impairment) is clearly established and fully resolved (ASCO [Griggs 2021]).

Dosing: Adjustment for Toxicity: Adult

Methotrexate toxicities:

Nonhematologic toxicity:

Anaphylaxis or other severe hypersensitivity reactions: Discontinue methotrexate (immediately) and manage as appropriate.

Dermatologic toxicity: Withhold or discontinue methotrexate as appropriate. For severe toxicity (toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme), discontinue methotrexate.

GI toxicity (severe): Withhold or discontinue methotrexate as appropriate. For diarrhea, stomatitis, or vomiting, which may lead to dehydration, withhold methotrexate until recovery.

Infection (serious): Withhold or discontinue methotrexate and manage infection as appropriate.

Neurotoxicity: Withhold or discontinue methotrexate as appropriate.

Pulmonary toxicity: Withhold or discontinue methotrexate as appropriate.

Secondary malignancy/lymphoproliferative disease: Discontinue methotrexate.

Withhold or discontinue (tablets) as appropriate for severe GI toxicity, hepatotoxicity, pulmonary toxicity, severe dermatological reaction, severe renal toxicity, serious infection, or neurotoxicity.

Discontinue (tablets) for anaphylaxis or other severe hypersensitivity reactions or for secondary malignancy (eg, lymphoproliferative disease).

Hematologic toxicity:

Oncologic uses:

Myelosuppression: Withhold, reduce dose, or discontinue methotrexate as appropriate.

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

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

Myelosuppression (tablets): Withhold, reduce dose or discontinue as indicated.

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

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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); 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: 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); 30 mg/0.6 mL (0.6 mL)

Solution Prefilled Syringe, Subcutaneous [preservative free]:

RediTrex: 7.5 mg/0.3 mL (0.3 mL); 10 mg/0.4 mL (0.4 mL); 12.5 mg/0.5 mL (0.5 mL); 15 mg/0.6 mL (0.6 mL); 17.5 mg/0.7 mL (0.7 mL); 20 mg/0.8 mL (0.8 mL); 22.5 mg/0.9 mL (0.9 mL); 25 mg/mL (1 mL)

Solution Reconstituted, Injection [preservative free]:

Generic: 1 g (1 ea)

Tablet, Oral:

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

Generic: 2.5 mg

Generic Equivalent Available: US

May be product dependent

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 ([DSC]); 15 mg/1.5 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: 22.5 mg/0.45 mL (0.45 mL); 25 mg/0.5 mL (0.5 mL)

Generic: 22.5 mg/0.45 mL (0.45 mL); 25 mg/0.5 mL (0.5 mL)

Solution Prefilled Syringe, Subcutaneous, as sodium:

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)

Generic: 15 mg/0.3 mL (1 ea, 4 ea); 17.5 mg/0.35 mL (0.35 mL); 20 mg/0.4 mL (0.4 mL)

Tablet, Oral:

Generic: 2.5 mg, 10 mg

Administration: Adult

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

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

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

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

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.

Otrexup, Rasuvo, and RediTrex are autoinjectors or prefilled syringes for once-weekly SUBQ use in the abdomen or thigh; patient may self-administer after appropriate training and with appropriate follow-up monitoring. Use a different injectable formulation for administration of routes other than SUBQ or for doses <7.5 mg/week or >25 mg/week. 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: Pediatric

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 (POGO [Dupuis 2011]; POGO [Paw Cho Sing 2019]); antiemetics may be recommended to prevent nausea and vomiting.

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.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Oncology uses:

Acute lymphoblastic leukemia: Treatment of acute lymphoblastic leukemia (as part of a combination chemotherapy regimen) in adults and pediatric patients.

Breast cancer: Treatment of breast cancer (as part of a combination chemotherapy regimen) in adults.

Cutaneous T-cell lymphoma (mycosis fungoides, advanced): Treatment of advanced mycosis fungoides.

Gestational trophoblastic neoplasia: Treatment of gestational trophoblastic neoplasia (as part of a combination chemotherapy regimen) in adults.

Head and neck cancer (squamous cell carcinoma): Treatment of squamous cell carcinoma of the head and neck (as a single agent) in adults.

Meningeal leukemia (prophylaxis and treatment): Prophylaxis and treatment of meningeal leukemia in adults and pediatric patients.

Non-Hodgkin lymphomas: Treatment of non-Hodgkin lymphomas in adults and pediatric patients.

Osteosarcoma: Treatment of osteosarcoma (as part of a combination chemotherapy regimen) in adults and pediatric patients.

Nononcology uses:

Polyarticular juvenile idiopathic arthritis: Treatment of active polyarticular juvenile idiopathic arthritis in patients whose disease is unresponsive to or who are intolerant of first-line therapy, including full-dose nonsteroidal anti-inflammatory drugs (NSAIDs)

Psoriasis: Symptomatic control of severe, recalcitrant, disabling psoriasis (in adults) that is not adequately responsive to other therapies.

Rheumatoid arthritis: Management of severe, active rheumatoid arthritis in adults whose disease is unresponsive to or who are intolerant of first-line therapy, including full-dose NSAIDs.

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

Use: Off-Label: Adult

Acute promyelocytic leukemia maintenance; Atopic dermatitis or eczema, moderate to severe; Bladder cancer; Bullous pemphigoid; Crohn disease, moderate to severe; Dermatomyositis, cutaneous; Dermatomyositis/Polymyositis; Discoid lupus erythematosus and subacute cutaneous lupus erythematosus, refractory; Eosinophilic granulomatosis with polyangiitis (Churg-Strauss); Giant cell arteritis; Graft-vs-host disease, acute, prophylaxis; Granulomatosis with polyangiitis and microscopic polyangiitis; Large granular lymphocyte leukemia (symptomatic); Morphea or localized scleroderma; Nonleukemic meningeal cancer; Primary CNS lymphoma, newly diagnosed; Primary cutaneous anaplastic large cell lymphoma; Sarcoidosis, pulmonary; Scleritis, idiopathic, noninfectious; Soft tissue sarcoma (desmoid tumors, aggressive fibromatosis), advanced; Still disease, adult-onset, moderate to severe; Systemic lupus erythematosus; Systemic sclerosis or scleroderma; Takayasu arteritis; Termination of intrauterine pregnancy, first trimester; Tubal ectopic pregnancy

Medication Safety Issues
Sound-alike/look-alike issues:

Methotrexate may be confused with mercaptopurine, methylPREDNISolone sodium succinate, metOLazone, metroNIDAZOLE, mitoXANTRONE, MXT Patch, PRALAtrexate.

Trexall may be confused with Paxil.

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication (with special emphasis on nononcologic uses) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

Administration issues:

Fatal errors have occurred when oral methotrexate was administered as a daily dose instead of a weekly dose. Verify the indication before administration; methotrexate is typically only administered daily for an oncology-related indication (ISMP 2020). The ISMP 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 all daily oral methotrexate orders. Provide patient and/or caregiver education for patients discharged on oral methotrexate (ISMP 2020).

Intrathecal medication safety: The American Society of Clinical Oncology (ASCO)/Oncology Nursing Society (ONS) chemotherapy administration safety standards (ASCO/ONS [Neuss 2016]) recommend the following safety measures for intrathecal chemotherapy:

• Intrathecal medication should not be prepared during the preparation of any other agents.

• After preparation, keep in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.

• Delivery to the patient should only be with other medications also intended for administration into the central nervous system.

• Administer immediately after a time-out/double-check procedure.

Other safety concerns:

MTX is an error-prone abbreviation (mistaken as mitoxantrone or multivitamin).

International issues:

Trexall [US] may be confused with Trexol brand name for tramadol [Mexico]; Truxal brand name for chlorprothixene [multiple international markets].

Adverse Reactions (Significant): Considerations
Dermatologic toxicity

Severe dermatologic reactions have been reported with methotrexate use, including erythema multiforme, erythroderma, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Ref). Skin reactions have been noted with single or multiple low and high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Methotrexate-induced skin necrosis has been described that mimics SJS/TEN but differs in pathology and presumed mechanism (Ref). Mucocutaneous ulcers have been reported within preexisting skin lesions (eg, psoriasis); this may be an initial presenting sign of long-term methotrexate toxicity (Ref). Other dermatologic reactions reported include papular rash (Ref); skin photosensitivity (eg, photodermatitis reactivation, skin abnormalities related to radiation recall, dyschromia) (Ref); acral erythema (also known as hand-foot syndrome and palmar-plantar erythrodysesthesia) (Ref); and accelerated nodulosis in patients with rheumatoid arthritis (RA) (Ref). Compared to classic rheumatoid nodule, accelerated nodules have a more rapid onset, are smaller, and mainly affect the hands (Ref).

Mechanism: SJS and TEN are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref). Methotrexate-induced skin necrosis is caused by direct toxicity to keratinocytes (Ref). Similarly, acute mucocutaneous lesions are the result of methotrexate toxicity to the mucosa (Ref).

Onset: Varied; SJS and TEN typically occur days to weeks after drug exposure (Ref). Skin necrosis occurs 3 to 90 days post-initiation (Ref); although, may occur after a single dose (Ref). Mucocutaneous ulcerations have occurred with acute and, less commonly, chronic treatment (Ref). Symptom onset with photo-recall (also known as UV recall) occurs within weeks to years of ultraviolet (UV) exposure, whereas UV enhancement is observed within 1 week of UV exposure (Ref). Accelerated nodulosis typically occurs from 3 months to 12 years after initiation (Ref).

Risk factors:

• Age >55 years (Ref)

• Drug-drug interactions (eg, nonsteroidal anti-inflammatory agents [NSAIDs], sulfamethoxazole/trimethoprim) (Ref)

• Folate deficiency and low serum albumin level (Ref)

• Increase in methotrexate dose (Ref)

• Kidney impairment (Ref)

• Photodermatitis reactivation: Sunburn (Ref)

• Photosensitivity reactions: Concurrent voriconazole (Ref)

• Skin necrosis: Age >60 years, chronic kidney disease, high initial methotrexate dose without folic acid supplement, leukopenia (Ref)

GI toxicity

GI toxicity is a frequently occurring adverse reaction of methotrexate. Although stomatitis occurs more frequently with high-dose methotrexate, life-threatening GI events and fatalities have been reported with low-dose methotrexate (Ref). Other dose-limiting GI manifestations include abdominal distress, diarrhea, gastrointestinal hemorrhage, gastrointestinal ulcer, indigestion, nausea, and vomiting (Ref). Stomatitis can be an early sign of methotrexate toxicity, as high tissue turnover rates make GI and mucosal cells especially sensitive to chemotherapy (Ref). Ulcerative stomatitis and diarrhea can progress to life-threatening enteritis and intestinal perforation. GI hemorrhage and ulcers are reported more frequently in patients with a history of ulcerative colitis or peptic ulcer disease (Ref).

Mechanism:

Dose-related; mucositis and stomatitis after high-dose methotrexate are caused by cellular damage to rapidly dividing epithelial cells along the entire GI tract; inadequate or delayed leucovorin rescue can lead to impaired epithelial cell growth and regeneration in patients treated with high-dose methotrexate (Ref). Endothelial and connective tissue insult along with mucosal barrier injury result in early development of mucositis and stomatitis (Ref).

Non–dose-related; additional reports have been published where intestinal toxicity occurred as a result of inflammatory effects of methotrexate in the intestinal epithelium and submucosal tissues. This mechanism appears to be non-dose-related and explains the toxicity observed with low-dose methotrexate (Ref). Nausea and vomiting occur as a result of insult to the chemoreceptor trigger zone inducing emesis. Methotrexate has low emetogenic potential (Ref).

Onset: Varied; nausea, vomiting, and diarrhea occur as early as 24 hours post high-dose methotrexate infusion and as long as 7 days post infusion. Similar symptoms appear 24 hours after low-dose methotrexate weekly dose (Ref). Oral mucositis occurs within the first week of low-dose methotrexate therapy with unintentional overdose (Ref). high-dose methotrexate-induced stomatitis and mucositis occur after the first course of treatment or up to 14 days post high-dose methotrexate infusion (Ref).

Risk factors:

High-dose methotrexate:

• Drug-drug interactions, especially concomitant use with nonsteroidal anti-inflammatory drugs (NSAIDs)

Low-dose methotrexate:

• Drug-drug interactions (Ref)

• High starting doses (>15 mg/week to 25 mg/week) (Ref)

• History of peptic ulcer disease (Ref) or ulcerative colitis

• Kidney impairment (Ref)

• Preexisting folate deficiency (Ref)

• Unintentional daily dosing (Ref)

• Higher frequency of nausea in adolescents and younger adults, SubQ methotrexate use, and duration of therapy >1 year (Ref)

• Higher risk of diarrhea associated with younger age and previous GI events (Ref)

Hematologic toxicity

Unexpectedly severe (sometimes fatal) bone marrow depression with agranulocytosis, anemia, aplastic anemia, leukopenia, neutropenia, pancytopenia, and thrombocytopenia may occur with low-dose methotrexate used for conditions such as rheumatoid arthritis (RA) or psoriasis (Ref). Neutropenia is encountered most frequently, but anemia and thrombocytopenia also occur. May also occur with high-dose methotrexate, most commonly in the presence of kidney dysfunction and specific concurrent medications delaying methotrexate clearance (Ref). Aplastic anemia has been reported when high-dose methotrexate is concomitantly administered with a nonsteroidal anti-inflammatory drug (NSAID). (Ref).

Mechanism: Non–dose-related; hematologic toxicity occurs secondary to methotrexate’s interference with stem cell DNA synthesis. Fast turnover of stem cells together with a high number of cells in the S phase cycle makes these cells especially labile to methotrexate-induced hematologic toxicity (Ref).

Onset: Varied; with low-dose methotrexate occurring at any time during treatment, from a rapid onset to many years of treatment (Ref).

Risk factors:

Note: Methotrexate bone marrow suppression with low-dose methotrexate, especially pancytopenia, can occur in the absence of identifiable risk factors (Ref)

• Absence of supplemental folic acid (Ref)

• Age >65 years (Ref)

• Concurrent infection (Ref)

• Concurrent use of NSAIDs, ciprofloxacin, penicillin-type drugs, sulfamethoxazole/trimethoprim, probenecid, phenytoin, and proton pump inhibitors (Ref)

• Dosing errors (ie, administering daily or 2 to 4 days per week) increase toxicity more often than once weekly dosing (Ref)

• Hypoalbuminemia or displacement of methotrexate from albumin (Ref)

• Fluid accumulations and third spacing (ie, ascites, pleural effusions) (Ref)

• Preexisting kidney impairment (Ref)

Hepatotoxicity

Methotrexate causes frequent increased liver enzymes. Less frequently, these elevations lead to chronic hepatotoxicity in the form of hepatic fibrosis and hepatic cirrhosis (Ref). Acute liver enzyme elevations are transient and asymptomatic and may not be predictive of subsequent hepatic disease (Ref). Delayed hepatic toxicity in the form of fibrosis or cirrhosis after 2 years or more of low-dose methotrexate use and a total dose of at least 1.5 g can be fatal (Ref). Cases of fibrosis have also been reported in rheumatoid arthritis (RA) patients receiving regular folic acid supplementation (Ref). Patients being treated for psoriasis may be predisposed to higher reported levels of liver enzymes more frequently than patients treated for RA (Ref). Fibrosis and cirrhosis may also occur without symptoms or liver enzyme elevations in psoriasis patients (Ref).

Mechanism: Dose-related; impaired function of folate cell transporters leading to excessive methotrexate in liver cells, accumulation of homocysteine causing oxidative stress, and inflammation resulting in fatty liver; depletion of hepatic folate stores and local toxicity due to folate deficiency; direct damage from methotrexate metabolites to hepatocytes and fibrosis forming as a result of adenosine production in response to toxins such as ethanol, viruses, or drugs (Ref).

Onset: Varied; higher frequency of hepatotoxicity after first infusion with high-dose methotrexate (Ref). Patients may exhibit increases in liver enzymes within 7 months of initiation (Ref). Biopsy-proven liver abnormalities have been detected in patients after 1 year (Ref).

Risk factors:

• Alcohol consumption (Ref)

• Concurrent use of hepatotoxic medications (eg, azathioprine, retinoids, sulfasalazine, leflunomide)

• Cumulative dose >1.5 g and duration of therapy ≥2 years

• Females (Ref)

• Older adults (Ref)

• Metabolic syndrome (Ref)

• Preexisting kidney disease (Ref)

• Preexisting hepatic disease, particularly nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (Ref)

Infection

Methotrexate rarely increases the risk for developing life-threatening or fatal infection (Ref), including bacterial, fungal, or viral infections, exacerbation of hepatitis B (Ref), tuberculosis (primary infection or reactivation) (Ref), disseminated herpes zoster infection (Ref), and cytomegalovirus disease. Immune suppression may lead to potentially fatal opportunistic infections, especially pneumonia due to Pneumocystis jirovecii (PJP) (Ref).

Mechanism: Unknown; immunosuppression may occur due to T-cell apoptosis and clonal deletion (Ref). Patients with rheumatoid arthritis (RA) have a high rate of infection when compared to healthy control population; therefore, infections (including opportunistic infections) arising during therapy may be due to RA or the immunosuppressive effects of methotrexate (Ref).

Onset: Varied; may occur at any time during treatment; however, most infections occur in the first 2 years (Ref).

Risk factors:

• Low-dose methotrexate (ie, ≤15 mg per week) (Ref)

• Duration of use (Ref)

• Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), ciprofloxacin, penicillin-type drugs, sulfamethoxazole/trimethoprim, probenecid, phenytoin, and proton pump inhibitors (Ref)

Nephrotoxicity

Methotrexate may cause acute kidney injury (Ref). Increases in serum creatinine may persist more than 4 months after therapy discontinuation (Ref). Other kidney adverse reactions reported with methotrexate use include azotemia, cystitis, proteinuria, and hematuria.

Mechanism: Dose-related; acute kidney injury arises from 2 primary mechanisms: Crystal nephropathy and direct tubular toxicity (Ref). Methotrexate parent drug and metabolite accumulation in renal tubules cause crystal nephropathy and renal tubular obstruction that presents with asymptomatic serum creatinine elevations that progresses to tubular necrosis and kidney injury. Secondly, direct tubular toxicity and cellular injury occur as a result of oxygen radical formation in the kidney (Ref). A third mechanism of methotrexate-induced kidney injury is hyperhomocysteinemia in patients with deficient folate metabolism (Ref). Methotrexate-induced kidney damage decreases clearance and results in sustained and elevated plasma methotrexate concentrations which then lead to systemic toxicities including further kidney impairment, myelosuppression, hepatotoxicity, stomatitis, and in rare cases, multi-organ failure (Ref).

Onset: Varied; occurs as early as 36 hours after high-dose methotrexate infusion and as late as 9 years after chronic low-dose methotrexate (Ref).

Risk factors:

• Age >49 years (Ref)

• Concurrent use of salicylates, sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), ciprofloxacin, penicillin-type drugs, probenecid, and proton pump inhibitors (Ref)

• Conditions associated with extravascular fluid accumulation (eg, ascites, pleural effusions, intracranial fluid) (Ref)

• Higher doses or rapid infusion (Ref)

• Low albumin (Ref)

• Preexisting kidney impairment (Ref)

• Sex (males > females) (Ref)

• Tumor lysis syndrome (Ref)

• Volume depletion (Ref)

• Acidic urine (Ref)

Neurotoxicity

Neurotoxicity secondary to methotrexate administration has been reported manifesting as encephalopathy, headache, hemiparesis, and leukoencephalopathy. Seizure activity has also been reported. Aseptic meningitis, myelopathy, and chemical arachnoiditis have been reported with intrathecal (IT), intraventricular, or IV methotrexate. Chemical conjunctivitis occurs rarely and can be managed with local treatment and methotrexate can be safely administered intraocular to control autoimmune diseases that affect the eye (Ref). Chronic leukoencephalopathy is a delayed complication of IT or IV high-dose methotrexate (that can lead to significant long-term neurological impairment). It has been reported in CNS lymphoma patients with repeated cycles of high-dose methotrexate even in the absence of cranial irradiation. Neurotoxicity may be reversible in some instances, but fatalities have occurred (Ref). Acute neurotoxicity often resolves spontaneously, rarely having long-term sequelae (Ref). Acute encephalopathy, aseptic meningitis, and myelopathy often resolve within hours after each episode (Ref). Neurotoxicity rarely occurs with low-dose methotrexate administration.

Mechanism: Dose-related; may occur secondary to accumulations of adenosine and homocysteine in the CNS resulting in endothelial injury, ischemia, demyelination, and white matter necrosis (Ref). Methotrexate may also cause direct toxic effects to the nervous system (Ref). More recently, single nucleotide polymorphisms have been investigated as contributing to the development of leukoencephalopathy (Ref).

Onset: Varied; acute neurotoxicity symptoms occur within 24 hours (Ref). Acute encephalopathy, aseptic meningitis, and myelopathy can occur within minutes to hours after IT or IV methotrexate with repeated episodes occurring hours later (Ref). May also be delayed, like myelopathy developing several days to weeks after treatment (Ref). Chronic leukoencephalopathy may begin with gradual impairment of cognitive function months after methotrexate treatment (Ref). However, intellectual decline is observed at least 1 year after treatment (Ref).

Risk factors:

• Concurrent CNS radiation (Ref)

• Higher cumulative dose (Ref)

• Higher homocysteine levels (Ref)

• Higher plasma methotrexate to leucovorin ratio (Ref)

• Hypertension (Ref)

• Females (Ref)

• Age ≥10 years (Ref)

• Polymorphisms in genes associated with neurodevelopment (Ref)

• Shorter intervals between IT/IV doses (Ref)

Pulmonary toxicity

Methotrexate-induced pulmonary toxicity, including acute, subacute, and chronic interstitial pneumonitis has been reported with low-dose methotrexate treatment (Ref). Pulmonary toxicity, such as pneumonitis, is rarely observed with high-dose methotrexate; however, cases have been published (Ref). Pneumonitis is not always fully reversible, and fatalities have been reported (Ref).

Mechanism: Multiple proposed mechanisms; pneumonitis is considered an immune or hypersensitivity reaction related to toxic accumulations of methotrexate in lung tissue (Ref). Others have suggested methotrexate-induced injury to alveolar epithelial walls may play a role (Ref).

Onset: Varied; classified as either early-onset (<6 months) or late-onset (>6 months) (Ref). Most often occurs within the first year; however, has occurred as early as days after initiation (Ref) and as late as 30 years after use (Ref). May occur up to 20 months after discontinuation (Ref).

Risk factors:

• Low-dose methotrexate (Ref)

• Age >60 years (Ref)

• Chronic kidney disease (Ref)

• Diabetes (Ref)

• Hypoalbuminemia (Ref)

• Males (Ref)

• Preexisting lung disease (Ref)

• Previous use of disease-modifying antirheumatic drugs (DMARDs) (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions vary by route, dosage, and indication.

>10%:

Gastrointestinal: Diarrhea (≤11%), nausea (≤11%), vomiting (≤11%)

Hepatic: Increased liver enzymes (14% to 15%)

1% to 10%:

Dermatologic: Alopecia (≤10%), burning sensation of skin (psoriasis: 3% to 10%), dermatitis (rheumatoid arthritis: 1% to 3%), pruritus (rheumatoid arthritis: 1% to 3%), skin photosensitivity (3% to 10%), skin rash (≤3%)

Gastrointestinal: Stomatitis (2% to 10%)

Hematologic & oncologic: Leukopenia (1% to 3%; WBC <3000/mm3), pancytopenia (rheumatoid arthritis: 1% to 3%), thrombocytopenia (rheumatoid arthritis: 3% to 10%; platelet count <100,000/mm3)

Nervous system: Dizziness (≤3%), headache (polyarticular juvenile idiopathic arthritis: 1%)

Respiratory: Interstitial pneumonitis (rheumatoid arthritis: 1%)

Frequency not defined:

Cardiovascular: Arterial thrombosis, cerebral thrombosis, chest pain, deep vein thrombosis, hypotension, pericardial effusion, pericarditis, pulmonary embolism, retinal thrombosis, thrombophlebitis, vasculitis

Dermatologic: Acne vulgaris, dermal ulcer, diaphoresis, dyschromia, ecchymoses, erythema multiforme (Blanes 2005), erythematous rash, exacerbation of psoriasis (plaque erosion), exfoliative dermatitis, furunculosis, skin abnormalities related to radiation recall (Lee 2012), skin necrosis, Stevens-Johnson syndrome (Lee 2012), telangiectasia, toxic epidermal necrolysis (Sancheti 2016), urticaria (Pugi 2012)

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

Gastrointestinal: Abdominal distress (Braun 2008), anorexia, aphthous stomatitis, enteritis, gastrointestinal hemorrhage, gastrointestinal ulcer, gingivitis, hematemesis, intestinal perforation, melena, pancreatitis

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

Hematologic & oncologic: Agranulocytosis, aplastic anemia (Dubey 2016), bone marrow depression (nadir: 7 to 10 days), eosinophilia, hypogammaglobulinemia, lymphadenopathy, lymphoproliferative disorder, malignant lymphoma, neutropenia, non-Hodgkin's lymphoma (in patients receiving low-dose oral methotrexate), tumor lysis syndrome

Hepatic: Hepatic failure, hepatitis (acute)

Hypersensitivity: Nonimmune anaphylaxis

Infection: Cryptococcosis, cytomegalovirus disease (including cytomegaloviral pneumonia), herpes simplex infection, herpes zoster (Patel 2015), histoplasmosis (LeMense 1994), infection (Ibrahim 2018; Lee 2020), nocardiosis, sepsis, vaccinia (disseminated; following smallpox immunization)

Nervous system: Abnormal cranial sensation (has been reported at low dosage), aphasia, chemical arachnoiditis (intrathecal; acute), chills, cognitive dysfunction (has been reported at low dosage), drowsiness, dysarthria, fatigue, hemiparesis, leukoencephalopathy (may be chronic), malaise, mood changes (has been reported at low dosage), paresis, seizure, severe neurotoxicity (reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate), speech disturbance

Neuromuscular & skeletal: Arthralgia, bone fracture (stress), myalgia, myelopathy (intrathecal; subacute), osteonecrosis (with radiotherapy), osteoporosis

Ophthalmic: Blurred vision, conjunctivitis, eye pain, transient blindness

Otic: Tinnitus

Respiratory: Chronic obstructive pulmonary disease, cough, epistaxis, pharyngitis, pneumonia, pulmonary alveolitis, pulmonary fibrosis, respiratory failure, upper respiratory tract infection

Miscellaneous: Fever, nodule, tissue necrosis (with radiotherapy)

Postmarketing:

Cardiovascular: Cerebrovascular accident (Morgan 2011)

Dermatologic: Palmar-plantar erythrodysesthesia (Karol 2017), papular rash (Mebazaa 2008), photodermatitis (reactivation) (DeVore 2010)

Gastrointestinal: Mesenteric ischemia (acute; Morgan 2011)

Hematologic & oncologic: Severe anemia (after 2 years of low-dose methotrexate: more frequent: ≥4% to <10%) (Dubey 2016), skin carcinoma (Solomon 2020)

Hepatic: Exacerbation of hepatitis B (Ostuni 2003) hepatic cirrhosis (chronic therapy; varies from rare [<1%] to common [≥10%]) (Dubey 2016), hepatic fibrosis (chronic therapy: more frequent: ≥4% to <10%) (Dubey 2016; MacDonald 2005), hepatotoxicity (in patients treated with 1, 2, or 5 g/m2, grades ≥3: common: ≥10%) (Ozdemir 2016)

Hypersensitivity: Anaphylaxis (Pugi 2012), angioedema (Freeman 1999)

Ophthalmic: Eye irritation (Doroshow 1981), optic neuropathy (Clare 2005), xerophthalmia

Renal: Acute kidney injury (varies with dose; common [≥10%] to less frequent [≥1% to <4%]) (Gilani 2012, May 2014, Verstappen 2007, Wiczer 2015, Widemann 2004)

Respiratory: Acute respiratory distress (Morgan 2011), Mycobacterium avium complex (LeMense 1994), pleuritic chest pain (Sharma 1999), pneumonia due to Pneumocystis jirovecii (Albrecht 2010; Krebs 1996), tuberculosis (Binymin 2001)

Contraindications

History of severe hypersensitivity (including anaphylaxis) 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:

• Infections: Use methotrexate with extreme caution in patients with an active infection.

Disease-related concerns:

• Renal impairment: Dosing adjustment may be required.

Concurrent drug therapy issues:

• Nonsteroidal anti-inflammatory drugs: Do not administer nonsteroidal anti-inflammatory drugs (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 rheumatoid arthritis (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 (in patients with neoplastic diseases); folate deficiency may increase methotrexate toxicity. Folic acid supplementation may be indicated in patients receiving methotrexate for non-neoplastic conditions.

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.

Other warnings/precautions:

• Administration schedules: Fatal errors have occurred when methotrexate was administered as a daily dose instead of a weekly dose. Verify the indication before administration; methotrexate is typically only administered daily for an oncology-related indication. 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 all daily oral methotrexate orders, and provide patient and/or caregiver education for patients discharged on oral methotrexate (ISMP 2020).

• Intrathecal safety: When used for intrathecal administration, intrathecal medications 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 also intended for administration into the CNS, and administer immediately after a time-out/double-check procedure (ASCO/ONS [Neuss 2016]).

• 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.

Metabolism/Transport Effects

Substrate of BCRP/ABCG2, OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Methotrexate. Risk X: Avoid combination

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: Methotrexate may enhance the immunosuppressive effect of Baricitinib. Management: Concomitant use of baricitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modification

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

BCG Products: Methotrexate may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

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

Brincidofovir: Methotrexate may diminish the therapeutic effect of Brincidofovir. 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: Methotrexate may enhance the immunosuppressive effect of Cladribine. 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: Methotrexate may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing methotrexate several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

Cola-Containing Drinks: May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

COVID-19 Vaccine (Adenovirus Vector): Methotrexate may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Consider holding methotrexate for 2 weeks after the single vaccine dose for patients with stable underlying rheumatic disease. Additionally, give an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose. Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Methotrexate may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Methotrexate may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider holding methotrexate therapy (used for rheumatic disease) for 1 week after each vaccine dose when possible for patients with stable underlying disease. Consider a 3rd dose of COVID-19 vaccine in patients 5 years of age and older on methotrexate. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Methotrexate may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). 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 C: Monitor therapy

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

Dengue Tetravalent Vaccine (Live): Methotrexate may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Methotrexate. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants, such as methotrexate. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

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

Echinacea: May diminish the therapeutic effect of Methotrexate. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants, such as methotrexate. If coadministered, monitor for reduced efficacy of methotrexate during concomitant use. Risk D: Consider therapy modification

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

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

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

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

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

Influenza Virus Vaccines: Methotrexate may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating methotrexate if possible. If vaccination occurs less than 2 weeks prior to or during methotrexate therapy, revaccinate 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Inhibitors of the Proton Pump (PPIs and PCABs): May increase the serum concentration of Methotrexate. Management: Consider temporarily interrupting PPI or PCAB therapy in patients receiving high-dose methotrexate. If coadministered, monitor for increased methotrexate toxicity (eg, mucositis, myalgias) and/or delayed methotrexate elimination. Risk D: Consider therapy modification

Leflunomide: Methotrexate may enhance the adverse/toxic effect of Leflunomide. Specifically, the risks of hepatoxicity and hematologic toxicity may be increased. Management: If leflunomide is coadministered with methotrexate, initiate leflunomide 20 mg once daily without use of a loading dose. Monitor for methotrexate-induced hepatic toxicity frequently (see monograph for details) and monitor blood counts monthly. Risk D: Consider therapy modification

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. 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

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

Natalizumab: Methotrexate may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Neomycin: May decrease the serum concentration of Methotrexate. Neomycin may increase the serum concentration of Methotrexate. Risk C: Monitor therapy

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

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

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Methotrexate. Management: Avoid coadministration of higher dose methotrexate (such as that used for the treatment of oncologic conditions) and NSAIDs. Use caution if coadministering lower dose methotrexate and NSAIDs. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (Topical): May increase the serum concentration of Methotrexate. Risk C: Monitor therapy

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

Ofatumumab: Methotrexate may enhance the immunosuppressive effect of Ofatumumab. 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

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

Pimecrolimus: May enhance the immunosuppressive effect of Methotrexate. Risk X: Avoid combination

Pneumococcal Vaccines: Methotrexate may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Methotrexate may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Methotrexate may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving methotrexate. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

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

Probenecid: May increase the serum concentration of Methotrexate. Management: If possible, the concomitant use of methotrexate and probenecid should be avoided. If used concomitantly, monitor closely for increased methotrexate serum concentrations and toxicities. Methotrexate dose reductions may be needed. Risk D: Consider therapy modification

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

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

Rabies Vaccine: Methotrexate may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of methotrexate therapy if possible. If post-exposure rabies vaccination is required during methotrexate therapy, administer a 5th dose of vaccine and check for rabies antibodies on day 14. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Rubella- or Varicella-Containing Live Vaccines: Methotrexate may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Methotrexate may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Salicylates: May increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Management: Consider avoiding coadministration of methotrexate and salicylates. If coadministration cannot be avoided, monitor for increased toxic effects 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

Sipuleucel-T: Methotrexate may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of methotrexate prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: Methotrexate may enhance the immunosuppressive effect of Sphingosine 1-Phosphate (S1P) Receptor Modulator. Risk C: Monitor therapy

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): Methotrexate may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

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

Talimogene Laherparepvec: Methotrexate may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. 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 (Clinically Relevant). Risk C: Monitor therapy

Tertomotide: Methotrexate may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

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: Concomitant use of tofacitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modification

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

Typhoid Vaccine: Methotrexate may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Upadacitinib: Methotrexate may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modification

Vaccines (Inactivated): Methotrexate may diminish the therapeutic effect of Vaccines (Inactivated). Management: Administer vaccines at least 2 weeks prior to methotrexate initiation, if possible. If patients are vaccinated less than 14 days prior to or during methotrexate therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. 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

Valproate Products: Methotrexate may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Voriconazole: Methotrexate may enhance the photosensitizing effect of Voriconazole. Risk C: Monitor therapy

Yellow Fever Vaccine: Methotrexate may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Methotrexate may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Food Interactions

Methotrexate peak serum levels may be decreased if taken with food. Management: Administer without regard to food.

Reproductive Considerations

[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 patients who may become pregnant during therapy and for at least 6 months after the final methotrexate dose. Effective contraception is recommended for patients with partners who may become pregnant during therapy and for at least 3 months after the final dose of methotrexate. Patients treated with methotrexate for gestational trophoblastic diseases should use reliable contraception during therapy and throughout the follow-up period (SOGC [Eiriksson 2021]).

Patients treated for inflammatory bowel disease, psoriasis, or rheumatic and musculoskeletal diseases should discontinue methotrexate at least 3 months prior to becoming pregnant (ACR [Sammaritano 2020]; Mahadevan 2019; Rademaker 2018). Because methotrexate can cause embryo-fetal toxicity, including fetal death, use is contraindicated during pregnancy in patients with non-neoplastic diseases.

When methotrexate is used for the treatment of rheumatic and musculoskeletal diseases in patients undergoing ovarian stimulation for oocyte retrieval or embryo cryopreservation, methotrexate may be continued in patients whose rheumatic or musculoskeletal condition is stable and discontinuation of treatment may lead to uncontrolled disease (ACR [Sammaritano 2020]).

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 patients. When used for the medical management of ectopic pregnancy, methotrexate has not been shown to adversely affect fertility or ovarian reserve. Future pregnancies should be delayed until resolution of the ectopic pregnancy has been confirmed and at least 3 months after the last methotrexate dose (ACOG 2018).

Use of methotrexate may be considered for patients with rheumatic and musculoskeletal diseases or psoriasis who are planning to father a child (recommendation based on limited human data) (ACR [Sammaritano 2020]; Lamb 2019; Rademaker 2018).

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). [US Boxed Warning]: The use of methotrexate for the treatment of rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy.

Methotrexate is recommended for the medical management of tubal ectopic pregnancy in appropriately selected patients. Intrauterine pregnancy should be excluded prior to methotrexate use. Various protocols are available; the choice should consider the initial hCG level and the risks and benefits of methotrexate treatment to the individual patient (ACOG 2018; ASRM 2013). Use of methotrexate for some nontubal ectopic pregnancies (eg, Cesarean scar, cervical or abdominal) has been described, however data are insufficient to make specific dosing recommendations (ASRM 2013; RCOG [Elson 2016]; SOGC [Po 2021]).

Methotrexate has been used for the medical termination of intrauterine pregnancy with a gestational age up to 49 days when misoprostol/mifepristone is not available or contraindications to that combination are present. A regimen containing methotrexate should not be used in patients with hemoglobin <9.5 g/dL, intrauterine device in place, diagnosis of inflammatory bowel disease, active hepatic or renal disease, hemorrhagic disorders, or concomitant use of anticoagulation therapy (Creinin 1996; SOGC [Costescu 2016]; Stubblefield 2004).

Breastfeeding Considerations

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

Information related to the use of methotrexate in patients who are breastfeeding 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 in patients who wish to breastfeed vary. Breastfeeding is contraindicated by some manufacturers during treatment. Other manufacturers recommend discontinuing breastfeeding during treatment and for 1 week after the final methotrexate dose.

Available guidelines contraindicate breastfeeding in patients taking methotrexate for the treatment of tubal ectopic pregnancy (ACOG 2018; ASRM 2013). Use of methotrexate is not recommended in breastfeeding patients when used for the treatment of inflammatory bowel disease (Mahadevan 2019), rheumatic and musculoskeletal diseases (ACR [Sammaritano 2020]), 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, alternative medications are recommended in patients who are breastfeeding (Ito 2000). If an infant is exposed to lower doses of methotrexate (maternal doses <0.4 mg/kg/week) via breast milk, consider monitoring the infant CBC at 1 and 3 months of age (Rademaker 2018).

Dietary Considerations

Some products may contain sodium.

Monitoring Parameters

Dermatologic toxicity, complications of hematologic toxicity, signs and symptoms of infection (during and after treatment); signs and symptoms of pneumonitis (particularly dry, nonproductive cough; fever, dyspnea, hypoxemia, or pulmonary infiltrate); 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. For high-dose methotrexate regimens, monitor serum creatinine and electrolytes at baseline and at least daily and monitor methotrexate levels, urine output, and urine pH at least daily. 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. The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Psoriasis:

CBC and LFTs (baseline and every 3 to 6 months, if no abnormal results); hepatitis B and C screening (baseline); pretreatment test for latent TB (baseline); chest radiograph with positive TB test (AAD/NPF [Menter 2020]).

Patients with impaired kidney function: BUN and creatine, CBC 5 to 7 days after test dose (AAD/NPF [Menter 2020]).

Liver biopsy: Baseline liver biopsy is not recommended. If persistent elevations in liver enzymes during a 12-month period or decline of serum albumin below the normal range with normal nutritional status, consider a biopsy. If abnormal baseline noninvasive blood serology in patients with risk factors for hepatotoxicity or after cumulative dose of 3.5 to 4 g, consider biopsy based on GI consult or vibration controlled transient elastography (AAD/NPF [Menter 2020]).

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 (baseline and at least monthly), renal function (baseline and 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; ACG [Lichtenstein 2018]): 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); renal function (baseline and periodic).

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 2018; RCOG [Elson 2016]). CBC with differential (baseline and periodic), LFTs, serum creatinine (baseline and periodic), blood type and Rh (ASRM 2013). Evaluate for medical conditions considered absolute contraindications for methotrexate treatment of ectopic pregnancy (ACOG 2018).

Single-dose regimen: Baseline serum hCG level on day 1 and posttreatment serum hCG levels on days 4 and 7; if the serum hCG decrease from day 4 to 7 is ≥15%, continue to measure serum hCG weekly until reaching a nonpregnant level. Consider surgical management if serum hCG does not decrease adequately after 3 doses. If serum hCG levels plateau or increase during follow-up period, consider methotrexate for treatment of persistent ectopic pregnancy or surgical management (ACOG 2018; Tulandi 2021).

Two-dose regimen: Baseline serum hCG level on day 1 and posttreatment serum hCG level on day 7, 11, and 14; if the serum hCG decrease is ≥15%, continue to measure serum hCG weekly until reaching a nonpregnant level. Consider surgical management if serum hCG does not decrease adequately after 4 doses. If hCG levels plateau or increase during follow-up period, consider methotrexate for treatment of persistent ectopic pregnancy or surgical management (ACOG 2018; Tulandi 2021).

Multidose regimen (in combination with leucovorin): Measure serum hCG on days of methotrexate administration. Once the serum hCG decrease is ≥15%, continue to measure serum hCG weekly until reaching a nonpregnant level. Consider surgical management if serum hCG does not adequately decrease after 5 doses. If hCG levels plateau or increase during follow-up period, consider methotrexate for treatment of persistent ectopic pregnancy or surgical management (ACOG 2018; Tulandi 2021).

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

Mechanism of Action

Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. Methotrexate 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.

Pharmacokinetics

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.

Vd: 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 (oral): 3 to 10 hours; High dose (IV): 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%).

Pharmacokinetics: Additional Considerations

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

Pricing: US

Solution (Methotrexate Sodium (PF) Injection)

1 g/40mL (per mL): $1.00 - $1.10

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

250 mg/10 mL (per mL): $1.08 - $1.14

Solution (Methotrexate Sodium Injection)

50 mg/2 mL (per mL): $4.36

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

Solution (Xatmep Oral)

2.5 mg/mL (per mL): $21.14

Solution (reconstituted) (Methotrexate Sodium Injection)

1 g (per each): $54.00 - $76.32

Solution Auto-injector (Otrexup Subcutaneous)

10 mg/0.4 mL (per 0.4 mL): $206.44

12.5 mg/0.4 mL (per 0.4 mL): $206.44

15 mg/0.4 mL (per 0.4 mL): $206.44

17.5 mg/0.4 mL (per 0.4 mL): $206.44

20 mg/0.4 mL (per 0.4 mL): $206.44

22.5 mg/0.4 mL (per 0.4 mL): $206.44

25 mg/0.4 mL (per 0.4 mL): $206.44

Solution Auto-injector (Rasuvo Subcutaneous)

7.5 mg/0.15 mL (per 0.15 mL): $152.70

10 mg/0.2 mL (per 0.2 mL): $152.70

12.5 mg/0.25 mL (per 0.25 mL): $152.70

15 mg/0.3 mL (per 0.3 mL): $152.70

17.5 mg/0.35ml (per 0.35 mL): $152.70

20 mg/0.4 mL (per 0.4 mL): $152.70

22.5 mg/0.45ml (per 0.45 mL): $152.70

25 mg/0.5 mL (per 0.5 mL): $152.70

30 mg/0.6 mL (per 0.6 mL): $152.70

Solution Prefilled Syringe (RediTrex Subcutaneous)

7.5 mg/0.3 mL (per 0.3 mL): $93.75

10 mg/0.4 mL (per 0.4 mL): $93.75

12.5 mg/0.5 mL (per 0.5 mL): $93.75

15 mg/0.6 mL (per 0.6 mL): $93.75

17.5 mg/0.7 mL (per 0.7 mL): $93.75

20 mg/0.8 mL (per 0.8 mL): $93.75

22.5 mg/0.9 mL (per 0.9 mL): $93.75

25 mg/mL (per mL): $93.75

Tablets (Methotrexate Oral)

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

Tablets (Methotrexate Sodium Oral)

2.5 mg (per each): $3.56 - $4.05

Tablets (Trexall Oral)

5 mg (per each): $21.14

7.5 mg (per each): $31.71

10 mg (per each): $42.28

15 mg (per each): $63.42

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.

Brand Names: International
  • Abitrexate (IL, SG, TH, TW, ZA, ZW);
  • Alltrex (LK, PH);
  • Artrait (AR, PE);
  • Atrexel (MX);
  • Bertanel (ES);
  • Biotrexate (IN);
  • Brimexate (IT);
  • Canceren (KR);
  • Cytotrex (LK);
  • Ebetrex (LV, SE);
  • Ebetrexat (AE, AT, BG, LB);
  • Ebetrexate (BE);
  • Emthexat (SE);
  • Emthexate (AT, BE, GR, HK, ID, JO, KW, MY, NL, PH, PK, PT, TH, TR, TW, ZA);
  • Emthexate PF (EG, KR);
  • Emthrxate (SI);
  • Ervemin (AR);
  • Hytas (BR);
  • Imutrex (LK);
  • Jylamvo (BE);
  • Lantarel (DE);
  • Ledertrexate (BE, FR, LU, MX, NZ);
  • Ledertrexato (PT);
  • Maxtrex (GB);
  • Medsatrexate (MX);
  • Meisusheng (CN);
  • Merox-50 (ET);
  • Metex (LV, NO, PT);
  • Methaccord (AU);
  • Methacor (ZA);
  • 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 (HK, ID, MY, PH, TH, TW);
  • Methotrexate Faulding (SE);
  • Methotrexate Pharmacia (SE);
  • Methotrexate Wyeth Lederle (SE);
  • Methotrexate ”Lederle” (HU);
  • Methotrexate[inj.] (HR, IT);
  • Methotrexato (EC);
  • Methox (BD);
  • Methtrexx (CH);
  • Metoject (CH, CZ, DK, ES, FR, HU, IE, IL, LB, RO, RU, SE, 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);
  • Nordimet (CH);
  • Novatrex (FR);
  • Onkomet (TH);
  • Otaxem (MX);
  • P&U Methotrexate (ZA);
  • Pterin (PH);
  • Quinux (ES);
  • Reumaflex (IT);
  • Reumatrex (PE);
  • Rheu-Trex (ID);
  • Rheumatrex (JP);
  • Sactiva (IT);
  • Sanotrexat (ID);
  • Securact (IT);
  • Tasxate (TH);
  • Texate (MX);
  • Trexan (CZ, EE, FI, HN, HU, LT, PL, SG, TR, TW);
  • Trexate (NZ);
  • Trexject (AU);
  • Trexol (LK);
  • Trexonate (BD);
  • Trexxol (ET);
  • Trixilem (MX, TH);
  • Unitrexates (VN);
  • Xantromid (PY);
  • Zexat (RU);
  • Zexate (ET, PH, UY, VE, VN, ZW);
  • Zlatel (GB)


For country abbreviations used in Lexicomp (show table)

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