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Methotrexate: Pediatric drug information

Methotrexate: Pediatric drug information
(For additional information see "Methotrexate: Drug information" and see "Methotrexate: Patient 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 infections and 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 can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate is contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception during and after treatment.

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
  • Jylamvo;
  • Otrexup;
  • Rasuvo;
  • RediTrex [DSC];
  • Trexall;
  • Xatmep
Brand Names: Canada
  • ACH-Methotrexate;
  • AURO-Methotrexate;
  • JAMP-Methotrexate [DSC];
  • Metoject;
  • PMS-Methotrexate
Therapeutic Category
  • Antineoplastic Agent, Antimetabolite;
  • Antirheumatic, Disease Modifying
Dosing: Pediatric

Dosage guidance:

Safety: Only preservative-free formulations should be used for intrathecal administration and for high-dose methotrexate regimens. Methotrexate doses between 100 to 500 mg/m2 may require leucovorin calcium rescue. Methotrexate doses >500 mg/m2 require leucovorin calcium rescue.

Dosing: 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 (including fatality) may occur if administered incorrectly (eg, if a weekly dose is given daily); 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.

Clinical considerations: Antiemetic prophylaxis: 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 (Ref); antiemetics may be recommended to prevent nausea and vomiting.

Acute lymphoblastic leukemia of infancy

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 depend on protocol phase (Ref).

Acute lymphoblastic leukemia/lymphoma, immature B-cell

Acute lymphoblastic leukemia (ALL)/lymphoma (LBL), immature B-cell : Limited data available; multiple regimens reported:

Note: Intrathecal therapy is also administered (refer to specific reference for intrathecal dosing used within protocol); methotrexate should be used as 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) in combination with vincristine, mercaptopurine, and intrathecal methotrexate (Ref).

Escalating-dose methotrexate (Capizzi [C-MTX]): Children and Adolescents: IV: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total in combination with vincristine, pegaspargase, and intrathecal methotrexate (Ref).

Maintenance: Children and Adolescents: Oral: 20 mg/m2 once weekly in combination with vincristine, prednisone, mercaptopurine, and intrathecal methotrexate. On weeks intrathecal methotrexate is administered, consider holding the oral methotrexate for that week; refer to specific protocol (Ref).

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 (Ref):

<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.

Acute lymphoblastic leukemia/lymphoma, immature T-cell

Acute lymphoblastic leukemia (ALL)/lymphoma (LBL), immature T-cell: Limited data available; multiple regimens reported:

Note: Intrathecal therapy is also administered (refer to specific reference for intrathecal dosing used within protocol); methotrexate should be used as part of a combination regimen; refer to specific protocols:

Interim maintenance:

Escalating-dose methotrexate (Capizzi [C-MTX]): Children and Adolescents: IV: Initial dose: 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total in combination with vincristine and pegaspargase (Ref).

CNS prophylaxis intrathecal therapy: Children and Adolescents: Intrathecal: Age-adjusted dosing: Days of administration vary based on risk status and protocol; refer to protocol for details (Ref):

1 to <2 years: 8 mg.

2 to <3 years: 10 mg.

3 to <9 years: 12 mg.

≥9 years: 15 mg.

CNS tumors, malignant

CNS tumors, malignant (medulloblastoma, PNET, ependymoma, brainstem glioma): Limited data available:

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 autotransplant) (Ref).

Crohn disease

Crohn disease: Limited data available:

BSA-directed dosing: 15 mg/m2 once weekly; maximum dose: 25 mg/dose (Ref).

Fixed dosing (Ref).

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.

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.

Dermatomyositis

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 (Ref).

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 (Ref).

Graft-versus-host disease, acute, prophylaxis

Graft-versus-host disease (aGVHD), acute, prophylaxis: Limited data available:

Note: Multiple regimens reported and may vary by dose and frequency of dosing.

Standard dose: 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) (Ref) 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) (Ref). Leucovorin rescue may be administered according to protocol.

Mini-dose: Children and Adolescents: IV: 5 mg/m2/dose; frequency of dosing reported is variable; following haploidentical stem cell transplant, doses were administered on days 5, 7, 10, and 15 in combination with posttransplant cyclophosphamide and cyclosporine and leucovorin rescue administered 24 hours after methotrexate dose (Ref); following cord blood transplant, doses were administered on days 1, 3, and 6 in combination with tacrolimus (Ref).

Juvenile idiopathic arthritis, polyarticular

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 (Ref). 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 (Ref).

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 are unchanged after 4 weeks, may increase to SUBQ: 1 mg/kg; maximum dose: 25 mg/dose (Ref).

Meningeal leukemia, prophylaxis or treatment

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 in 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 BSA; CSF volume correlates with age and not to BSA (Ref):

Infants, Children, and Adolescents: Intrathecal (Ref):

<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.

Non-Hodgkin lymphoma, mature B-cell

Non-Hodgkin lymphoma, mature B-cell:

Intermediate risk: Limited data available (Ref): 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 (Ref): 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 depend on protocol phase and clinical factors (eg, CNS positive).

Non-Hodgkin lymphoma, mature T-cell

Non-Hodgkin lymphoma, mature T-cell (anaplastic large cell lymphoma [ALCL]): Limited data available: Note: Both intravenous and intrathecal methotrexate dosing were part of protocol; use extra precaution ensuring route and dose.

Infants, Children, and Adolescents: IV: 3,000 mg/m2 over 3 hours with leucovorin rescue (in combination with multi-agent chemotherapy, depending on cycle) for a total of 6 cycles (Ref).

Osteosarcoma

Osteosarcoma: 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) (Ref); reported frequencies and durations have varied (Ref).

Psoriasis, severe; recalcitrant to topical therapy

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 (Ref).

Scleroderma, localized

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 (Ref).

Uveitis, recalcitrant

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 (Ref); 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 (Ref).

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

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:

Myelosuppression: Withhold, reduce dose, or discontinue methotrexate as appropriate; refer to individual protocol; provide supportive care as needed.

Profound granulocytopenia and fever: Evaluate immediately; consider broad-spectrum parenteral antimicrobial coverage. Withhold, reduce dose, or discontinue methotrexate as appropriate.

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 (Ref):

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 (Ref):

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

Bilirubin >5 mg/dL: Avoid use.

Dosing: Adult

(For additional information see "Methotrexate: Drug information")

Dosage guidance:

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 (Ref). Only preservative-free formulations should be used for intrathecal administration and for high-dose methotrexate regimens. 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).

Dosing: For nononcology uses, 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 (Ref). 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) (Ref).

Clinical considerations: Antiemetic prophylaxis: Methotrexate IV doses ≥250 mg/m2 are associated with moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting.

Oncology uses :

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 (Ref).

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 (Ref).

CNS prophylaxis/interim maintenance phase:

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

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

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

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) (Ref).

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

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

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) (Ref).

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) (Ref).

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 (Ref).

Acute promyelocytic leukemia, maintenance phase

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

Oral: 15 mg/m2 once weekly for 2 years (Ref) or 20 mg/m2 once weekly for 1 year (Ref).

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

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 (Ref).

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 (Ref) 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 (Ref) 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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

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

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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

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 (Ref).

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) (Ref).

Graft-versus-host disease, acute, prophylaxis

Graft-versus-host disease, acute, prophylaxis (off-label use): IV: 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) (Ref) or 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) (Ref) 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 (Ref).

Head and neck cancer

Head and neck cancer (squamous cell carcinoma): IV: 40 mg/m2 once weekly until disease progression or unacceptable toxicity (Ref).

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 (Ref) 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 (Ref) 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 (Ref) or 7.5 mg/m2 once weekly (Ref).

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 (Ref).

Non-Hodgkin lymphoma

Non-Hodgkin lymphoma:

Burkitt lymphoma:

Modified CODOX-M/IVAC regimen ± rituximab (Ref): 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) (Ref).

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) (Ref).

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) (Ref).

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 (Ref) or 10 mg twice weekly for 4 weeks, then weekly for 1 month, then every 2 weeks for 2 months (Ref) or 10 to 15 mg twice weekly for 4 weeks, then once weekly for 4 weeks, then a maintenance regimen of once a month (Ref).

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) (Ref); 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 (Ref).

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) (Ref) 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 (Ref) or autologous stem cell transplant (Ref) 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 (Ref) 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 (Ref) 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 (Ref).

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 (Ref) 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 (Ref).

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 (Ref).

Nononcology uses:

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 (in combination with folic acid). 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) (Ref). Consider discontinuation if no improvement after 12 to 16 weeks on dosages ≥15 mg/week (Ref).

Bullous pemphigoid

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

Oral, IM, SUBQ: Initial: 5 mg once weekly (in combination with folic acid); often also 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 (Ref). Consider discontinuation if no improvement after 4 weeks on dosages ≥15 mg/week (Ref).

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 (Ref). 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 (in combination with folic acid); 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 (Ref).

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 (Ref).

Oral, SUBQ, IM: Initial: 5 to 15 mg once weekly (in combination with folic acid). 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 (Ref).

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 (Ref).

Oral, SUBQ, IM: Initial: 7.5 to 15 mg once weekly (in combination with folic acid); 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) (Ref).

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 (in combination with folic acid) (Ref).

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 combination with glucocorticoids) in patients with mild disease, or as maintenance therapy; efficacy data are limited (Ref).

Oral, SUBQ: Initial: 15 mg once weekly (in combination with folic acid), 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 (Ref).

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 (Ref).

Oral, SUBQ: Initial: 10 to 15 mg once weekly (in combination with folic acid) (Ref). Adjust dose by 2.5 to 5 mg/week if needed based on response (usual dosage range: 7.5 to 15 mg/week; some experts use doses up to 25 mg/week); may discontinue therapy after 24 months if disease remission is achieved (Ref).

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 (Ref).

Oral, SUBQ, IM: Initial: 15 to 20 mg once weekly (in combination with folic acid), 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 (Ref).

Lichen sclerosus, extragenital, extensive

Lichen sclerosus, extragenital, extensive (adjunctive agent) (off-label use):

Note: For use in patients with persistent, active disease despite topical corticosteroids; may use with systemic glucocorticoids for rapidly progressing disease. Efficacy data are limited (Ref).

Oral, SUBQ, IM : Initial: 10 to 15 mg once weekly (in combination with folic acid); may increase to 17.5 to 25 mg once weekly after 4 to 12 weeks if needed based on response. If remission is sustained after 6 to 9 months, may gradually taper dosage (eg, reduce by 2.5 mg/week every 2 to 4 weeks) until lowest effective dose or discontinued (Ref).

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 (Ref).

SUBQ, Oral: 12.5 to 25 mg once weekly (in combination with folic acid). May gradually taper therapy after 6 to 12 months of disease inactivity (usual total duration: 1 to 2 years) (Ref). Note: May consider a second (or third) course of methotrexate in patients who experience disease relapse (Ref).

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 (in combination with folic acid). Adjust dose gradually (eg, every 4 to 8 weeks) if needed based on response (usual dosage range: 7.5 to 25 mg/week); do not exceed 30 mg/week (Ref).

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 (in combination with folic acid). 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 (Ref).

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 (Ref).

Oral, SUBQ, IM: Initial: 5 to 7.5 mg once weekly (in combination with folic acid). Increase dose gradually (eg, by 2.5 mg/week every 2 weeks) if needed up to 20 mg/week; usual dosage range: 10 to 15 mg/week (Ref).

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 (Ref).

SUBQ, Oral: Initial: 7.5 to 15 mg once weekly (in combination with glucocorticoids and folic acid). 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 (Ref).

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 (Ref).

Oral, SUBQ: Initial: 10 to 15 mg once weekly (in combination with folic acid); increase dose by 2.5 mg/week every week if needed after the first 4 weeks based on response (maximum: 25 mg/week) (Ref). 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 (Ref).

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 (Ref).

Oral, SUBQ: Initial: 5 to 15 mg once weekly (in combination with folic acid). Increase dose gradually (eg, by 2.5 mg/week every 4 weeks) if needed based on response (maximum: 20 to 25 mg/week) (Ref).

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 (Ref).

Oral, SUBQ: Initial: 10 mg once weekly (in combination with folic acid); adjust dose by 2.5 mg/week every 4 weeks up to target dose of 15 to 25 mg/week (Ref).

Takayasu arteritis

Takayasu arteritis (off-label use): Oral, SUBQ: Initial: 15 mg once weekly in combination with a glucocorticoid and folic acid. Increase dose by 2.5 to 5 mg/week every 1 to 2 weeks if needed based on response (maximum: 25 mg/week) (Ref).

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 (Ref). Do not administer folic acid (including folic acid-containing vitamins) during methotrexate therapy for this indication (Ref).

IM: 50 mg/m2 once, followed by vaginal misoprostol 3 to 7 days later (Ref); maximum dose has not been established; some experts do not exceed a methotrexate dose of 100 mg (Ref).

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 (Ref). 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 (Ref).

IM: 50 mg/m2 on day 1; maximum dose has not been established; 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 (maximum dose has not been established; some experts do not exceed 100 mg/dose for each dose). Consider surgical management if hCG does not adequately decrease after 3 doses (Ref).

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

IM: 50 mg/m2 on days 1 and 4; maximum dose has not been established; some experts do not exceed 100 mg/dose for each dose. Measure serum hCG level on days 1, 4, and 7; if the hCG decrease from day 4 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 (Ref).

Multidose regimen (in combination with leucovorin): IM: 1 mg/kg on day 1; maximum dose has not been established; 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; maximum dose has not been established; 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) (Ref).

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 (Ref).

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 (Ref).

Peritoneal dialysis: Cases of methotrexate toxicity (including death) have been reported in peritoneal dialysis patients receiving methotrexate, even at low doses. Avoid use (Ref).

CRRT: Administer 50% of methotrexate dose (Ref).

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 (Ref)): 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 (Ref).

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 (Ref)); CrCl is measured or can be calculated using the Cockcroft-Gault equation (Ref): 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 (Ref):

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.

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 pustular rash (Ref), hyperpigmentation (Ref), 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)

• Exposure to UV radiation may aggravate psoriasis

• Excessive sun exposure

• 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 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 (16%) (Sherbini 2022), nausea (31%) (Sherbini 2022), oral mucosal ulcer (11%) (Sherbini 2022), vomiting (≤11%)

Hepatic: Hepatic cirrhosis (chronic therapy; <1% to ≥10%) (Dubey 2016), hepatotoxicity (in patients treated with 1, 2, or 5 g/m2, grades ≥3: ≥10%) (Ozdemir 2016), increased liver enzymes (14% to 15%; increased serum alanine aminotransferase: >1 × ULN: 20%; >2 × ULN: 4% [Sherbini 2022])

Nervous system: Dizziness (13%) (Sherbini 2022), fatigue (31%) (Sherbini 2022), headache (19%) (Sherbini 2022)

Respiratory: Cough (16%) (Sherbini 2022)

1% to 10%:

Dermatologic: Alopecia (≤10%), burning sensation of skin (psoriasis: 3% to 10%), dermatitis (rheumatoid arthritis: 1% to 3%), pruritus (9%) (Sherbini 2022), skin photosensitivity (3% to 10%), skin rash (≤3%)

Endocrine & metabolic: Weight loss (5%) (Sherbini 2022)

Gastrointestinal: Anorexia (4%) (Sherbini 2022), stomach pain (9%) (Sherbini 2022), stomatitis (2% to 10%)

Hematologic & oncologic: Anemia (3% [Sherbini 2022]; severe anemia [after 2 years of low-dose methotrexate: ≥4% to <10%] [Dubey 2016]), leukopenia (1% to 3%; WBC <3000/mm3), neutropenia (≤1%) (Sherbini 2022), pancytopenia (rheumatoid arthritis: 1% to 3%), thrombocytopenia (rheumatoid arthritis: 3% to 10%; platelet count <100,000/mm3)

Hepatic: Hepatic fibrosis (chronic therapy: ≥4% to <10%) (Dubey 2016; MacDonald 2005)

Infection: Chest infection (3%) (Sherbini 2022)

Ophthalmic: Blurred vision (5%) (Sherbini 2022)

Respiratory: Dyspnea (6%) (Sherbini 2022), interstitial pneumonitis (rheumatoid arthritis: 1%), pharyngitis (8%) (Sherbini 2022)

Miscellaneous: Fever (3%) (Sherbini 2022)

Frequency not defined:

Cardiovascular: Chest pain

Dermatologic: Diaphoresis, dyschromia, exacerbation of psoriasis (plaque erosion)

Gastrointestinal: Aphthous stomatitis, enteritis, gastrointestinal hemorrhage

Genitourinary: Dysuria, infertility, oligospermia, vaginal discharge

Hematologic & oncologic: Agranulocytosis, bone marrow depression, eosinophilia, malignant lymphoma, non-Hodgkin lymphoma (in patients receiving low-dose oral methotrexate), tumor lysis syndrome

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

Nervous system: Chemical arachnoiditis (intrathecal; acute), chills, malaise

Neuromuscular & skeletal: Osteonecrosis (with radiotherapy)

Ophthalmic: Eye discomfort, transient blindness

Otic: Tinnitus

Respiratory: Epistaxis, pneumonia, upper respiratory tract infection

Miscellaneous: Tissue necrosis (with radiotherapy)

Postmarketing:

Cardiovascular: Arterial thrombosis, deep vein thrombosis, heart failure (Shah 2022), hypotension, pericarditis (Guevara 2023), pulmonary embolism, thrombophlebitis, vasculitis

Dermatologic: Acne vulgaris, cutaneous nodule (Kwon 2023), dermal ulcer (Bahnson 2021), ecchymoses, erythema multiforme (Blanes 2005), erythematous rash, exfoliative dermatitis, furunculosis, palmar-plantar erythrodysesthesia (Karol 2017), papular rash (Mebazaa 2008), photodermatitis (reactivation) (DeVore 2010), skin abnormalities related to radiation recall (Lee 2012), skin carcinoma (including basal cell carcinoma of skin, malignant melanoma, squamous cell carcinoma of skin) (Polesie 2023; Solomon 2020), skin necrosis, Stevens-Johnson syndrome (Lee 2012), telangiectasia, toxic epidermal necrolysis (Sancheti 2016), urticaria (Pugi 2012)

Endocrine & metabolic: Decreased libido (AlEssa 2021), decreased serum albumin, diabetes mellitus, gynecomastia, hyperglycemia, menstrual disease

Gastrointestinal: Abdominal distress (Braun 2008), gastrointestinal ulcer (Tun 2023), gingivitis, hematemesis, hemorrhagic gastroenteritis, intestinal perforation, melena, mesenteric ischemia (acute; Morgan 2011), pancreatitis

Genitourinary: Azotemia, crystalluria (Santiago 2020), cystitis, defective oogenesis, defective spermatogenesis, erectile dysfunction, hematuria, proteinuria

Hematologic & oncologic: Aplastic anemia (Dubey 2016), febrile neutropenia (Bayraktar 2021), hypogammaglobulinemia, lymphadenopathy, lymphoproliferative disorder (including intestinal follicular lymphoma, large B-cell lymphoma, T-cell lymphoma [follicular]) (Muto 2021; Osaki 2021), myelodysplastic syndrome (Khan 2023)

Hepatic: Exacerbation of hepatitis B (Ostuni 2003), hepatic failure (Miyata 2023), hepatitis (acute)

Hypersensitivity: Anaphylaxis (Pugi 2012), angioedema (Freeman 1999), hypersensitivity angiitis (Dewan 2021), nonimmune anaphylaxis, severe hypersensitivity reaction (including hyperpigmentation, pustular rash, severe stomatitis) (Shafie 2021)

Infection: Herpes zoster infection (Patel 2015), histoplasmosis (LeMense 1994), infection (Ibrahim 2018; Lee 2020), septicemia (Tiewsoh 2021)

Local: Hypersensitivity reaction at injection site (including fixed drug eruption at injection site) (Sadoghi 2021), injection-site reaction (including tissue necrosis at injection site)

Nervous system: Abnormal cranial sensation (has been reported at low dosage), cerebral thrombosis, cerebrovascular accident (Morgan 2011), cognitive dysfunction (has been reported at low dosage), drowsiness, encephalopathy (Teshima 2021), leukoencephalopathy (may be chronic) (Magge 2015), mood changes (has been reported at low dosage), neurotoxicity (including hemiparesis, stroke-like syndromes) (Dabagh 2020; Leitão Santos 2023; Yap 2016), paresis, seizure (Dabagh 2020), speech disturbance (including aphasia, dysarthria)

Neuromuscular & skeletal: Arthralgia, bone fracture (including stress) (Singh 2023), myalgia, myelopathy (intrathecal; subacute) (Bidikian 2021), osteoporosis

Ophthalmic: Conjunctivitis, dry eye syndrome, eye irritation (Doroshow 1981), eye pain, optic neuropathy (Clare 2005), retinal thrombosis

Renal: Acute kidney injury (Gilani 2012; May 2014; Verstappen 2007; Wiczer 2015; Widemann 2004)

Respiratory: Acute respiratory distress (Morgan 2011), chronic obstructive pulmonary disease, Mycobacterium avium complex (LeMense 1994), pleuritic chest pain (Sharma 1999), pneumonia due to Pneumocystis jirovecii (Albrecht 2010; Krebs 1996), pulmonary alveolitis, pulmonary fibrosis, respiratory failure, thickening of pleura, 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, alcohol use disorder, 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.

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

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.

Dosage Forms: US

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

Solution, Injection:

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

Solution, Injection [preservative free]:

Generic: 1 g/40 mL (40 mL); 250 mg/10 mL (10 mL); 50 mg/2 mL (2 mL)

Solution, Oral:

Jylamvo: 2 mg/mL (60 mL) [contains ethylparaben, methylparaben sodium, polyethylene glycol (macrogol)]

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 [DSC]); 10 mg/0.4 mL (0.4 mL [DSC]); 12.5 mg/0.5 mL (0.5 mL [DSC]); 15 mg/0.6 mL (0.6 mL [DSC]); 17.5 mg/0.7 mL (0.7 mL [DSC]); 20 mg/0.8 mL (0.8 mL [DSC]); 22.5 mg/0.9 mL (0.9 mL [DSC]); 25 mg/mL (1 mL [DSC])

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

Pricing: US

Solution (Jylamvo Oral)

2 mg/mL (per mL): $17.53

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): $24.10

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): $220.68

12.5 mg/0.4 mL (per 0.4 mL): $220.68

15 mg/0.4 mL (per 0.4 mL): $220.68

17.5 mg/0.4 mL (per 0.4 mL): $220.68

20 mg/0.4 mL (per 0.4 mL): $220.68

22.5 mg/0.4 mL (per 0.4 mL): $220.68

25 mg/0.4 mL (per 0.4 mL): $220.68

Solution Auto-injector (Rasuvo Subcutaneous)

7.5 mg/0.15 mL (per 0.15 mL): $163.20

10 mg/0.2 mL (per 0.2 mL): $163.20

12.5 mg/0.25 mL (per 0.25 mL): $163.20

15 mg/0.3 mL (per 0.3 mL): $163.20

17.5 mg/0.35ml (per 0.35 mL): $163.20

20 mg/0.4 mL (per 0.4 mL): $163.20

22.5 mg/0.45ml (per 0.45 mL): $163.20

25 mg/0.5 mL (per 0.5 mL): $163.20

30 mg/0.6 mL (per 0.6 mL): $163.20

Tablets (Methotrexate Sodium Oral)

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

Tablets (Trexall Oral)

5 mg (per each): $25.30

7.5 mg (per each): $37.95

10 mg (per each): $50.60

15 mg (per each): $75.90

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.

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 ([DSC]); 10 mg/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

Extemporaneous Preparations

Note: A methotrexate oral solution (2 mg/mL) is commercially available (Jylamvo).

2 mg/mL Oral Solution

To prepare a 2 mg/mL methotrexate oral solution, first prepare a stock diluent solution by mixing 250 mL of 0.05% saccharin in cherry-flavored glycol or aqueous base, add sodium bicarbonate 20 g, then add a sufficient quantity of chloroform water solution to a final volume of 1,000 mL. Chloroform water solution may be prepared with 2.5 mL of pharmaceutical-grade chloroform added to 997.5 mL of distilled water. Prepare the 2 mg/mL methotrexate oral solution using 1.6 mL of 25 mg/mL methotrexate injection (preservative free) and add to 18.4 mL of the prepared stock diluent solution. The methotrexate 2 mg/mL oral solution is stable for 1 month at room temperature or refrigerated in clear or amber glass storage bottles.

Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31(2):164-192.

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 (Ref); 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 (Ref).

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.

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. Jylamvo: Only use the oral syringe that is provided as a measuring device.

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.

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).

Storage/Stability

Injection: Note: Storage times vary by product; refer to individual product labeling for details. Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

IV, IM, or SUBQ: Store intact vials, autoinjectors, and prefilled syringes between 20°C and 25°C (68°F and 77°F); excursions may be permitted between 15°C and 30°C (59°F and 86°F). Protect from light (keep in carton until time of use). Solution diluted for infusion in D5W or NS may be stored for 4 to 24 hours (depending on product; refer to product labeling) at room temperature (21°C to 25°C [69°F to 77°F]) or up to 24 hours refrigerated at 2°C to 8°C (36°F to 46°F). Preservative-free (PF) solutions (eg, prepared with PF methotrexate and PF diluent) should be reconstituted (if lyophilized powder), diluted (if diluting), and administered immediately after preparation.

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

Oral:

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

Oral solution:

Jylamvo: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep bottle tightly closed. Once open, discard any amount not used within 3 months.

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

Use

Note: Approved indications and ages vary by product; see product-specific labeling for details.

Oncologic indications: Treatment of acute lymphoblastic leukemia (as part of a combination chemotherapy regimen) (oral, parenteral: FDA approved in pediatric patients [age not specified] and adults); prophylaxis and treatment of meningeal leukemia (parenteral: FDA approved in pediatric patients [age not specified] and adults); treatment of non-Hodgkin lymphoma (parenteral: FDA approved in pediatric patients [age not specified] and adults; oral: FDA approved in adults); treatment of osteosarcoma (as part of a combination chemotherapy regimen) (parenteral: FDA approved in pediatric patients [age not specified] and adults); treatment of gestational trophoblastic neoplasia (as part of a combination chemotherapy regimen), breast cancer (as part of a combination chemotherapy regimen), and squamous cell carcinoma of the head and neck (as a single agent) (parenteral: FDA approved in adults); treatment of cutaneous T-cell lymphoma (advanced mycosis fungoides) (oral: FDA approved in adults); has also been used for CNS tumors (including nonleukemic meningeal cancers). Note: Otrexup, Rasuvo, and RediTrex are not indicated for the treatment of neoplastic diseases.

Nononcologic indications: Treatment of active polyarticular juvenile idiopathic arthritis (JIA) in patients who have failed to respond to other agents (oral, parenteral: FDA approved in pediatric patients [age not specified]); treatment of psoriasis (eg, severe, recalcitrant, disabling) and severe, active rheumatoid arthritis in patients whose disease is unresponsive to or who are intolerant of first-line therapy, including full-dose nonsteroidal anti-inflammatory drugs (oral, parenteral: FDA approved in adults). Has also been used for the treatment of and maintenance of remission in Crohn disease, dermatomyositis, uveitis, and scleroderma.

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].

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

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy

Antithymocyte Globulin (Equine): Methotrexate may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of methotrexate is reduced. Methotrexate may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy

AzaTHIOprine: 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

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

Capecitabine: Methotrexate may enhance the nephrotoxic effect of Capecitabine. Risk C: Monitor therapy

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

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

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

Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination

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 Vaccines: Methotrexate may diminish the therapeutic effect of COVID-19 Vaccines. Management: Rheumatology guidelines recommend holding methotrexate for 1 to 2 weeks after vaccine administration as permitted by underlying disease. This is specific to patients using methotrexate for rheumatic and musculoskeletal disease. Risk D: Consider therapy modification

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

Dapsone (Systemic): May increase the serum concentration of Methotrexate. Management: Avoid coadministration of dapsone and methotrexate if possible. If coadministration is required, monitor closely for methotrexate toxicities (eg, hematological, gastrointestinal, nephrotoxicity toxicities). Risk D: Consider therapy modification

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

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

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

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

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

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

Filgotinib: Methotrexate may enhance the immunosuppressive effect of Filgotinib. Management: Concomitant use of filgotinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted. 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

HydroCHLOROthiazide: May enhance the nephrotoxic effect of Methotrexate. 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

Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy

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

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

Nadofaragene Firadenovec: Methotrexate may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination

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

Neomycin (Systemic): May decrease the serum concentration of Methotrexate. Neomycin (Systemic) 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

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. 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

PEMEtrexed: May increase the serum concentration of Methotrexate. Management: Avoid coadministration of pemetrexed and methotrexate if possible. If coadministration is required, monitor closely for methotrexate toxicities (eg, hematological, gastrointestinal, nephrotoxicity toxicities). 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

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy

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 immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification

Retinoic Acid Derivatives: May enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy

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

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

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

Taurursodiol: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). 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

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

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

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

Vaccines (Inactivated/Non-Replicating): Methotrexate may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). 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

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. 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.

Dietary Considerations

Some products may contain sodium.

Reproductive Considerations

Patients who could become pregnant:

Verify the pregnancy status of patients who could become pregnant prior to initiating therapy. Effective contraception is recommended for patients who may become pregnant during therapy and for 6 months after the final methotrexate dose.

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). However, 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]).

There may be a low risk of amenorrhea associated with methotrexate therapy (ESMO [Lambertini 2020]. Product labeling notes the use of methotrexate may impair fertility and cause menstrual irregularities 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).

Patients who could father a child:

According to the manufacturer, effective contraception is recommended for patients with partners who may become pregnant during therapy and for 3 months after the final dose of methotrexate.

There may be a low risk of azoospermia associated with methotrexate therapy (ESMO [Lambertini 2020]. Product labeling notes that methotrexate may impair fertility and cause oligospermia during treatment and following therapy; it is not known if infertility may be reversed in all affected patients. However, available data are inconclusive (Boussaid 2022). A study evaluating low-dose methotrexate (dosage range 7.5 to 25 mg/week) for the treatment of inflammatory joint disease or inflammatory bowel disorders did not find adverse effects on sperm quality (Grosen 2022). In addition, paternal use of methotrexate has not been found to cause adverse pregnancy outcomes (Bermas 2020, Gubatan 2022). Autoimmune disease may also influence male infertility (Boussaid 2022).

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).

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.

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). The use of methotrexate for the treatment of non-neoplastic indications including, 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). Methotrexate administered by intra-gestational injection with or without systemic methotrexate or other treatments is recommended for the management of cesarean scar pregnancies; however, various protocols have been described and the optimal regimen is not known. Use of systemic methotrexate alone is not recommended for the treatment of cesarean scar pregnancy (Liu 2020; Salari 2020; SMFM [Miller 2020]). Use of methotrexate for other nontubal ectopic pregnancies (eg, cervical or abdominal) has been described; however, data are insufficient to make specific dosing recommendations (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).

Monitoring Parameters

Laboratory tests should be performed on day 5 or day 6 of the weekly methotrexate cycle (eg, psoriasis, RA, JIA) to detect the leukopenia nadir and to avoid elevated LFTs 1 to 2 days after taking dose.

Indication-specific recommendations: Note: Additional recommendations may vary based upon patient age and specific protocols (refer to specific references); for all pediatric patients receiving long-term therapy (ie, chronic disease), growth parameters should also be monitored.

Psoriasis: CBC with differential and platelets (baseline, 7 to 14 days after initiating therapy or dosage increase, every 2 to 4 weeks for first few months, then every 1 to 3 months); BUN and serum creatinine (baseline and every 2 to 3 months); consider PPD for latent TB screening (baseline); LFTs (baseline, monthly for first 6 months, then every 1 to 2 months); chest x-ray (baseline if underlying lung disease); pulmonary function test (if methotrexate-induced lung disease suspected).

Liver biopsy:

Patients with risk factors for hepatotoxicity: Baseline or after 2 to 6 months of therapy and with each 1 to 1.5 g cumulative dose interval in adults.

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

Juvenile idiopathic arthritis: Children and Adolescents: PPD screening (baseline and annually); CBC with differential and platelets, C-reactive protein, ESR, ferritin, and LDH [baseline, at follow-up visits (1 to 2 weeks, 1, 2, 6, and 9 months] and with any treatment change (DeWitt 2012). Also based on adult recommendations in RA, consider serum creatinine and LFTs (baseline then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy) and liver biopsy: Baseline (if 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).

Rheumatoid arthritis:

CBC with differential and platelets, serum creatinine and LFTs (baseline, then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy); chest x-ray (baseline); pulmonary function test (if methotrexate-induced lung disease suspected); hepatitis B or C testing (baseline).

Liver biopsy: Baseline (if 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).

Cancer: Baseline and frequently during treatment: CBC with differential and platelets, serum creatinine, BUN, LFTs; chest x-ray (baseline); serum methotrexate concentrations and urine pH (with high-dose therapy); pulmonary function test (if methotrexate-induced lung disease suspected).

Crohn disease:

Children and Adolescents: In pediatric trials, frequency of monitoring varied with study protocol and duration; may vary based on clinical status and concurrent medication; consider the following: CBC with differential and platelets, LFTs, C-reactive protein, and ESR (baseline, then every 2 to 4 weeks during initial 8 to 12 weeks of therapy, then every 4 to 12 weeks while on therapy); chest x-ray and PFTs (annually) (Mack 1998; Sandhu 2010; Turner 2007; Weiss 2009). Also, based on adult recommendations for Crohn disease, consider serum creatinine (baseline, then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy), hepatitis B or C testing (baseline) and liver biopsy: Baseline (if 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).

Adults: CBC with differential and platelets, serum creatinine and LFTs (baseline then every 2 to 4 weeks for initial 3 months of therapy, then every 8 to 12 weeks for 3 to 6 months of therapy and then every 12 weeks after 6 months of therapy); chest x-ray (baseline); pulmonary function test (if methotrexate-induced lung disease suspected); hepatitis B or C testing (baseline) and liver biopsy: Baseline (if 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).

Ectopic pregnancy: Prior to therapy, measure serum hCG, CBC with differential, liver function tests, serum creatinine. Serum hCG concentrations should decrease between treatment days 4 and 7. If hCG decreases by >15%, additional courses are not needed; however, continue to measure hCG weekly until no longer detectable. If <15% decrease is observed, repeat dose per regimen (Barnhart 2009).

Reference Range

Therapeutic levels: Variable; toxic concentration: Variable; therapeutic range is dependent upon therapeutic approach. Note: 0.1 micromole/L = 100 nanomole/L.

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 (Adult Data Unless Noted)

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 (Adult Data Unless Noted)

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

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Ebetrexat | Methotrexat;
  • (AR) Argentina: Artrait | Ervemin | Metotrexate | Metotrexato | Metotrexato asofarma | Metotrexato dosa | Metotrexato eczane | Metotrexato filaxis | Metotrexato martian | Metotrexato microsules | Trixate;
  • (AT) Austria: Ebetrexat | Methofill | Methotrexat ebewe | Methotrexat lederle | Methotrexate ebewe | Metoject | Mtx ratiopharm | Nordimet;
  • (AU) Australia: Ledertrexate | Methoblastin | Methotrexate | Trexject;
  • (BD) Bangladesh: Meth | Methox | Metorax | Mtx | Trexonate;
  • (BE) Belgium: Emthexate | Ledertrexate | Methofill | Metoject | Nordimet;
  • (BG) Bulgaria: Ebetrexat | Methotrexate | Methotrexate accord | Namaxir;
  • (BR) Brazil: Biometrox | Emthexate | Hytas | Methotrexate | Metotrexato | Metrexato | Metrotex | Reutrexato | Tecnomet | Tevametho | Trexeron | Unitrexate;
  • (CH) Switzerland: Methotrexat accord | Methotrexat lederle | Methotrexat mepha | Methotrexat Orion | Methotrexat pfizer | Methotrexat Proreo | Methotrexat sandoz | Methotrexat Sandoz | Methotrexate farmos | Methrexx | Metoject | Nordimet;
  • (CL) Chile: Brexil | Metoject | Metotrexato | Nordimet;
  • (CN) China: Methotrexate;
  • (CO) Colombia: Emthexate | Methotrexate | Methoven | Metoject | Metotrexato | Metrex | Metrexato | Mexat | Nordixate;
  • (CZ) Czech Republic: Injexate | Methotrexat accord | Methotrexat ebewe | Methotrexate | Metoject pen | Nordimet | Trexan | Trexan neo;
  • (DE) Germany: Bendatrexat | Metex | Methofill | Methotrexamed | Methotrexat | Methotrexat 1 A pharma | Methotrexat 1a pharma | Methotrexat al | Methotrexat biosyn | Methotrexat ebewe | Methotrexat Kohne | Methotrexat lederle | Methotrexat Medac | Methotrexat mundipharma | Methotrexate | Metotrexato | Mtx Dura | Mtx hexal | Mtx Medac FS | Mtx mylan | Mtx Orion | Mtx ratiopharm | Mtx sandoz | Neotrexat | Nordimet | Trexject;
  • (DK) Denmark: Methotrexate singad;
  • (DO) Dominican Republic: Methotrexat | Methotrexate | Metotrexato | Metoxate;
  • (EC) Ecuador: Methotrexate | Methotrexato | Metotrexato;
  • (EE) Estonia: Ebetrex | Metex | Methotrexat | Methotrexate | Methotrexate Orion | Metoject | Trexan;
  • (EG) Egypt: Methotrexat ebewe | Methotrexate | Metoject;
  • (ES) Spain: Bertanel | Glofer | Imeth | Methofill | Methotrexate orion pharma | Metoject | Metoject pen | Metotrexato cipla | Metotrexato lederle | Metotrexato Lederle | Nordimet;
  • (ET) Ethiopia: Emthex | Unitrexate;
  • (FI) Finland: Ebetrex | Emthexat | Injexate | Methotrexat accord | Methotrexate | Methotrexate mayne | Metoject | Metoject pen | Nordimet | Trexan;
  • (FR) France: Imeth | Izixate | Ledertrexate | Methotrexate accord | Methotrexate merck | Methotrexate teva | Metoject | Prexate;
  • (GB) United Kingdom: Ebetrex | Maxtrex | Methofill | Methotrexate | Methotrexate dup | Metoject | Nordimet | Trav methotrexate | Zlatal;
  • (GR) Greece: Methotrexate | Methotrexate ebewe | Methox f | Metoject | Nordimet;
  • (HK) Hong Kong: Emthexate | Methotrexate;
  • (HR) Croatia: Ebetrexat | Methotrexate lederle | Metoject | Metotreksat cipla | Metotreksat sandoz;
  • (HU) Hungary: Ebetrexat | Methotrexat ebewe | Methotrexate orion | Namaxir | Trexan;
  • (ID) Indonesia: Emthexate | Farmitrexat | Ferxate | Methotrexat ebewe | Methotrexate | Rheu trex | Texorate;
  • (IE) Ireland: Methofill | Metoject;
  • (IL) Israel: Emthexate | Methotrexat | Methotrexate;
  • (IN) India: Alltrex | Arthrate | Auratrex | Biotrexate | Caditrex | Carditrex | Cytotrex | Dermatrax | Dermotrex | Ethitrex | Folitrax | Hi trex | Imotrax | Imutrex | Meditrex | Methorex | Methotrexate | Mevotrex | Mexate | Mext | Mxte | Neotrexate | Oncotrex | Oncotrex-pf | Onotrex | Plastomet | Ra mex | Remtrex | Trex | Trexo | Valuxate | Vibzi | Zexate;
  • (IT) Italy: Immutrex | Methotrexate | Metother | Metotrexato accord | Metotrexato Addenda | Metotrexato doc generici | Reumaflex | Trexodem | Trexother | Velos;
  • (JO) Jordan: Ebetrexat;
  • (JP) Japan: Methotrexate towa | Methotrexate Wyeth | Metolate;
  • (KE) Kenya: Trexglo;
  • (KR) Korea, Republic of: Emthexate | Emthexate pf | Jeil methotrexate | Kbp methotrexate | M.T.X | Methotrexate koreaunited | Unitrexate | Yuhan methotrexate;
  • (KW) Kuwait: Emthexate;
  • (LB) Lebanon: Ebetrexat | Imutrex | Methotrexate | Methotrexate ebewe | Metoject;
  • (LT) Lithuania: Ebetrex | Ebetrexat | Metex | Methotrexate | Metoject | Metother | Mtx sandoz | Trexan;
  • (LU) Luxembourg: Ebetrexat | Ledertrexate | Mtx hexal | Nordimet;
  • (LV) Latvia: Ebetrex | Ebetrexat | Methotrexate | Methotrexate accord | Methotrexate ebewe | Metoject | Trexan;
  • (MA) Morocco: Quinux;
  • (MX) Mexico: Ac vonda | Atrexel | Ifamet | Karxitran | Ledertrexate | Medsatrexate | Methotrexate | Metoject | Metotrexate | Metotrexato | Metotrexato ultra | Texate | Texate t | Tratoben | Trixilem | Ulmextral | Zumotrex;
  • (MY) Malaysia: Emthexate | Methotrexate | Methotrexate ebewe | Mtx | Zexate;
  • (NG) Nigeria: Sjstrex;
  • (NL) Netherlands: Ebetrex | Emthexate | Emthexate pf | Injexate | Ledertrexate | Methotrexaat | Methotrexaat 5 mg=0,133 ml focus | Methotrexaat accord | Methotrexaat cf | Methotrexaat sandoz | Metoject;
  • (NO) Norway: Ebetrex | Emthexat | Metex | Methofill | Methotrexat accord | Methotrexate | Methotrexate cipla | Methotrexate singad | Methotrexate teva | Metoject | Nordimet;
  • (NZ) New Zealand: Methoblastin | Methotrexate | Methotrexate sandoz | Trexate;
  • (PE) Peru: Artrait 10 | Artriplus | Methocel | Methotrexate | Meticil | Metotrex | Metotrexato | Reumatrex;
  • (PH) Philippines: Emthexate | Hextrate | Methobax | Methotrexate disodium | Mpl methoxil | Pterin | Zexate;
  • (PK) Pakistan: Blutrexate | Cytotrexate | Emthexate | Imutrex | Methobel | Methotrexate | Metrex | Mtx | Neumethoxate | Pharmatrexate | Trexate | Unitrexate;
  • (PL) Poland: Ebetrexat | Metex | Methofill | Methofill SD | Methotrexat Medac | Methotrexate | Methotrexate ebewe | Methotrexate knoll | Metoject | Metotab | Namaxir | Trexan | Trexan neo;
  • (PR) Puerto Rico: Methotrexate | Reditrex | Trexall;
  • (PT) Portugal: Ledertrexato | Metex | Methofill | Metoject | Metotrexato | Nordimet;
  • (PY) Paraguay: Metotrexato cipla | Metotrexato dosa | Metotrexato imedic | Metotrexato microsules | Metrex;
  • (QA) Qatar: Methotrexate Ebewe;
  • (RO) Romania: Antifolan | Methotrexate pch | Metorthrit | Namaxir | Nordimet;
  • (RU) Russian Federation: Methortrit | Methotrexat ronc | Methotrexate | Methotrexate ebewe | Methotrexate Ferein | Methotrexate lachema | Methotrexate sz | Metoject | Metortrit | Vero methotrexate | Zexate;
  • (SA) Saudi Arabia: Apo methotrexate | Methotrexate | Methotrexate spc | Metoject;
  • (SE) Sweden: Ebetrex | Injexate | Metex | Methotrexate | Methotrexate ebewe | Methotrexate mayne | Methotrexate Orion | Methotrexate paranova | Methotrexate pfizer | Methotrexate pharmacia | Methotrexate sandoz | Methotrexate teva | Metoject | Metojectpen | Metotab | Metotrexat | Metotrexat ebb | Nordimet | Tremetex;
  • (SG) Singapore: Abitrexate | Emthexate | Methotrexate pfizer | Mtx;
  • (SI) Slovenia: Methotrexat ebewe | Methotrexate | Metoject | Metotreksat ebewe | Metotreksat Lederle;
  • (SK) Slovakia: Methotrexat | Methotrexat ebewe | Methotrexate | Metoject | Nordimet | Trexan | Trexan neo;
  • (TH) Thailand: Abitrexate | Biotrexate | Emthexate | Methotrexate ebewe | Methotrexate remedica | Onkomet | Unitrexate;
  • (TN) Tunisia: Ebetrexat | Methotrexate | Methotrexate ebewe | Methotrexate mylan;
  • (TR) Turkey: Artroject | Emthexate s | Meksratu | Methotrexate | Methotrexate r | Metoart | Metoart con | Mextu | Mtx hexal | Trexan;
  • (TW) Taiwan: Emthexate | Emthexate pf | Methopterin | Methotrexate | Trexan;
  • (UA) Ukraine: Methotrexat Orion | Methotrexate | Metoject | Metortrat romfarm | Metotab;
  • (UY) Uruguay: Artrait | Ervemin | Methotrexate | Metotrexate | Metotrexato | Metotrexato libra;
  • (VE) Venezuela, Bolivarian Republic of: Mebiotrexato | Trixate | Zexate;
  • (ZA) South Africa: Abitrexate | Emthexate | Methoblastin | Methotrexate accord;
  • (ZM) Zambia: Biotrexate | Emthex
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Topic 12595 Version 622.0

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