Brand names: Otrexup, Rheumatrex, Trexall
Drug class: Antineoplastic Agents
- Disease-modifying Antirheumatic Drugs
- DMARDs
VA class: AN300
Molecular formula: C₂₀H₂₂N₈O₅
CAS number: 59-05-2

Medically reviewed by Drugs.com on Sep 28, 2023. Written by ASHP.

Introduction

Antineoplastic agent and immunosuppressant; folic acid antagonist.

Uses for Methotrexate

Breast Cancer

Treatment (alone or, more commonly, in combination chemotherapy) of breast cancer.

First-line adjuvant chemotherapy in combination with other drugs (i.e., cyclophosphamide and fluorouracil, with or without hormonal therapy). An anthracycline-containing regimen is preferred in patients with node-positive disease.

Some studies suggest a slight advantage for anthracycline-containing regimens in relapse-free and survival rates in both premenopausal and postmenopausal patients.

Also used in patients with metastatic disease.

Head and Neck Cancer

Palliative treatment (alone and in combination therapy) of recurrent or metastatic head and neck carcinoma.

Frequently used in combination regimens with other antineoplastic agents (e.g., bleomycin, fluorouracil, vincristine).

Combination therapy with cisplatin, methotrexate, bleomycin, and vincristine has been used for recurrent or metastatic squamous cell carcinoma of the head and neck.

Further study needed to establish comparative benefit of methotrexate-containing regimens.

Leukemias

Component of various chemotherapy regimens in palliative treatment of acute leukemias.

Intrathecally for prophylaxis and treatment of meningeal leukemia.

First-line therapy in combination with mercaptopurine for maintenance of drug-induced remissions of acute lymphoblastic leukemia (ALL).

Has been used in high doses as a component of some alternative combination chemotherapy regimens for remission induction in ALL, but not generally considered a drug of choice for remission induction.

Rarely effective alone for treatment of acute myeloblastic leukemia (AML); has been used as an additional component in some chemotherapy regimens for induction or post-induction therapy of AML.

Lung Cancer

Has been used in second-line therapy of recurrent small cell lung cancer.

Although labeled for use in squamous cell type of non-small cell lung cancer, other agents are preferred.

Lymphomas

Component of combination chemotherapeutic regimens as first-line palliative therapy for high-grade Burkitt’s lymphoma or maintenance therapy for high-grade lymphoblastic non-Hodgkin’s lymphoma.

Component of alternative combination chemotherapy regimens for treatment of intermediate-grade non-Hodgkin’s lymphomas (diffuse large cell, diffuse small cell, diffuse mixed, follicular large cell).

Has been used intrathecally in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab for first-line therapy of intermediate-grade non-Hodgkin’s lymphomas.

Although radiation or topical therapy is generally used for treatment of localized histiocytic lymphoma, lymphosarcoma, and mycosis fungoides, chemotherapy may be useful in generalized stages of these diseases.

First-line systemic chemotherapy for advanced cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome).

First-line therapy of primary CNS lymphoma.

Hodgkin’s disease responds poorly to methotrexate.

Osteosarcoma

High-dose therapy, followed by leucovorin or levoleucovorin rescue, in combination chemotherapy regimens as adjunct to surgical resection or amputation of primary tumor in patients with nonmetastatic osteosarcoma (designated an orphan drug by FDA for this use).

Also has been used as a component of adjunctive combination chemotherapy regimens in patients with metastatic osteosarcoma.

Psoriasis

Symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy in carefully selected patients; not curative.

Use only after diagnosis definitely established (e.g., biopsy, after dermatologic consultation).

Rheumatoid Arthritis

Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.

Management of active polyarticular-course juvenile rheumatoid arthritis in children who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy (i.e., full-dose NSAIAs). (See Pediatric Use under Cautions.)

One of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.

Substantially greater long-term efficacy than other DMARDs; used as the initial or anchor DMARD in many patients with rheumatoid arthritis. Also has been used in combination with other DMARDs.

Use only as part of a comprehensive treatment program, including nondrug therapies (e.g., rest, physical therapy).

No substantial evidence that methotrexate permanently arrests or reverses the underlying disease process, although disease progression is slowed in some patients.

Trophoblastic Neoplasms

Treatment (with or without leucovorin) of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens, hydatidiform mole) in women (except those with impaired renal or hepatic function or who have failed to respond to previous methotrexate therapy, in which case dactinomycin is used).

Most effective in patients who have had disease for only a short period prior to initiation of chemotherapy, who have low initial gonadotropin concentrations, and who do not have metastases.

First-line therapy with or without leucovorin in patients with nonmetastatic or good-prognosis metastatic gestational trophoblastic neoplasms.

Component of combination chemotherapy regimen with dactinomycin and chlorambucil in patients with good-prognosis metastatic gestational trophoblastic neoplasms with refractory disease.

In patients with poor-prognosis metastatic trophoblastic neoplasms, methotrexate in combination with etoposide, dactinomycin, vincristine, and cyclophosphamide (EMA-CO) is a standard treatment option. A dose-intensive regimen, EMA-CE, in which etoposide and cisplatin are substituted for vincristine and cyclophosphamide of the EMA-CO regimen, may offer additional benefits.

Has been used prophylactically against malignant trophoblastic disease in patients with hydatidiform mole.

Testicular choriocarcinomas are usually resistant to methotrexate alone; has been used as component of combination therapy in patients with metastatic tumors of the testes.

Bladder Cancer

Used in combination regimens with vinblastine and cisplatin, with or without doxorubicin, as first- or second-line therapy for invasive and advanced bladder cancer^{† [off-label]}.

Use of leucovorin rescue or deletion of methotrexate is advised if methotrexate-containing regimens are being considered for the treatment of advanced or metastatic bladder cancer in patients with renal dysfunction, edema, pleural fluid collections, or ascites.

Crohn’s Disease

Management of chronically active Crohn’s disease^{† [off-label]}.

Ectopic Pregnancy

Used as an alternative to surgical management of ectopic pregnancy^{† [off-label]} in selected patients with small, unruptured tubal pregnancies.

Multiple Sclerosis

Low-dose oral therapy has been used in patients with chronic progressive multiple sclerosis^{† [off-label]}.

Psoriatic Arthritis

Has been used for its immunosuppressive and/or anti-inflammatory effects in treatment of psoriatic arthritis^{† [off-label]}.

Related/similar drugs

Kisqali, Otezla, Rybrevant, Verzenio, Ibrance, Trodelvy, Taltz

Methotrexate Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Do not prescribe or dispense on as-needed (“prn”) basis.

• If toxicity previously necessitated discontinuance, reinstitute with caution; consider further need for drug and risk of toxicity recurrence.

High-Dose Methotrexate Therapy with Leucovorin or Levoleucovorin Rescue

• Use of high-dose regimens employed in adjunctive treatment of osteosarcoma requires meticulous understanding of risks associated with therapy and leucovorin or levoleucovorin rescue.

• Hydrate patients with 1 L/m² of IV fluid over 6 hours prior to initiation of methotrexate infusion. Continue hydration at 125 mL/m² per hour (3 L/m² daily) during methotrexate infusion and for 2 days after completion of infusion.

• Alkalinize urine with sodium bicarbonate to maintain pH ≥7 during methotrexate infusion and rescue therapy with a folic acid antidote (e.g., leucovorin, levoleucovorin); administer sodium bicarbonate orally or via a separate IV solution.

• S_cr must be normal and Cl_cr >60 mL/minute before therapy initiation. Repeat S_cr and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate concentration is <0.023 mcg/mL (0.05 µM).

• Measure S_cr prior to each subsequent course of therapy; if S_cr increases by ≥50% compared to prior value, measure and document that Cl_cr >60 mL/minute (even if S_cr is still within normal range).

• May consider adding glucarpidase to leucovorin or levoleucovorin rescue therapy to treat toxic plasma methotrexate concentrations (>0.454 mcg/mL or >1 µM) in patients with delayed methotrexate clearance due to renal impairment. If glucarpidase is used, do not administer leucovorin or levoleucovorin within 2 hours before or after a dose of glucarpidase.

• Also consult manufacturers’ labelings and published protocols for specific recommendations based on laboratory and clinical findings.

Administration

Administer orally or by IM, IV, or intrathecal injection; may also administer intra-arterially. Has been administered by sub-Q injection.

Do not use formulations or diluents containing preservatives (e.g., benzyl alcohol) for intrathecal administration or high-dose therapy.

Oral Administration

Administer orally as tablets.

Oral administration is often preferred when low doses are used since absorption is rapid and effective serum concentrations are achieved.

Manufacturer makes no specific recommendations regarding administration with meals; food delays absorption and reduces peak serum concentrations.

Inadvertent daily instead of weekly administration in patients with rheumatic conditions (e.g., rheumatoid arthritis, psoriasis) or certain inflammatory GI conditions (e.g., Crohn’s disease^†) may result in fatal toxicity; careful review of intended use should be undertaken to ensure that inadvertent overdosage (e.g., administration of antineoplastic rather than anti-inflammatory dosages) does not occur. Carefully instruct patient regarding regimen and frequency of administration. (See Advice to Patients.)

Mnemonic dispensing packages (e.g., Rheumatrex Dose Pack) may be used for initial and maintenance therapy in patients receiving weekly doses of 5–20 mg but are not recommended for titration to weekly doses >20 mg.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV injection or infusion.

Reconstitution

Reconstitute lyophilized powder for injection immediately before use with a sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).

Reconstitute 1 g vial with 19.4 mL of appropriate solution to yield a concentration of 50 mg/mL.

Dilution

When high doses are administered by IV infusion, dilute total dose of reconstituted solution in 5% dextrose injection.

Preservative-free solutions may be diluted immediately prior to use with an appropriate sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).

IM Administration

Administer by IM injection.

Reconstitution

Reconstitute lyophilized powder for injection immediately before use with a sterile, preservative-free solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).

Intrathecal Administration

Preservative-free solutions (1 mg/mL) are used for intrathecal injection. Do not administer solutions containing preservatives intrathecally.

Must administer intrathecally for treatment of meningeal leukemia since passage of drug from blood to CSF is minimal.

Prior to intrathecal administration, a volume of CSF approximately equivalent to volume of solution to be injected (e.g., 5–15 mL) is usually removed.

If lumbar puncture is traumatic, do not administer intrathecally; allow 2 days to elapse before again attempting injection.

Inject intrathecally only if there is easy flow of blood-free spinal fluid.

Some clinicians recommend that entire volume of methotrexate injection be injected intrathecally in 15–30 seconds. Aspiration should not be performed.

Appears in systemic circulation following intrathecal administration; adjust, reduce, or discontinue any concomitant systemic administration as appropriate.

Systemic administration of leucovorin calcium simultaneously with intrathecal methotrexate may prevent systemic toxicity without abolishing drug’s activity in CNS.

Reconstitution

For intrathecal injection, reconstitute lyophilized powder to a concentration of 1 mg/mL with an appropriate sterile preservative-free diluent (e.g., 0.9% sodium chloride injection).

Dilution

For intrathecal injection, dilute methotrexate preservative-free solution for injection to a concentration of 1 mg/mL with an appropriate sterile preservative-free diluent (e.g., 0.9% sodium chloride injection).

Dosage

Available as methotrexate sodium; dosage is expressed in terms of methotrexate.

Various dosage schedules have been used; individualize dosage, route of administration, and duration of therapy according to disease being treated, other therapy employed, and condition, response, and tolerance of the patient. Consult published protocols for additional information on alternative regimens and dosages.

Pediatric Patients

Juvenile Rheumatoid Arthritis

Oral

May administer an initial test dose prior to regular dosage schedule to detect possible sensitivity to adverse effects associated with the drug.

Initially, 10 mg/m² once weekly. May adjust dosage gradually to achieve optimal response.

Dosages up to 30 mg/m² weekly have been used in children, but published data are too limited to assess risk of serious toxicity at dosages >20 mg/m² weekly.

Children receiving 20–30 mg/m² (0.65–1 mg/kg) weekly may have better absorption and fewer adverse GI effects if administered either IM or sub-Q.

Optimum duration of therapy is unknown.

IM or Sub-Q

Children receiving 20–30 mg/m² (0.65–1 mg/kg) weekly may have better absorption and fewer adverse GI effects if administered either IM or sub-Q.

Leukemias

Meningeal Leukemia

Intrathecal

Regardless of method used to determine intrathecal dosage, carefully check dose prior to administration to minimize risk of inadvertent intrathecal overdosage.

Clinical studies indicate that intrathecal dosage regimens based on age may be more effective and less neurotoxic than dosage regimens based on body surface area.

Intrathecal doses based on body surface area (i.e., 12 mg/m², maximum 15 mg) reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients.

Treatment: may administer at intervals of 2–5 days until CSF cell count returns to normal, at which point 1 additional dose is advisable. Administration at intervals of <1 week may result in increased subacute toxicity.

Prophylaxis: dosage is the same as for treatment; administration intervals differ from regimen used in treatment. Consult specialized references and medical literature for specific recommendations.

Adults

Breast Cancer

Various combination chemotherapy regimens have been used in the treatment of breast cancer; consult published protocols for dosages and method and sequence of administration.

Dose intensity of adjuvant combination chemotherapy appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; avoid arbitrary reductions in dose intensity.

IV

Dosage of 40 mg/m² IV on days 1 and 8 of each cycle in combination with cyclophosphamide 100 mg/m² on days 1–14 of each cycle and fluorouracil 600 mg/m² on days 1 and 8 of each cycle is commonly employed for treatment of early breast cancer.

In patients >60 years of age, initial dosage is reduced to 30 mg/m² and initial fluorouracil dosage is reduced to 400 mg/m²; dosage also reduced if myelosuppression develops.

Cycles are generally repeated monthly (i.e., allowing a 2-week rest period between cycles) for a total of 6–12 cycles (i.e., 6–12 months of therapy).

In a sequential regimen in which several courses of doxorubicin are administered prior to a regimen of cyclophosphamide, methotrexate, and fluorouracil in patients with early breast cancer and >3 positive axillary lymph nodes, 4 doses of doxorubicin hydrochloride 75 mg/m² were administered initially at 3-week intervals followed by 8 cycles of methotrexate 40 mg/m², cyclophosphamide 600 mg/m², and fluorouracil 600 mg/m² at 3-week intervals for a total of approximately 9 months of therapy. If myelosuppression developed with this sequential regimen, the subsequent cycle generally was delayed rather than dosage reduced.

Leukemia

ALL (Induction Therapy)

Oral

Not generally a drug of choice, but 3.3 mg/m² daily in combination with prednisone 60 mg/m² daily for 4–6 weeks has been used.

ALL (Maintenance Therapy)

Oral or IM

After remission attained, 30 mg/m² total weekly dose, administered in divided doses twice weekly.

IV

Alternatively, 2.5 mg/kg has been administered IV every 14 days.

Meningeal Leukemia

Intrathecal

Treatment: 12 mg administered at intervals of 2–5 days until CSF cell count returns to normal, at which point 1 additional dose is advisable. However, administration at intervals of <1 week may result in increased subacute toxicity.

Prophylaxis: 12 mg; administration intervals differ from regimen used in treatment. Consult specialized references and medical literature for specific recommendations.

Intrathecal doses of 12 mg/m² (maximum 15 mg) reported to result in high CSF methotrexate concentrations and neurotoxicity in adults.

Lymphomas

Oral

For Burkitt’s lymphoma (stage I or II), 10–25 mg daily for 4–8 days. In stage III Burkitt’s lymphoma, commonly given with other antineoplastic agents. In all stages, several courses are usually administered, interposed with 7- to 10-day rest periods.

Stage III lymphosarcomas may respond to combined drug therapy with methotrexate given in doses of 0.625–2.5 mg/kg daily.

Cutaneous T-cell Lymphoma; Mycosis Fungoides

Oral, IM, or Sub-Q

Usually, 5–50 mg weekly in early stages. Dose reduction or discontinuance is determined by hematologic monitoring and patient response.

Also has been administered twice weekly in doses ranging from 15–37.5 mg in patients who have responded poorly to weekly therapy.

IV

Combination chemotherapy regimens that include higher-dose methotrexate with leucovorin rescue have been used in advanced stages. Consult published protocols for dosages.

Osteosarcoma

High-Dose Methotrexate Therapy with Leucovorin or Levoleucovorin Rescue

IV

Initially, 12 g/m² infused over 4 hours on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery on a schedule in combination with other chemotherapy agents (e.g., doxorubicin; cisplatin; combination of bleomycin, cyclophosphamide, and dactinomycin). If initial dosage is not sufficient to produce peak serum methotrexate concentrations of 454 mcg/mL (1000 µM [10^-3 mol/L]) at the end of IV infusion, may increase dose to 15 g/m² in subsequent treatments.

Initiate rescue therapy with leucovorin or levoleucovorin to prevent acute toxicity. If leucovorin is used, administer at a dosage of 15 mg orally every 6 hours for 10 doses beginning 24 hours after the start of the methotrexate IV infusion; may give leucovorin IV or IM if patient experiences GI toxicity (e.g., nausea, vomiting) or cannot tolerate oral therapy. If levoleucovorin is used, administer at a dosage of 7.5 mg IV every 6 hours for 10 doses beginning 24 hours after the start of the methotrexate IV infusion. If clinically important methotrexate toxicity is observed, extend leucovorin or levoleucovorin therapy for an additional 24 hours (total of 14 doses instead of 10) in subsequent courses. Adjustment of rescue schedule may be required (see Table 2).

Delay subsequent methotrexate administration until recovery if the following adverse effects occur: if WBC count is <1500/mm³; neutrophil count is <200/mm³; platelet count is <75,000/mm³; serum bilirubin concentration is >1.2 mg/dL; ALT concentration is >450 units; mucositis is present (until there is evidence of healing); or persistent pleural effusion is present (drain dry prior to infusion).

Psoriasis

Oral

Administration of a single 5- to 10-mg dose 1 week prior to initiation of therapy has been recommended to detect idiosyncratic reactions.

Divided oral dosage schedule: 2.5 mg at 12-hour intervals for 3 doses each week. May gradually adjust dosage by 2.5 mg/week to achieve optimal response; do not exceed 30 mg weekly ordinarily.

Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period. Use may permit return to conventional topical therapy.

Oral, IM, or IV

Weekly single-dosage schedule: 10–25 mg as a single dose once weekly until adequate response achieved. May gradually adjust dosage to achieve optimal response; do not exceed 30 mg weekly ordinarily. Once optimal response obtained, reduce dosage schedule to lowest possible dose and longest possible rest period.

Rheumatoid Arthritis

Oral

May administer an initial test dose prior to regular dosage schedule to detect possible sensitivity to adverse effects.

Initially, 7.5 mg once weekly or a course once weekly of 2.5 mg administered at 12-hour intervals for 3 doses. May gradually adjust dosage to achieve an optimal response.

At dosages >20 mg weekly, possible increased incidence and severity of serious toxic reactions, especially myelosuppression.

Optimal duration of therapy is not known; limited data indicate that initial improvement is maintained for at least 2 years with continued therapy.

Trophoblastic Neoplasms

Oral or IM

Usually, 15–30 mg daily for 5 days. A repeat course may be given after a period of ≥1 week, provided all signs of residual toxicity have disappeared; 3–5 courses are usually employed. Clinical assessment before each course is essential.

Therapy is usually evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which usually normalizes after third or fourth course; complete resolution of measurable lesions usually occurs 4–6 weeks later.

1 or 2 courses of therapy are usually given after normalization of urinary hCG concentrations is achieved.

Crohn’s Disease†

Chronically Active Refractory Disease

IM

25 mg once weekly has been administered for 16 weeks.

Oral

12.5–22.5 mg once weekly has been administered for up to 1 year.

Maintenance Therapy

IM

15 mg once weekly has been used.

Ectopic Pregnancy†

IM

50 mg/m² as a single dose. May require second dose or surgical intervention if hCG concentration fails to decrease by at least 15% from day 4 to day 7 after methotrexate administration.

Alternatively, 1 mg/kg (on days 0, 2, 4, and 6) alternating with 0.1 mg/kg of leucovorin IM (on days 1, 3, 5, and 7) has been used.

Prescribing Limits

Pediatric Patients

Juvenile Rheumatoid Arthritis

Oral, IM, or Sub-Q

Although there is experience with dosages up to 30 mg/m² weekly in children, published data are too limited to assess how dosages >20 mg/m² weekly might affect risk of serious toxicity.

Children receiving 20–30 mg/m² (0.65–1 mg/kg) weekly may have better absorption and fewer GI effects if administered either IM or sub-Q.

Adults

Psoriasis

Oral, IM, or IV

Do not ordinarily exceed 30 mg weekly.

Rheumatoid Arthritis

Oral, IM, or IV

Do not ordinarily exceed 20 mg weekly.

Limited experience suggests substantial increase in incidence and severity of serious toxic reactions, especially bone marrow suppression, at dosages >20 mg weekly.

Special Populations

Renal Impairment

Dose reduction and especially careful monitoring for toxicity required.

Geriatric Patients

Select dosage with caution since hepatic and renal function and folate stores may be decreased; closely monitor for early signs of toxicity.

Patients with Ascites or Pleural Effusions

Dose reduction and especially careful monitoring for toxicity required.

Cautions for Methotrexate

Contraindications

• Pregnant women with psoriasis or rheumatoid arthritis; use in treatment of neoplastic diseases only when potential benefit outweighs risk to fetus. (See Boxed Warning.)

• Nursing women.

• Excessive alcohol consumption, alcoholic liver disease, or other chronic liver disease in patients with psoriasis or rheumatoid arthritis.

• Overt or laboratory evidence of immunodeficiency syndromes in patients with psoriasis or rheumatoid arthritis.

• Preexisting blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, clinically important anemia) in patients with psoriasis or rheumatoid arthritis.

• Known hypersensitivity to methotrexate.

Warnings/Precautions

Warnings

Also see Boxed Warnings.

Fetal/Neonatal Morbidity and Mortality

Fetal death and/or congenital anomalies reported. Exclude pregnancy before initiating treatment. Avoid pregnancy if either partner is receiving methotrexate; avoid pregnancy during therapy and for ≥3 months after therapy in male patients and for at least one ovulatory cycle after therapy in female patients. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Severe, occasionally fatal cutaneous or sensitivity reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme) reported in pediatric and adult patients within days of receiving drug at various dosages, by various routes, and for various conditions.

Erythematous rashes, pruritus, dermatitis, urticaria, folliculitis, photosensitivity, depigmentation, hyperpigmentation, petechiae, ecchymoses, telangiectasia, acne, furunculosis, and skin ulceration also reported.

Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation; possible “recall” radiation dermatitis and sunburn with methotrexate use.

Major Toxicities

Hematologic Effects

Possible suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Use with caution in patients with malignancy and preexisting hematopoietic impairment.

Perform CBCs, including differential and platelet counts, at least weekly in patients with neoplastic disease and at least monthly in patients with psoriasis or rheumatoid arthritis.

In patients with psoriasis or rheumatoid arthritis, discontinue if clinically important decrease in blood counts occurs and institute appropriate alternative therapy; in patients with neoplastic disease, continue only if potential benefit warrants risk of severe myelosuppression.

If profound granulocytopenia and fever occur, observe patient closely and initiate broad-spectrum antibiotic therapy if there are signs of infection.

Blood or platelet transfusions may be necessary in patients with severe myelosuppression.

GI Effects

Risk of vomiting, diarrhea, or stomatitis resulting in dehydration; discontinue drug until recovery occurs. (See GI Toxicity in Boxed Warning.)

Use with extreme caution in presence of peptic ulcer disease or ulcerative colitis.

Hepatic Effects

Possible hepatotoxicity; may be acute (increased serum aminotransferase concentrations) or chronic (fibrosis and cirrhosis).

Chronic hepatotoxicity, potentially fatal, generally occurs after prolonged use (≥2 years) and after a total dose of ≥1.5 g.

Risk of hepatotoxicity in patients with psoriasis appears to be related to cumulative dose and may be enhanced by alcoholism, obesity, diabetes, and advanced age. These risk factors also may apply to patients with rheumatoid arthritis; age at first use and duration of therapy also reported as risk factors in rheumatoid arthritis patients.

Use with particular caution in patients with preexisting liver damage or hepatic impairment.

Psoriasis: Perform liver function tests, including serum albumin, periodically prior to dosing, although results may be normal despite developing fibrosis or cirrhosis. Liver biopsy recommended before therapy or shortly after therapy initiation (2–4 months), at cumulative dose of 1.5 g, and after each additional 1–1.5 g. Usually discontinue drug if moderate fibrosis or any cirrhosis; repeat biopsy in 6 months if mild fibrosis. Continue use with caution if milder changes (e.g., fatty changes, low-grade portal inflammation).

Rheumatoid arthritis: Prolonged, substantial abnormalities in liver function test results may precede appearance of hepatic fibrosis or cirrhosis; perform liver function tests at baseline and at 4- to 8-week intervals. Pretreatment liver biopsy recommended if history of excessive alcohol consumption, persistently abnormal baseline liver function tests, or chronic hepatitis B or C infection. Perform liver biopsy during therapy if persistent liver function test abnormalities or serum albumin concentrations fall below normal (in setting of well-controlled rheumatoid arthritis). If liver biopsy shows mild changes (Roenigk grade I, II, or IIIa), continue therapy and monitoring; discontinue if persistently abnormal liver function tests, if biopsy shows moderate to severe changes (Roenigk grade IIIb or IV), or if patient refuses biopsy.

Respiratory Effects

Potentially fatal pulmonary toxicity; can progress rapidly and may not be fully reversible. Adverse pulmonary effects (i.e., acute or chronic interstitial pneumonitis, pulmonary fibrosis) may occur at any dosage at any time during therapy.

If manifestations (e.g., fever, cough [especially dry and nonproductive], dyspnea, chest pain, hypoxemia [possibly severe], radiographic evidence of pulmonary infiltrates [usually diffuse and/or alveolar]) occur, discontinue and carefully evaluate, including exclusion of possible infectious causes.

Management is mainly supportive and may include mechanical ventilation.

Potentially fatal opportunistic infections (e.g., P. jiroveci pneumonia) reported; consider possibility of P. jiroveci pneumonia in patients who develop pulmonary symptoms.

Renal Effects

May cause renal damage that may lead to acute renal failure.

Nephrotoxicity is due principally to precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules.

Careful attention to renal function, including adequate hydration, urine alkalinization, and measurement of methotrexate and S_cr concentrations is essential.

Perform renal function tests prior to and periodically during therapy (at 1- to 2-month intervals in patients with psoriasis or rheumatoid arthritis; more frequently in patients with neoplastic disease).

If renal impairment develops during therapy, reduce dosage or discontinue drug until renal function is improved or restored.

Immunosuppressive Effects

Consider immunosuppressive effects when evaluating use in patients in whom immune response may be important or essential. (See Vaccines under Interactions.)

Usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. (See Contraindications under Cautions.)

Use with extreme caution in presence of active infection.

Hypogammaglobulinemia reported rarely.

Neurologic Effects

Leukoencephalopathy reported following IV administration in patients who had received craniospinal irradiation; chronic leukoencephalopathy also reported in patients receiving repeated high-dose therapy with leucovorin rescue even without cranial irradiation.

Severe neurotoxic effects, manifested mainly by focal or generalized seizures, reported with increased frequency in pediatric patients with ALL who received intermediate-dose IV therapy (1 g/m²); leukoencephalopathy and/or microangiopathic calcifications usually were observed in diagnostic imaging procedures of symptomatic patients.

A transient acute neurologic syndrome observed in patients receiving high-dosage regimens; exact cause unknown. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures, and coma.

Intrathecal Administration

Possible acute chemical arachnoiditis manifested by headache, back pain, nuchal rigidity, and/or fever; subacute myelopathy manifested by paraparesis/paraplegia involving one or more spinal nerve roots; chronic leukoencephalopathy (may be progressive and fatal) manifested by confusion, irritability, somnolence, ataxia, dementia, and occasionally seizures and coma; and increased CSF pressure.

Systemic toxicity also may occur following intrathecal administration.

Inadvertent intrathecal overdosage has occurred; symptoms generally include CNS effects (i.e., headache, nausea, vomiting, seizure, acute toxic encephalopathy), although in some cases, no symptoms were reported. Death has occurred following intrathecal overdose; in these cases, cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy also reported.

Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin (intrathecal leucovorin contraindicated), alkaline diuresis, and rapid CSF drainage and ventriculolumbar perfusion.

Focal leukemic involvement of the CNS may not respond to intrathecal methotrexate and may best be treated with radiation therapy.

General Precautions

Adequate Patient Evaluation and Monitoring

Therapeutic response is not likely without some evidence of toxicity. Severity of toxic reactions may be increased when used in combination with other antineoplastic agents and/or radiation therapy.

Closely monitor patients with complete hematologic studies, urinalysis, renal function tests, liver function tests, and chest radiographs. (See Major Toxicities under Cautions.)

If serious toxicity occurs, reduce dosage or discontinue and institute appropriate corrective measures (e.g., use of leucovorin calcium, acute intermittent hemodialysis with a high-flux dialyzer).

Third-Space Compartments

Exits slowly from third-space compartments (e.g., pleural effusions, ascites), resulting in prolonged elimination and unexpected toxicity in patients with substantial third-space accumulations. Evacuation of fluid recommended before treatment; monitor plasma methotrexate concentrations.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality in Boxed Warning and under Cautions.)

Lactation

Distributed into milk. Contraindicated in nursing women because of risk to nursing infant.

Pediatric Use

Safety and efficacy established only for cancer chemotherapy or polyarticular-course juvenile rheumatoid arthritis.

In clinical studies, safety in pediatric patients 2–16 years of age with juvenile rheumatoid arthritis was similar to that observed in adults with rheumatoid arthritis.

Severe neurotoxic effects (e.g., focal or generalized seizures) reported in pediatric patients with ALL who received intermediate-dose IV therapy (1 g/m²). (See Neurologic Effects under Cautions.)

Preparations containing benzyl alcohol preservative not recommended in neonates because of toxicity.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution due to greater frequency of decreased hepatic and renal function and folate stores and of concomitant disease and drug therapy (i.e., that interfere with renal function or methotrexate or folate metabolism) observed in the elderly.

Occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age.

Closely monitor geriatric patients for early signs of hepatic, bone marrow, and renal toxicity; certain toxicities may be reduced by folate supplementation. S_cr may overestimate renal function in geriatric patients; consider more accurate methods (i.e., Cl_cr). Serum methotrexate concentrations may be helpful.

Hepatic Impairment

Contraindicated in patients with psoriasis or rheumatoid arthritis who have alcoholic liver disease or other chronic liver disease. Use with extreme caution, if at all, in patients with malignant disease who have preexisting liver damage or impaired hepatic function.

Renal Impairment

Usually contraindicated.

Debilitated Patients

Use with extreme caution.

Common Adverse Effects

Ulcerative stomatitis, leukopenia, nausea, abdominal distress, malaise, undue fatigue, chills, fever, dizziness, decreased resistance to infection.

Drug Interactions

Protein-bound Drugs

Possible increased methotrexate toxicity because of displacement from protein binding sites. (See Specific Drugs under Interactions.)

Weak Organic Acids

Potential to delay renal excretion and increase accumulation of methotrexate. (See Specific Drugs under Interactions.)

Hepatotoxic Agents

Increase in adverse hepatic effects expected.

Nephrotoxic Drugs

Possible altered renal elimination of methotrexate. Exercise caution if high-dose methotrexate administered in conjunction with nephrotoxic drugs in patients with osteosarcoma.

Specific Drugs

Methotrexate Pharmacokinetics

Absorption

Bioavailability

Oral absorption appears to be highly variable and dose dependent; oral bioavailability may be <50%. Bioavailability decreases with increasing oral doses; absorption may be substantially reduced at doses >80 mg/m². Following oral administration, peak serum concentrations are attained in 1–2 hours.

Appears to be completely absorbed following IM administration at doses ≤100 mg; peak serum concentrations are attained within 30–60 minutes.

Onset

In patients with rheumatoid arthritis, effects on articular swelling and tenderness may be observed after 3–6 weeks of treatment; improvement may continue for another 12 weeks or more.

Duration

In patients with arthritis, limited data indicate that initial improvement is maintained for at least 2 years with continued therapy. Arthritis usually worsens within 3–6 weeks after methotrexate discontinuance.

Food

Food delays absorption and decreases peak serum concentrations following oral administration.

Special Populations

Absorbed through the ileum; placement of a Foley catheter or frequent emptying of the reservoir is advised in patients with long ileal loops or internal reservoirs during administration of methotrexate-containing regimens for the treatment of advanced or metastatic bladder cancer.

Distribution

Extent

Widely distributed into body tissues, with highest concentrations in the kidneys, gallbladder, spleen, liver, and skin. Distributes into third-space fluids.

High-dose systemic therapy can result in peak CSF concentrations above the therapeutic threshold. Intrathecal administration may result in potentially cytotoxic serum concentrations that can persist for 24–48 hours.

Crosses the placenta and is distributed into milk.

Plasma Protein Binding

About 50% (mainly albumin).

Special Populations

Presence of pleural effusions or ascites can substantially alter drug disposition.

Elimination

Metabolism

Undergoes hepatic and intracellular metabolism to polyglutamate metabolites; partially metabolized by intestinal flora after oral administration.

Polyglutamate metabolites may be converted back to methotrexate by hydrolysis, and metabolites may remain in tissues for extended periods of time.

Elimination Route

Excreted principally by the kidneys and to a lesser extent via feces.

Half-life

At low-doses (<30 mg/m²), terminal half-life is about 3–10 hours. At high doses, elimination half-life is about 8–15 hours.

Special Populations

Excretion is impaired and accumulation occurs more rapidly in patients with impaired renal function, pleural effusion, or other substantial third-space accumulations (e.g., ascites).

Stability

Storage

Oral

Tablets

Well-closed containers at 20–25°C. Protect from light.

Parenteral

Injection

20–25°C. Protect from light.

Use preservative-free solution immediately after further dilution.

Powder for Injection

20–25°C. Protect from light.

Use immediately after reconstitution.

Compatibility

Parenteral

Solution Compatibility262 HID

Drug Compatibility

Actions

• Methotrexate and its polyglutamate metabolites reversibly inhibit dihydrofolate reductase (enzyme that reduces folic acid to tetrahydrofolic acid); inhibition of tetrahydrofolate formation limits availability of one-carbon fragments necessary for synthesis of purines and conversion of deoxyuridylate to thymidylate in DNA synthesis and cell reproduction.

• Also causes an increase in intracellular deoxyadenosine triphosphate, which is thought to inhibit ribonucleotide reduction, and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair.

• Tissues with high rates of cellular proliferation (e.g., neoplasms, psoriatic epidermis, bone marrow, lining of GI tract, hair matrix, fetal cells, urinary bladder) are most sensitive.

• Also has immunosuppressive activity, possibly because of lymphocyte multiplication inhibition.

• Mechanism(s) of action in rheumatoid arthritis not known; suggested mechanisms have included immunosuppressive and/or anti-inflammatory effects.

Advice to Patients

• Necessity of informing patients of potential benefits and risks of therapy and importance of remaining under care of clinician throughout therapy.

• Risk of hematologic, hepatic, pulmonary, and renal toxicities; importance of close follow-up, including periodic laboratory tests to monitor toxicity.

• Importance of recognizing early manifestations of toxicity and informing clinician promptly if such manifestations occur.

• Importance of emphasizing to patients that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of recommended dose has led to fatal toxicity. Encourage patients to read patient instruction sheet provided with mnemonic dispensing packages, paying particular attention to frequency of administration.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of informing both male and female patients of risks to fetus if pregnancy occurs. Advise patients to avoid pregnancy while either partner is receiving methotrexate, and for a minimum of 3 months after therapy in men and at least 1 ovulatory cycle after therapy in women.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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Frequently asked questions

• Why should I take folic acid with methotrexate?
• How do I know if methotrexate is working for rheumatoid arthritis?
• Does it cause weight gain?
• How long does it take to work?
• What are the different brands of methotrexate?
• How long does methotrexate stay in your system?
• What causes Plaque Psoriasis?
• How does methotrexate work for ectopic pregnancy?

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