Methotrexate, a folic acid antagonist, is an antineoplastic agent and immunosuppressant.1,2,3,4,5,6,265,269
Methotrexate injection and powder for injection are used as part of a combination chemotherapy regimen for the treatment of trophoblastic diseases (choriocarcinoma, invasive mole [formerly known as chorioadenoma destruens], and hydatidiform mole) in adults.1,2,7
Methotrexate has been studied as a first-line treatment option for patients with low-risk gestational trophoblastic neoplasia; low-risk disease is defined as having an invasive mole or choriocarcinoma histology with 1) International Federation of Gynecology and Obstetrics (FIGO) stage I disease (confined to the uterus) or 2) FIGO stage II or III disease (extending to genital structures outside the uterus or to the lungs, respectively) and a World Health Organization (WHO) risk score of <7 (indicating a low likelihood of resistance to single-agent chemotherapy).7 A 2016 Cochrane review of 7 clinical trials (N=667 female patients) compared various regimens of IM methotrexate with various regimens of IV dactinomycin for treatment of gestational trophoblastic neoplasia and found that dactinomycin was probably more likely to lead to primary cure compared with methotrexate.8 However, the individual trials included in the Cochrane review had substantial heterogeneity in the treatment regimens administered for both agents, and many of the studies dosed methotrexate once weekly, which has been shown to be less effective compared with other dosing strategies.7 More recent evidence has shown higher primary remission rates with methotrexate compared with dactinomycin for low-risk gestational trophoblastic neoplasia when a multiple-day regimen of methotrexate is used.7,9
Gestational trophoblastic disease is a broad term used to describe benign (i.e., hydatidiform mole) and malignant (e.g., invasive moles, choriocarcinoma) growths stemming from abnormal fertilization events during conception.11 One benign form of gestational trophoblastic disease is hydatidiform mole, which is classified as complete or partial depending on the presence of fetal tissue within the tumor.7,10,11 Complete hydatidiform moles, which do not contain any fetal tissue, can develop into invasive moles up to 25% of the time, while partial hydatidiform moles are much less likely to undergo malignant transformation.11 Malignant forms of gestational trophoblastic disease, which include invasive moles, choriocarcinoma, and other rare trophoblastic tumors, are collectively referred to as gestational trophoblastic neoplasias.11
In 2021, the Society of Gynecologic Oncology published recommendations for treatment of gestational trophoblastic disease.10 For the treatment of hydatidiform mole, suction dilation and curettage is the initial treatment of choice for women who wish to preserve fertility; hysterectomy is an alternative option for women who have completed childbearing and have risk factors for development of gestational trophoblastic neoplasia (i.e., human chorionic gonadotropin [hCG] >100,000 IU/L at diagnosis, very large uterus, theca lutein cysts, ≥40 years of age).10 While prophylactic chemotherapy can reduce the risk of gestational trophoblastic neoplasia following molar pregnancy, it may also increase tumor resistance to future treatment if subsequent gestational trophoblastic neoplasia were to develop; because of this, it is generally not recommended.10,11
In those diagnosed with gestational trophoblastic neoplasia, the FIGO/WHO risk score must be determined to assess the risk of disease progression and/or resistance to chemotherapeutic treatment with a single agent.10 Low-risk gestational trophoblastic neoplasia should be treated with methotrexate or dactinomycin.10 Multiple-day regimens of methotrexate (8-day or 5-day) and pulse regimens of dactinomycin are the most efficacious for this purpose.10 If resistance or relapse occurs following single agent chemotherapy, treatment with a different single agent or with combination chemotherapy (etoposide, methotrexate, dactinomycin, vincristine, and cyclophosphamide [EMA-CO]) is recommended; hysterectomy is also an option for select patients.10 EMA-CO is recommended as first line treatment of high-risk disease.10 Various other regimens with multiple chemotherapeutic agents can also be utilized in this setting.10
Methotrexate is used as part of a combination chemotherapy maintenance regimen to treat acute lymphoblastic leukemia (ALL).1,2,5,6,265,269 Methotrexate injection, powder for injection, oral solution (Jylamvo® only), and oral tablets are approved for this indication in adults and pediatric patients.1,2,5,265,269 Xatmep®(methotrexate oral solution) is approved for this indication in pediatric patients only;6 Xatmep® has been designated an orphan drug by the FDA for this indication in pediatric patients who are 0-16 years of age.12 Methotrexate injection and powder for injection are also used for the prophylaxis and treatment of meningeal leukemia in adults and pediatric patients.1,2
Treatment of ALL typically involves 4 treatment phases administered over a period of 2-3 years: induction, consolidation, intensification, and then a longer maintenance phase over about 2 years.13 Induction therapy consists of combination chemotherapy (typically including a corticosteroid, vincristine, L-asparaginase, and an anthracycline) administered with a goal to achieve complete remission.13 Next, consolidation therapy is administered with short, sequential courses of treatment over 12 weeks; common agents used for consolidation include cytarabine, high-dose methotrexate (defined as a dose >500 mg/m2, given with folic acid rescue), vincristine, asparaginase, 6-mercaptopurine, and corticosteroids.13 Allogeneic hematopoietic stem cell transplantation is recommended for consolidation treatment in select high-risk patients.13 After consolidation, intensive chemotherapy is administered with similar agents to those used for induction.13 Finally, maintenance treatment with daily 6-mercaptopurine and weekly methotrexate is given over 2 years.13 Additional agents, including vincristine and corticosteroid pulses, may also be administered as part of maintenance treatment.13 Throughout all phases of ALL treatment, CNS prophylaxis is given to prevent ALL relapse in the CNS.13 Intrathecal methotrexate is typically used for this purpose, either alone or in combination with cytarabine and hydrocortisone along with high-dose IV methotrexate and cytarabine.13 This treatment strategy has led to 5-year survival rates of 90% among pediatric patients with ALL.13 However, 5-year survival rates are much lower among adults following a similar treatment strategy, below 45%, with higher cure rates among those with a good prognosis (about 70%) and much lower cure rates (below 20%) among elderly patients.13
High-dose methotrexate injection or powder for injection, followed by rescue therapy with either leucovorin or levoleucovorin, is used in combination chemotherapy regimens as an adjunct to surgical resection or amputation of the primary tumor in patients with nonmetastatic osteosarcoma.1,2 These regimens appear to improve the chance of relapse-free survival in such patients.14,15 Methotrexate is designated an orphan drug by FDA for use in osteogenic sarcoma.12
Methotrexate injection and powder for injection have been used alone or, more commonly, as part of a combination chemotherapy regimen for the treatment of breast cancer.1,2 Guidelines from the American Society of Clinical Oncology (ASCO) on the selection of optimal adjuvant chemotherapy for early breast cancer recommend adjuvant chemotherapy with an anthracycline-taxane combination.16 Combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) is recommended as an alternative option to doxorubicin-cyclophosphamide when an anthracycline-taxane combination is contraindicated.16 This recommendation is based on studies that found similar breast cancer recurrence rates and mortality rates in patients treated with 4 cycles of doxorubicin-cyclophosphamide (4AC) or CMF; CMF was found to be less effective than anthracycline-based regimens with a much higher cumulative dosage than standard 4AC, such as cyclophosphamide-doxorubicin-fluorouracil or cyclophosphamide-epirubicin-fluorouracil.17
Methotrexate is used for the treatment of various types of lymphoma.1,2,5,265,269 Methotrexate injection, powder for injection, tablets, and oral solution (Jylamvo® only) are used for the treatment of non-Hodgkin lymphomas in adults; non-injectable formulations of methotrexate specify that it should be used as part of a metronomic combination regimen for this indication.1,2,5,265,269 Methotrexate injection and powder for injection are also approved for the treatment of non-Hodgkin lymphomas in pediatric patients.1,2 Methotrexate powder for injection, tablets, and oral solution (Jylamvo® only) are also used as a single agent or as part of a combination chemotherapy regimen to treat mycosis fungoides (cutaneous T-cell lymphoma) in adults.2,5,265,269
The non-Hodgkin lymphomas are a heterogeneous group of malignancies that cause uncontrolled lymphocyte production.18,19 Various B-cell lymphomas account for the majority of cases of non-Hodgkin lymphomas (85%), while T-cell lymphomas make up <15% of cases.18,19 Methotrexate is often administered intrathecally or in high doses as part of the chemotherapy regimen for the treatment of advanced-stage non-Hodgkin B-cell lymphomas to prevent relapse to the tissues around the brain and spinal cord in the CNS.20 Systemic chemotherapy, including methotrexate, may also be used for more advanced cases of mycosis fungoides; methotrexate can be administered as a single agent or in combination with other chemotherapy drugs.21,22
Methotrexate (all formulations except Xatmep® oral solution) is used in carefully selected adult patients for the treatment of severe psoriasis;1,2,3,4,5,265,269 methotrexate powder for injection and injection for subcutaneous (sub-Q) use (Rasuvo® and Otrexup®) are specifically used in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy.2,3,4
In 2023, a Cochrane review of 179 clinical trials (N=62,339 patients) was conducted to compare the efficacy of nonbiologic systemic therapies, small molecule drugs, and biologic agents used for the treatment of moderate to severe chronic plaque psoriasis.25 A network meta-analysis found that the most effective drugs (listed in order of effectiveness compared to placebo) for achieving a Psoriasis Area and Severity Index (PASI) 90 response (defined as a PASI score improvement of 90% or greater compared with baseline) were infliximab, bimekizumab, ixekizumab, and risankizumab.25 A higher proportion of patients treated with biologic agents (including medications targeting interleukin [IL]-17, IL-12/23, IL-23, and tumor necrosis factor [TNF] alpha) reached PASI 90 compared to those treated with nonbiologic systemic agents.25 No substantial difference in efficacy was found between apremilast and cyclosporine or methotrexate.25
The American Academy of Dermatology and the National Psoriasis Foundation have issued joint guidelines for the treatment of psoriasis in adults.2007,2008,2009,2010,2011 Phototherapy and topical treatments (e.g., vitamin D analogues, calcineurin inhibitors, keratolytics, and corticosteroids) are frequently used to treat mild psoriasis present on limited areas of the body, but these therapies may be inadequate to obtain skin clearance in patients with more extensive or severe disease.2007,2008,2009,2012 Systemic biologic and nonbiologic therapies are mainstays of treatment for moderate to severe psoriasis, and may also be useful for treating psoriasis on parts of the body that are difficult to treat with topical therapy (e.g., scalp, palms and soles of the feet, genitals).2007,2009,2012 Nonbiologic oral therapies used in the treatment of psoriasis include methotrexate, apremilast, cyclosporine, acitretin, and dimethyl fumarate.2009,2012 Biologics used in the treatment of psoriasis include TNF blocking agents, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab.2007,2012 Treatment selection is primarily based on disease characteristics (e.g., severity, location, presence of psoriatic arthritis), with additional consideration being given to patient age and comorbidities.2010,2011,2012
Guidelines from the American Academy of Dermatology and the National Psoriasis Foundation on the treatment of psoriasis with nonbiologic agents recommend methotrexate (administered orally or sub-Q) and apremilast for the treatment of moderate to severe psoriasis in adults; cyclosporine is recommended for patients who have severe, recalcitrant psoriasis.2009 These guidelines note that methotrexate is less effective than adalimumab and infliximab for cutaneous psoriasis.2009 Recommendations for the use and selection of psoriasis therapies vary based on patient age, disease characteristics (e.g., severity, location, presence of psoriatic arthritis), and comorbidities (e.g., inflammatory bowel disease).2007,2008,2009,2010,2011,2012 Consult the American Academy of Dermatology/National Psoriasis Foundation guidelines for additional details.2007,2008,2009,2010,2011
Methotrexate (all formulations except Xatmep® oral solution) is used for the management of rheumatoid arthritis in adults;1,2,3,4,5,265,269 methotrexate powder for injection and injection for sub-Q use (Rasuvo® and Otrexup®) are specifically used in adults with severe, active disease who are intolerant to or whose symptoms progress despite adequate first-line treatment.2,3,4
In 2014, a Cochrane review of 7 clinical trials (N=732 patients) was conducted to compare the short-term efficacy (over ≥12 weeks) of methotrexate to placebo for the treatment of rheumatoid arthritis.23 The included trials enrolled patients with severe rheumatoid arthritis of long duration who previously failed treatment with a different second-line disease-modifying antirheumatic drug (DMARD).23 Methotrexate was administered orally or parenterally at a dose of ≥5 mg per week.23 Major outcomes that were assessed included the number of tender/swollen joints per patient, pain (via a visual analog scale), physician and patient global assessment, functional status (measured by a validated scale), and levels of acute phase reactants (i.e., erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]).23 Disease severity and remission were measured by the American College of Rheumatology (ACR) score (ACR 20, 50, and 70 responses) and the disease activity score (DAS), respectively.23 Radiologic evidence of joint damage was also assessed.23 The Cochrane review found that methotrexate administration led to substantially improved outcomes and clinically important differences compared to placebo for most of the efficacy outcomes assessed.23
The American College of Rheumatology issued guidelines for the treatment of rheumatoid arthritis in 2021.2003 Disease-modifying treatments for rheumatoid arthritis include conventional DMARDs (e.g., hydroxychloroquine, leflunomide, methotrexate, sulfasalazine), biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab, sarilumab, rituximab), and/or targeted synthetic DMARDs (e.g., Janus kinase [JAK] inhibitors).2003 Specific agents for rheumatoid arthritis treatment are selected according to current disease activity, prior therapies used, and the presence of comorbidities.2003 A “treat-to-target” approach is typically employed, with the goal of achieving a predefined target of low disease activity or remission.2003
For patients with rheumatoid arthritis who are DMARD-naïve and have moderate to high disease activity, methotrexate monotherapy is strongly recommended over monotherapy with hydroxychloroquine, sulfasalazine, a biologic DMARD, or a targeted synthetic DMARD, or combination therapy with methotrexate and a non-TNF-blocking biologic or targeted synthetic DMARD.2003 In the same patient population, methotrexate is conditionally recommended over leflunomide, dual or triple conventional DMARD therapy, and combination therapy with methotrexate and a TNF inhibitor.2003 Methotrexate is also conditionally recommended over leflunomide for initiation of treatment in DMARD-naïve patients with low disease activity.2003 In patients with moderate to high disease activity who have previously been treated with a conventional synthetic DMARD but who are methotrexate-naïve, methotrexate monotherapy is conditionally recommended over combination therapy with methotrexate and a biologic or targeted synthetic DMARD.2003 When initiating treatment, oral methotrexate is conditionally recommended over sub-Q methotrexate; when patients are not at target with oral methotrexate, switching to a sub-Q formulation is conditionally recommended over adding on or switching to alternative DMARDs.2003 Consult the American College of Rheumatology guidelines for additional details.2003
Polyarticular Juvenile Idiopathic Arthritis
Methotrexate is used for the management of polyarticular juvenile idiopathic arthritis in pediatric patients.1,2,3,4,5,6,265,269 Methotrexate powder for injection, injection for sub-Q use (Rasuvo® and Otrexup®), and oral solution (Xatmep® only) are specifically used in pediatric patients with severe, active disease who are intolerant to or whose symptoms progress despite adequate first-line treatment.2,3,4,6 Xatmep® has been designated an orphan drug by the FDA for this indication in pediatric patients.12
In 2024, a Cochrane review of 5 randomized controlled trials (N=575 patients) was conducted to compare the efficacy of methotrexate to placebo, no treatment, or other DMARDs for the treatment of juvenile idiopathic arthritis.24 The included trials enrolled patients <18 years of age with a diagnosis of juvenile idiopathic arthritis.24 Efficacy outcomes that were assessed included the ACR Pediatric response (ACR Pediatric 70, 50, and 30 responses), evidence of sustained clinically inactive disease, pain, function, and patient global assessment of well-being.24 The Cochrane review found that after 6 months, methotrexate was more likely to improve symptoms compared to placebo (n=3 studies) but had similar effects on pain and well-being.24 Two individual studies that compared methotrexate to intra-articular corticosteroids or leflunomide found no difference in outcomes between treatments.24
The American College of Rheumatology and the Arthritis Foundation issued a joint guideline for the treatment of juvenile idiopathic arthritis manifesting as nonsystemic polyarthritis (including polyarticular disease), sacroiliitis, or enthesitis in 2019.2013 Several drug classes are used to treat juvenile idiopathic arthritis, including nonsteroidal anti-inflammatory agents (NSAIAs), systemic and intra-articular corticosteroids, conventional DMARDs (e.g., methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), and biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab, rituximab).2013 Specific agents for juvenile idiopathic arthritis treatment are selected according to the presence of certain risk factors (e.g., positive anti-cyclic citrullinated peptide antibodies, positive rheumatoid factor, joint damage), level of disease activity, involvement of specific joints, presence of certain comorbidities (e.g., uveitis), and prior therapies used.2013,2022 An individualized “treat-to-target” approach is typically employed, with the goal of achieving remission or minimal/low disease activity.2014
For pediatric patients with juvenile idiopathic arthritis and active polyarthritis, initial treatment with a DMARD is strongly recommended over NSAIA monotherapy and conditionally recommended over treatment with a biologic.2013 Methotrexate monotherapy is conditionally recommended over sulfasalazine, leflunomide, and triple DMARD therapy with all 3 agents.2013 Sub-Q formulations of methotrexate are conditionally recommended over oral formulations.2013 In pediatric patients with active sacroiliitis despite NSAIA therapy, the guideline strongly recommends against methotrexate monotherapy.2013 In pediatric patients with active enthesitis despite NSAIA therapy, TNF blocking agents are conditionally recommended over methotrexate or sulfasalazine.2013 Consult the American College of Rheumatology/Arthritis Foundation guidelines for additional details.2013,2022
Methotrexate injection and powder for injection are used alone and as part of combination therapy for the palliative treatment of recurrent or metastatic head and neck carcinoma.1,2,210 When used alone, at a dosage of 40-60 mg/m2 once weekly, methotrexate produces an average objective response rate of approximately 6% with an overall survival of about 6 months.26,27,210,211
In a randomized study, patients with recurrent or metastatic squamous cell carcinoma of the head and neck who received cisplatin and fluorouracil, carboplatin and fluorouracil, or methotrexate alone had objective response rates of 32, 21, or 10%, respectively.211 Although the objective response rate achieved with cisplatin and fluorouracil was greater than that observed with methotrexate alone, combination chemotherapy was associated with increased toxicity and no difference in survival was observed.211 Other studies comparing methotrexate to different combination chemotherapy regimens in patients with recurrent or metastatic head and neck cancer similarly found no survival advantage with combination chemotherapy regimens.28,29
Methotrexate has been used for its anti-inflammatory effects in the management of Crohn disease †.250,251,2001 Results of 2 separate Cochrane reviews have shown that IM methotrexate is effective for induction (7 studies, 495 patients) and maintenance (5 studies, 333 patients) of remission in patients with refractory Crohn disease.250,251 Guidelines from the American College of Gastroenterology and the American Gastroenterological Association support the use of IM and sub-Q methotrexate for induction and maintenance of remission in patients with moderate to severe Crohn disease.2001
Methotrexate is used in combination regimens with cisplatin and vinblastine, with or without doxorubicin, for the treatment of invasive and advanced bladder cancer†.30,31 Guidelines from the American Urological Association for the management of non-metastatic muscle-invasive bladder cancer recommend administering cisplatin-based neoadjuvant chemotherapy to appropriate patients prior to radical cystectomy;31 the 2 large randomized controlled trials cited for this recommendation both included methotrexate as part of the chemotherapy regimen.32,33
Although methotrexate is labeled for use in the treatment of the squamous cell type of non-small cell lung cancer,2 other agents are preferred for the treatment of this neoplasm.34
Methotrexate is also used for the treatment of tubal ectopic pregnancy †.42 According to guidelines from the American College of Obstetricians and Gynecologists, medical management with IM methotrexate can be considered in women with the following characteristics: high clinical suspicion or confirmation of ectopic pregnancy, hemodynamically stable, unruptured mass, and no absolute contraindications to methotrexate.42
Methotrexate has been used for its immunosuppressive and/or anti-inflammatory effects in the treatment of atopic dermatitis†,35 psoriatic arthritis†,2005 systemic lupus erythematosus†,36 antineutrophil cytoplasmic antibody-associated vasculitides†,37 dermatomyositis†,38 polymyositis†,38 and a variety of dermatologic and chronic refractory ocular diseases† .39,40
Methotrexate has also been used for prophylaxis of acute graft-versus-host disease† following stem cell transplantation for hematologic malignancies.41
Dispensing and Administration Precautions
Methotrexate is administered orally as tablets or an oral solution.5,6,265,269 Methotrexate sodium is administered by IM, IV, sub-Q, or intrathecal injection;1,2,3,4 methotrexate powder for injection may also be administered intraarterially.2 Some injectable preparations of methotrexate sodium (Rasuvo® and Otrexup®) are only administered sub-Q.3,4 Rasuvo® is only available in doses between 7.5-30 mg in 2.5 mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <7.5 mg per week, dosages >30 mg per week, high-dose regimens, or dosage adjustments in increments that are <2.5 mg.3 Otrexup® is only available in doses between 10-25 mg in 2.5 mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <10 mg per week, dosages >25 mg per week, high-dose regimens, or dosage adjustments between the available doses.4
Methotrexate sodium powder for injection should be reconstituted according to the manufacturers' directions.2 Methotrexate sodium injection is available as a single-dose vial that is ready for use.1 Rasuvo® and Otrexup® (methotrexate sodium injection for sub-Q use) are commercially available in single-use, prefilled auto-injectors.3,4
Instruct patients or caregivers on proper dosing of methotrexate oral solution, including the importance of using an accurate measuring device.5,6 A household teaspoon is not an accurate measuring device.5,6 Jylamvo® oral solution comes copackaged with a syringe and bottle adapter for oral administration, which should be used to measure the dose.5
Do not administer methotrexate tablets to patients who are unable to swallow tablets.265,269
Store methotrexate 2.5 mg tablets at 20-25°C; excursions permitted between 15-30°C.265
Store methotrexate high-dose tablets (Trexall®) at 20-25°C and protect from light.269
Store Jylamvo® (methotrexate 2 mg/mL oral solution) at 20-25°C; excursions permitted between 15-30°C.5 Once in use, store Jylamvo® at 20-25°C and keep the bottle tightly closed.5 Discard any unused medicine after 3 months from the date of opening.5
Store Xatmep® (methotrexate 2.5 mg/mL oral solution) at 2-8°C tightly closed in the original container.6 Once dispensed, Xatmep® can be stored refrigerated at 2-8°C or at room temperature at 20-25°C, with excursions permitted between 15-30°C.6 Discard any unused medicine after 60 days if stored at room temperature.6 Avoid freezing and exposure to excessive heat.6
Reconstitute methotrexate powder for injection immediately prior to use with an appropriate sterile, preservative-free medium such as 5% dextrose or 0.9% sodium chloride injection.2 Reconstitute the 1 gram vial with 19.4 mL of diluent to obtain a concentration of 50 mg/mL.2 For administration of high-dose therapy, dilute the total dose further using 5% dextrose.2
If the product is to be administered intrathecally, dilute reconstituted methotrexate powder for injection to a concentration of 1 mg/mL with an appropriate sterile, preservative-free medium such as 0.9% sodium chloride injection.2 Methotrexate formulations or diluents containing preservatives must not be used for intrathecal administration or high-dose methotrexate therapy; also use only preservative-free products when treating neonates or low-birth weight infants.2
Store methotrexate powder for injection at 20-25°C and protect from light.2
Methotrexate injection is available as a single-dose solution that is ready for use; however, it may be further diluted immediately prior to use with preservative-free 0.9% sodium chloride.1
Methotrexate injection requires dilution prior to intrathecal administration.1 Dilute methotrexate injection to a concentration of 1 mg/mL using preservative-free 0.9% sodium chloride injection.1 Methotrexate formulations or diluents containing preservatives must not be used for intrathecal administration or high-dose methotrexate therapy; also use only preservative-free products when treating neonates or low-birth weight infants.1
Store methotrexate injection at 20-25°C and protect from light.1
Injection for Subcutaneous Use
Methotrexate injection for sub-Q use (Rasuvo® and Otrexup®) is available as single-dose auto-injectors for sub-Q use only.3,4 Administer these products in the abdomen or thigh.3,4
Store methotrexate injection for sub-Q use at 20-25°C (excursions permitted between 15-30°C) and protect from light.3,4
Dosage of methotrexate sodium is expressed in terms of methotrexate.1,2,6,265,269
Although methotrexate is not generally a drug of choice for induction of remission of acute lymphoblastic leukemia (ALL), methotrexate dosages of 3.3 mg/m2daily and prednisone 60 mg/m2 daily for 4-6 weeks have been used.2,13 In general, recommended dosages of methotrexate for the treatment of ALL are highly variable, and can range from 10-5000 mg/m2 IV.1 Individualize the dose and schedule based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment.1
When used as part of a combination chemotherapy maintenance regimen to treat ALL in pediatric patients, the dosage of methotrexate varies based on the dosage form.1,2,5,6,265,269 Oral forms of methotrexate, including methotrexate oral solution and tablets, are administered at a lower dosage of 20 mg/m2, given once weekly.5,6,265,269 After treatment initiation, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dosage as appropriate.5,6,265,269 Methotrexate powder for injection has been administered twice weekly at a dose of 30 mg/m2 IM or once every 14 days at a dose of 2.5 mg/kg IV for this purpose.2
Methotrexate injection and powder for injection are the only formulations of methotrexate that are approved for intrathecal administration for the prophylaxis and treatment of meningeal leukemia.1,2 For prophylaxis of meningeal leukemia, methotrexate is administered no more than once per week.1 For treatment of meningeal leukemia, methotrexate is administered up to twice weekly.1 The recommended intrathecal dosage of methotrexate for this indication is based on age:1,2
•<1 year: 6 mg
•1 to <2 years: 8 mg
•2 to <3 years: 10 mg
•3 to <9 years: 12 mg
•≥9 years: 12-15 mg
The recommended initial dosage for high-dose methotrexate treatment of nonmetastatic osteosarcoma is 12 g/m2 (maximum 20 g dose) administered by IV infusion over 4 hours1,2 on postoperative weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45, on a schedule in combination with other chemotherapy agents (e.g., doxorubicin, cisplatin, the combination of bleomycin, cyclophosphamide, and dactinomycin [BCD regimen]).2 If the 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 the infusion, the dose may be increased to 15 g/m2 in subsequent treatments.2
For the treatment of non-Hodgkin lymphomas in pediatric patients, the dosage of methotrexate injection or powder for injection varies.1,2 When used as part of a combination chemotherapy regimen, methotrexate 1000 or 3000 mg/m2 is given IV over 24 hours.1 When used for CNS-directed therapy, methotrexate is given as an IV infusion over 4 hours at a dosage of 8000 mg/m2 (as a single agent) or at dosages ranging between 3000-8000 mg/m2 (in combination with immunochemotherapy).1 The dosage of methotrexate for intrathecal injection is based on age (see Leukemias under Pediatric Dosage).
Polyarticular Juvenile Idiopathic Arthritis
For the treatment of polyarticular juvenile idiopathic arthritis, the recommended starting dosage of methotrexate is 10 mg/m2, given subcutaneously or intramuscularly once weekly.1,2,3,4,5,6,265,269 The dosage can then be gradually increased to achieve an optimal response.1,2,3,4,5,6,265,269 Doses between 20-30 mg/m2may have better absorption and fewer GI adverse effects if administered by a nonoral route (i.e., IM, sub-Q).2,3,4,6,265,269 Therapeutic response usually is apparent within 3-6 weeks, but optimum response may not be achieved for another 3 or more months of therapy.1,2,3,4,6,265,269
For the treatment of trophoblastic diseases, the usual dosage of methotrexate is 15-30 mg daily, administered orally or IM for 5 days.2 A repeat course may be given after a period of one or more weeks, provided all signs of residual toxicity have disappeared.2 Three to 5 courses of therapy are usually employed.2 Therapy is usually evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin which should return to normal or <50 IU/24 hours, usually after the third or fourth course.2 Complete resolution of measurable lesions usually occurs 4-6 weeks later.2 One or 2 courses of methotrexate therapy are usually given after normalization of urinary chorionic gonadotropin hormone concentrations is achieved.2
The prescribing information for methotrexate injection recommends methotrexate IV or IM for this indication, with the dosage varying based on the level of disease risk.1 For low-risk disease, the recommended dosage of methotrexate injection is 30-200 mg/m2 or 0.4-1 mg/kg IV or IM.1 For high-risk disease, the recommended dosage is 300 mg/m2 given as a component of a multi-drug regimen via IV infusion over 12 hours.1
Although methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukemia, methotrexate dosages of 3.3 mg/m2 daily and prednisone 60 mg/m2 daily for 4-6 weeks have been used.2,13 In general, recommended dosages of methotrexate for the treatment of ALL are highly variable, and can range from 10-5000 mg/m2 IV.1 Individualize the dose and schedule based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment.1
When used as part of a combination chemotherapy maintenance regimen to treat ALL, the dosage of methotrexate varies based on the dosage form.1,2,5,6,265,269 Oral forms of methotrexate, including methotrexate oral solution and tablets, are administered at a lower dosage of 20 mg/m2, given once weekly.5,6,265,269 After treatment initiation, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dosage as appropriate.5,6,265,269 Methotrexate powder for injection has been administered twice weekly at a dose of 30 mg/m2 IM or once every 14 days at a dose of 2.5 mg/kg IV for this purpose.2
Methotrexate injection and powder for injection are the only formulations of methotrexate that are approved for intrathecal administration for the prophylaxis and treatment of meningeal leukemia.1,2 For prophylaxis of meningeal leukemia, methotrexate is administered no more than once per week.1 For treatment of meningeal leukemia, methotrexate is administered up to twice weekly.1 The recommended intrathecal dosage of methotrexate for this indication in adults is 12-15 mg.1,2
The recommended initial dosage for high-dose methotrexate treatment of nonmetastatic osteosarcoma is 12 g/m2 (maximum 20 g/dose) administered by IV infusion over 4 hours1,2 on postoperative weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45, on a schedule in combination with other chemotherapy agents (e.g., doxorubicin, cisplatin, the combination of bleomycin, cyclophosphamide, and dactinomycin [BCD regimen]).2 If the 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 the infusion, the dose may be increased to 15 g/m2 in subsequent treatments.2
Various methotrexate-containing combination chemotherapy regimens have been used in the treatment of breast cancer, and published protocols should be consulted for dosages and the method and sequence of administration.16
The prescribing information for methotrexate injection includes a methotrexate dosage of 40 mg/m2 (administered IV) as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen.1
For the treatment of non-Hodgkin lymphomas in adults, the dosage of methotrexate injection or powder for injection varies.1,2 When used as part of a combination chemotherapy regimen, methotrexate 1000 or 3000 mg/m2 is given IV over 24 hours.1 When used for CNS-directed therapy, methotrexate is given as an IV infusion over 4 hours at a dosage of 8000 mg/m2 (as a single agent) or at dosages ranging between 3000-8000 mg/m2 (in combination with immunochemotherapy).1 The dosage of methotrexate for intrathecal injection is 12-15 mg.1 When oral methotrexate is used as part of a metronomic combination regimen to treat relapsed or refractory non-Hodgkin lymphomas in adults, the dosage is 2.5 mg given orally 2-4 times per week (maximum 10 mg per week).5,265,269
When used to treat mycosis fungoides (cutaneous T-cell lymphoma) in adults, oral methotrexate is administered at a dosage of 25-75 mg once per week when administered as a single agent or 10 mg/m2 twice weekly when administered as part of a combination chemotherapy regimen.5,265,269 The prescribing information for methotrexate injection also suggests a dosage of 5-75 mg IV.1 In patients with advanced stages of mycosis fungoides, combination chemotherapy regimens that include IV methotrexate in higher doses followed by leucovorin rescue have been used.2
For the management of psoriasis, a starting dosage of 10-25 mg, given as a single oral, IM, sub-Q, or IV dose once weekly, is recommended.1,2,3,4,5,265,269 The dosage can then be gradually titrated to achieve the desired clinical response; typically, the weekly dose should not exceed 30 mg per week.2,3,4,5,265,269 Once an optimal response is achieved, reduce the dosage to the lowest possible dosage and the longest possible rest period.2,3,4,5,265,269 Use of methotrexate for the treatment of psoriasis may allow patients to return to using conventional topical treatments, which should be encouraged.2,3,4
For the management of rheumatoid arthritis, methotrexate is administered in low-dose, intermittent (i.e., weekly rather than daily) regimens. The usual initial dosage in adults is 7.5 mg, given as a single IM, sub-Q, or oral dose once weekly.1,2,3,4,5,265,269 Dosage may be gradually increased until an optimum therapeutic response is achieved.1,2,3,4,5,265,269 However, dosage usually should not exceed 20 mg weekly, since higher dosages have been associated with a substantially increased incidence and severity of serious adverse reactions (e.g., bone marrow suppression).1,2,3,4,5,265,269 Therapeutic response in patients with rheumatoid arthritis usually is apparent within 3-6 weeks, but optimum response may not be achieved for another 3 or more months of therapy.1,2,3,4,5,265,269
For the management of Crohn disease†, methotrexate has been administered in low-dose, intermittent (i.e., weekly rather than daily) regimens.2001 The American College of Gastroenterology and the American Gastroenterological Association recommend methotrexate 25 mg sub-Q or IM once weekly for induction of remission following steroid induction in patients with moderate to severe Crohn disease.2001 If steroid-free remission is maintained for ≥4 months at this dosage, the dosage can be lowered to 15 mg once weekly.2001 The American Gastroenterological Association does not recommend oral methotrexate for induction and maintenance of remission in patients with Crohn disease.2001
Patients with hepatic impairment may be more likely to experience adverse reactions from methotrexate based on the hepatic metabolism of the drug.1,5,6,265,269 Use of methotrexate powder for injection or injection for sub-Q use (Rasuvo® and Otrexup®) is contraindicated for the treatment of psoriasis or rheumatoid arthritis in patients with alcoholism, alcoholic liver disease, or other chronic liver disease.2,3,4 Consider reducing the dosage or discontinuing methotrexate in patients with hepatic impairment as appropriate.1,3,5,6,265,269
Elimination of methotrexate is reduced in patients with renal impairment (i.e., creatinine clearance <90 mL/minute using the Cockcroft-Gault calculation).1,3,4,5,6,265,269 Such patients are at an increased risk for adverse reactions from methotrexate.1,3,4,5,6,265,269 Follow recommendations to promote elimination of methotrexate and decrease the risk of acute kidney injury and other methotrexate-associated toxicities in patients receiving intermediate- or high-dose regimens of methotrexate injection.1 Consider reducing the dosage or discontinuing methotrexate injection in patients with renal impairment as appropriate.1,3,4,5,6,265,269
The manufacturer makes no specific dosage recommendations for geriatric patients.1,2,3,4,5,265,269 Due to the reduced hepatic and renal function, decreased folate stores, and possibility of concomitant diseases or drug therapies in this population, consider relatively low doses and closely monitor for early signs of renal, hepatic, and bone marrow toxicity.2,3,4
Fetal/Neonatal Morbidity and Mortality
A boxed warning about the risk of embryofetal toxicity, including fetal death, is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Abortion, fetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy.1,2,3,4,5,6,265,269 Methotrexate is contraindicated in the management of all non-neoplastic disorders (i.e., psoriasis or rheumatoid arthritis [including polyarticular juvenile idiopathic arthritis]) in pregnant women.1,2,3,4,5,6,265,269 Verify pregnancy status in female patients of reproductive potential prior to initiating treatment with methotrexate.1,2,3,4,5,6,265,269 Advise female patients of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months following the final dose; advise male patients with such female partners to use effective contraception during treatment with methotrexate and for 3 months following the final dose.1,2,3,4,5,6,265,269 Women of childbearing potential should be fully informed of the potential hazard to the fetus should they become pregnant during methotrexate therapy.1,2,3,4,5,6,265,269 Benzyl alcohol is present in certain formulations of methotrexate injection and powder for injection and can cross the placenta.1,2 If methotrexate injection is administered to treat a neoplastic disease in a pregnant patient, use a preservative-free formulation when possible.1
Hypersensitivity and Dermatologic Reactions
A boxed warning about the risk of hypersensitivity reactions and/or severe dermatologic reactions is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving methotrexate.1,5,6,265,269 Methotrexate is contraindicated in patients with a history of severe hypersensitivity reactions.1,2,3,4,5,6,265,269 If signs or symptoms of anaphylaxis or any other serious hypersensitivity reaction occur, immediately discontinue methotrexate and institute appropriate therapy.1,5,6,265,269 Severe, sometimes fatal, dermatologic reactions (e.g., Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme) have occurred in patients treated with methotrexate.1,2,3,4,5,6,265,269 Such reactions have occurred following single or multiple doses of methotrexate administered via the oral, IM, IV, or intrathecal route in patients with neoplastic and non-neoplastic diseases; recovery has occurred following discontinuation of the drug.2,3,4 Methotrexate can also cause radiation recall dermatitis and photodermatitis (sunburn) reactivation.1,2,3,4,5,6,265,269 In patients with psoriasis treated with methotrexate, exposure to ultraviolet radiation can aggravate their condition.1,2,3,4,5,265,269 Monitor patients receiving methotrexate for signs of dermatologic toxicity during therapy.1,2,3,4,5,265,269 Methotrexate may need to be withheld or permanently discontinued if dermatologic reactions occur.1,3,4,5,6,265,269 Counsel patients to use sun protection measures and to avoid excessive exposure to the sun.1,5,265,269
Risks of Serious Adverse Reactions due to Benzyl Alcohol Preservative
A boxed warning about the risk of serious adverse reactions due to the preservative benzyl alcohol is included in the prescribing information for methotrexate injection and powder for injection.1,2 Formulations of methotrexate injection or powder for injection that contain benzyl alcohol can cause severe CNS toxicity or metabolic acidosis when administered to neonates or low-birth weight infants, or when given intrathecally or in high-dose regimens.1,2 Serious, sometimes fatal reactions including “gasping syndrome” (a condition characterized by CNS depression, metabolic acidosis, and gasping respirations) can occur when preserved formulations of methotrexate are administered to low-birth weight infants and neonates.1,2 Serious neurotoxicity can occur when preserved formulations of methotrexate are administered intrathecally.1 Severe metabolic acidosis can also occur with high-dose methotrexate therapy when preserved formulations are used.1 When administering methotrexate to neonates or low-birth weight infants, only use preservative-free formulations.1 If administering methotrexate to infants who are not neonates and are not low-birth weight and a preservative-free formulation is not available, consider the combined daily metabolic load of benzyl alcohol from all sources and other drugs; methotrexate injection contains 9.4 mg of benzyl alcohol per mL.1 The minimum amount of benzyl alcohol necessary to elicit serious adverse reactions is not known.1 Use preservative-free formulations of methotrexate for intrathecal administration.1,2 Preserved formulations of methotrexate should also be avoided for high-dose regimens,1,2 unless immediate treatment is needed and a preservative-free formulation is not available.1
A boxed warning about the risk of serious adverse reactions, including myelosuppression, is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Methotrexate suppresses hematopoiesis and can cause myelosuppression, including severe and life-threatening cases of pancytopenia, anemia, aplastic anemia, leukopenia, neutropenia, and thrombocytopenia.1,2,3,4,5,6,265,269 In clinical trials evaluating 128 patients treated with methotrexate injection for rheumatoid arthritis, leukopenia (WBC count <3000/mm3), thrombocytopenia (platelets <100,000/mm3), and pancytopenia were seen in 2, 6, and 2 patients, respectively.2,3,4 Unexpectedly severe, and sometimes fatal, myelosuppression and aplastic anemia have also been reported with concomitant use of methotrexate (usually high-dose regimens) and nonsteroidal anti-inflammatory agents (NSAIAs).2,3,4,6 Use with caution in patients with malignancy and preexisting hematopoietic impairment.2 Obtain blood counts at baseline and periodically during treatment with methotrexate.1,6,265,269 Monitor patients for possible complications of myelosuppression.1,2,3,4,5,6,265,269 If myelosuppression occurs, the dose may need to be reduced or withheld, or methotrexate may need to be discontinued; additional supportive care may also be necessary.1,2,3,4,5,6,265,269 Patients with fever and profound granulocytopenia should be evaluated immediately; such patients typically require parenteral broad-spectrum antibiotic therapy.2,3,4
A boxed warning about the risk of serious adverse reactions, including life-threatening or fatal bacterial, fungal, or viral infections, is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Patients treated with methotrexate are at an increased risk for serious opportunistic infections, including Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia, invasive fungal infections, hepatitis B reactivation, primary infection or reactivation of tuberculosis, and disseminated Herpes zoster and cytomegalovirus infections.1,2,3,4,5,6,265,269 Immunizations administered during treatment with methotrexate may be ineffective.1,2,3,4,6 Disseminated infections have been reported following administration of live vaccines in patients receiving methotrexate;1,2,3,4,5,6,265,269 hypogammaglobulinemia has also rarely been reported.3,4 Administer all appropriate vaccines according to immunization guidelines prior to initiation of methotrexate therapy.1,5,265,269 Administration of live vaccines is not recommended during treatment with methotrexate.1,2,3,4,5,6,265,269 Use methotrexate with extreme caution in patients with active infection; methotrexate powder for injection and injection for subcutaneous (sub-Q) use (Rasuvo® and Otrexup®) are contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes.2,3,4 Monitor patients closely for signs and symptoms of infection during and after treatment with methotrexate.1,2,5,6,265,269 Methotrexate therapy may need to be modified, withheld, or discontinued in patients with serious infections.1,3,4,5,6,265,269
A boxed warning about the risk of serious adverse reactions, including renal toxicity that may lead to irreversible acute renal failure, is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Renal toxicity primarily occurs as a result of precipitation of methotrexate and its metabolite, 7-hydroxymethotrexate, in the renal tubules.2,3,4 Patients with renal impairment are at an increased risk for development of toxicity from methotrexate.1,5,265,269 Monitor renal function at baseline and periodically during treatment; withhold or discontinue methotrexate as needed if severe renal toxicity develops.1,2,3,4,5,6,265,269 Adequate hydration and urine alkalinization may help to ensure safe administration.2,3,4 Follow recommendations to decrease the risk of renal injury and mitigate renal toxicity in patients receiving high-dose methotrexate regimens.1,2 Consider administration of glucarpidase in patients who have laboratory evidence of methotrexate toxicity (i.e., plasma concentrations >1 µmol/L) and delayed clearance because of impaired renal function.1,5,6,265,269
A boxed warning about the risk of serious adverse reactions, including severe and potentially irreversible hepatotoxicity that may cause fibrosis, cirrhosis, and fatal liver failure, is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Hepatotoxicity generally occurs following prolonged use of methotrexate (generally ≥2 years), with liver biopsy often showing histologic changes.2,3,4 Heavy alcohol consumption contributes to the risk of hepatotoxicity.1,5,265,269 Acute elevations in liver enzymes occur frequently, and are usually transient and not associated with symptoms; such elevations do not appear to predict subsequent hepatic disease.2,3,4,6 The safety of using methotrexate in patients with hepatic disease is not known; methotrexate should generally be avoided in patients with chronic liver disease unless the benefits of therapy clearly outweigh the risk of hepatotoxicity.1,2,3,4,5,6,265,269 In patients with psoriasis, severe hepatotoxicity can occur without the presence of symptoms or abnormal hepatic function tests.1,2,3,4,5,265,269 In these patients, the risk of hepatotoxicity increases in a dose-dependent manner and generally occurs in association with cumulative doses of ≥1.5 grams.1,2,3,4,5,265,269 Alcoholism, obesity, diabetes, and advanced age have also been identified as risk factors for hepatotoxicity in this population.2,3,4,6 Therefore, periodic liver biopsies may be warranted in patients with psoriasis who receive long-term treatment with methotrexate.2,3,4 In patients with rheumatoid arthritis, persistently abnormal liver function tests may precede the development of fibrosis and cirrhosis.2,3,4,6 Age at first use of methotrexate and duration of therapy have been identified as risk factors for hepatotoxicity in this population.2,3,4,6 Evaluate liver function prior to initiating methotrexate therapy and continue to monitor during treatment.1,2,3,4,5,6,265,269 Pretreatment liver biopsy should be performed in patients with excessive alcohol consumption, chronic hepatitis B or C infection, or persistently elevated liver function tests at baseline.2,3,4 Liver biopsy should also be performed during treatment based on laboratory findings (e.g., persistent liver function abnormalities or a decrease in serum albumin below the normal range in those with well-controlled rheumatoid arthritis).2,3,4 Methotrexate may need to be withheld or discontinued as appropriate.1,2,3,4,5,6,265,269
A boxed warning about the risk of serious adverse reactions, including severe acute and chronic neurotoxicity which can be progressive, irreversible, and fatal, is included in the prescribing information for methotrexate (with the exception of Xatmep® oral solution).1,2,3,4,5,265,269 Serious neurotoxicity, including generalized and focal seizures, has occurred in pediatric patients receiving methotrexate.1,2,3,4 Administration of methotrexate in high-dose IV regimens, intrathecally, and in low-dose regimens can cause leukoencephalopathy;1,2,3,4 this risk is further increased in those who have previously received cranial radiation.1,2,3,4,5,265,269 High-dose methotrexate can also cause a transient, acute stroke-like syndrome manifested as confusion, hemiparesis, transient blindness, seizures, and coma.1,2,3,4 Intrathecal administration of methotrexate can cause acute chemical arachnoiditis (characterized by symptoms of headache, back pain, nuchal rigidity, and fever) or subacute myelopathy (with symptoms such as paraparesis or paraplegia).1,2,3,4 Monitor patients receiving methotrexate for signs of neurotoxicity.1,5,265,269 Therapy may need to be withheld or discontinued as appropriate.1,5,265,269 Avoid intrathecal administration of methotrexate products that contain the preservative benzyl alcohol, which can increase the risk for serious neurotoxicity.1
A boxed warning about the risk of serious adverse reactions, including severe GI toxicity, is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Methotrexate can cause GI symptoms including diarrhea, vomiting, stomatitis, hemorrhagic enteritis, and fatal intestinal perforation.1,2,3,4,5,6,265,269 Patients with peptic ulcer disease or ulcerative colitis have an increased risk of developing such adverse reactions.1,2,3,4,5,6,265,269 Unexpectedly severe, and sometimes fatal, GI toxicity has also been reported with concomitant use of methotrexate (usually high-dose regimens) and NSAIAs.2,3,4,6 If severe GI toxicity occurs during treatment with methotrexate, withhold or discontinue therapy and institute supportive care as appropriate.1,2,3,4,5,6,265,269
A boxed warning about the risk of serious adverse reactions, including pulmonary toxicity, is included in the prescribing information for methotrexate.1,2,3,4,5,6,265,269 Pulmonary toxicity, including acute or chronic interstitial pneumonitis, can occur with methotrexate therapy at any dose level; irreversible and fatal cases have been reported.1,2,3,4,5,6,265,269 Monitor patients receiving methotrexate for pulmonary symptoms (e.g., dry, nonproductive cough); therapy may need to be withheld or discontinued as appropriate.1,2,3,4,5,6,265,269
Additional Boxed Warnings Unique to Specific Formulations
A boxed warning about the need to use methotrexate only in select patient populations with severe disease is included in the prescribing information for methotrexate powder for injection and Rasuvo® (methotrexate injection for sub-Q use).2,3 These products should be reserved for use in patients with life-threatening malignancies or in those with psoriasis or rheumatoid arthritis that is severe, recalcitrant, disabling, and unresponsive to other forms of therapy.2,3 Deaths have been reported when methotrexate was used to treat malignancy, psoriasis, and rheumatoid arthritis.2,3 Patients should be informed of these risks and remain under a physician's care throughout treatment with methotrexate.2,3 Use of high-dose regimens of methotrexate powder for injection for treatment of osteosarcoma requires meticulous care; use of high-dose regimens for other malignancies is investigational, and a therapeutic advantage of this dosing strategy has not been established.2 A boxed warning about the occurrence of secondary malignant lymphomas, which may regress after discontinuation of methotrexate therapy, is included in the prescribing information for methotrexate powder for injection and Rasuvo® (methotrexate injection for sub-Q use).2,3 Such lymphomas may occur in patients prescribed low-dose methotrexate therapy, and may not require cytotoxic treatment.2,3 The manufacturer recommends discontinuing methotrexate when such lymphomas occur, and instituting appropriate treatment if the lymphoma does not regress.2,3 Methotrexate injection, injection for sub-Q use (Otrexup®), oral solution (both formulations), and tablets also contain a warning pertaining to the risk of secondary malignancies.1,4,5,6,265,269 A boxed warning about the risk of tumor lysis syndrome occurring in patients with rapidly growing tumors is included in the prescribing information for methotrexate powder for injection and Rasuvo® (methotrexate injection for sub-Q use).2,3 This complication may be alleviated or prevented with appropriate supportive or pharmacologic measures.2,3 Methotrexate injection, injection for sub-Q use (Otrexup®), oral solution (Jylamvo® only), and tablets also contain a warning pertaining to this risk.1,4,5,265,269 A boxed warning about the risk of soft tissue necrosis and osteonecrosis occurring when methotrexate is given concomitantly with radiotherapy is included in the prescribing information for methotrexate powder for injection and Rasuvo® (methotrexate injection for sub-Q use).2,3 Methotrexate injection, injection for sub-Q use (Otrexup®), and oral solution (Xatmep® only) also contain a warning pertaining to this risk.1,4,6
In patients with neoplastic diseases, products containing folic acid or its derivatives may reduce the effectiveness of methotrexate and should be avoided unless clinically indicated.1,2,5,265,269 In patients with non-neoplastic diseases, folate deficiency may increase the likelihood of experiencing adverse reactions from methotrexate.1,2,5,265,269 When methotrexate is prescribed for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, or psoriasis, administer concomitant folic acid or folinic acid.1,5,265,269
Based on published reports, methotrexate can impair fertility and cause oligospermia and menstrual dysfunction.1,2,3,4,5,6,265,269 It is unknown whether infertility is reversible when it occurs.1,3,4,5,6,265,269 These risks should be discussed with patients of reproductive potential prior to initiating therapy with methotrexate.1,2,3,4,5,6,265,269
Increased Toxicity Due to Third Space Accumulation
Methotrexate can exit slowly from third-space accumulations (e.g., pleural effusions or ascites), leading to a prolonged terminal half-life and associated toxicity.1,2,3,4,5,6,265,269 Evacuate any third-space accumulations that are present prior to initiation of methotrexate therapy.1,2,3,4,5,6,265,269
Risk of Severe Adverse Reactions with Medication Errors
Serious adverse reactions, including death, have occurred as the result of medication errors with methotrexate.1,3,4,5,265,269 The most common errors that have occurred involved patients who took methotrexate daily when a weekly dosing regimen was prescribed.1,3,4,5,265,269 Clinicians should verify that all patients prescribed methotrexate receive the recommended dosage.1,3,4,5,265,269
Methotrexate oral solution should be measured using an accurate milliliter measuring device.5,6 Inform patients that a household teaspoon is not an accurate measuring device and use of such could result in overdosage leading to serious adverse reactions.5,6 Advise patients to ask their pharmacist to recommend an appropriate measuring device and counsel on how to measure the proper dosage.6
Methotrexate powder for injection and injection for sub-Q use (Rasuvo® and Otrexup®) can cause adverse reactions, such as dizziness and fatigue, which can affect a patient's ability to drive or operate machinery.2,3,4
Abortion, fetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy.1 Methotrexate is contraindicated in the management of all non-neoplastic disorders (i.e., psoriasis or rheumatoid arthritis [including polyarticular juvenile idiopathic arthritis]) in pregnant women.1,2,3,4,5,6,265,269 Verify pregnancy status in female patients of reproductive potential prior to initiating treatment with methotrexate.1,2,3,4,5,6,265,269 Advise female patients of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months following the final dose; advise male patients with such female partners to use effective contraception during treatment with methotrexate and for 3 months following the final dose.1,2,3,4,5,6,265,269 Women of childbearing potential should be fully informed of the potential hazard to the fetus should they become pregnant during methotrexate therapy.1,2,3,4,5,6,265,269
Benzyl alcohol is present in certain formulations of methotrexate injection and powder for injection and can cross the placenta.1,2 If methotrexate injection is administered to treat a neoplastic disease in a pregnant patient, use a preservative-free formulation when possible.1
Methotrexate is distributed into breast milk, with a reported breast milk to plasma concentration ratio as high as 0.08:1.1,2,3,4,5,6,265,269 The potential effects of methotrexate on the breast-fed infant or on milk production are not known.1,3,4,5,6,265,269 Methotrexate powder for injection is contraindicated in nursing mothers due to the potential for serious adverse reactions in breast-fed infants exposed to methotrexate.2 Advise patients taking all other formulations of methotrexate not to breast-feed during treatment and for 1 week after the final dose.1,3,4,5,6,265,269
Females and Males of Reproductive Potential
Defective oogenesis or spermatogenesis, oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving methotrexate.1,2,3,4,5,6,265,269 Methotrexate can cause fetal malformations and fetal death when administered to a pregnant patient.1,2,3,4,5,6,265,269 Methotrexate can also cause chromosomal damage to sperm cells.1,3,4,5,6,265,269
Verify pregnancy status in female patients of reproductive potential prior to initiating treatment with methotrexate.1,2,3,4,5,6,265,269 Advise female patients of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months following the final dose.1,2,3,4,5,6,265,269 Advise male patients with such female partners to use effective contraception during treatment with methotrexate and for 3 months following the final dose.1,2,3,4,5,6,265,269
The safety and efficacy of methotrexate (all formulations) have been established in pediatric patients for the treatment of polyarticular juvenile idiopathic arthritis.1,2,3,4,5,6,265,269
The safety and efficacy of methotrexate injection and powder for injection have been established in pediatric patients for the treatment of acute lymphoblastic leukemia (ALL), meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, and osteosarcoma.1,2 Severe neurotoxic effects, manifested mainly by focal or generalized seizures, have been reported with increased frequency in pediatric patients with ALL who were receiving intermediate-dose IV methotrexate (1 g/m2).1,2 The safety and efficacy of methotrexate injection and powder for injection have not been established in pediatric patients for the treatment of other types of cancer, including breast cancer, squamous cell carcinoma of the head and neck, and gestational trophoblastic diseases.1,2
The safety and efficacy of methotrexate oral solution and tablets have also been established in pediatric patients for the treatment of ALL, but have not been established for the treatment of other neoplastic diseases.5,6,265,269 The safety and efficacy of Rasuvo® and Otrexup® (methotrexate injection for sub-Q use) have not been established in pediatric patients for the treatment of any neoplastic diseases.3,4
The safety and efficacy of methotrexate (all formulations) have not been established in pediatric patients for the treatment of rheumatoid arthritis or psoriasis.1,2,3,4,5,6,265,269
Clinical studies of methotrexate did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.1,2,3,4,5,6,265,269 Post-marketing reports have suggested that the risk of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age.2,3,4 Due to the reduced hepatic and renal function, decreased folate stores, and possibility of concomitant diseases or drug therapies in this population, consider relatively low doses and closely monitor for early signs of renal, hepatic, and bone marrow toxicity.2,3,4
The pharmacokinetics and safety of methotrexate in patients with hepatic impairment are not known.1,3,4,5,6,265,269 Such patients may be at an increased risk for adverse reactions to methotrexate based on how it is eliminated.1,5,6,265,269 Methotrexate powder for injection and injection for sub-Q use (Rasuvo® and Otrexup®) are contraindicated for treatment of psoriasis or rheumatoid arthritis in patients with alcoholism, alcoholic liver disease, or other chronic liver disease.2,3,4 Consider reducing the dose or discontinuing methotrexate in patients with hepatic impairment as appropriate.1,3,5,6,265,269 Patients with obesity, diabetes, hepatic fibrosis, or steatohepatitis are at an increased risk for hepatic injury and fibrosis secondary to methotrexate; monitor such patients closely during therapy.3,4
Elimination of methotrexate is reduced in patients with renal impairment (i.e., creatinine clearance <90 mL/minute using the Cockcroft-Gault calculation).1,3,5,6,265,269 The elimination half-life of methotrexate increases as the severity of renal impairment increases.1,265,269 Patients with renal impairment are at an increased risk for adverse reactions from methotrexate.1,5,6,265,269
Follow recommendations to promote elimination of methotrexate and decrease the risk of acute kidney injury and other methotrexate-associated toxicities (i.e., administration of leucovorin rescue or glucarpidase) in patients receiving intermediate- or high-dose regimens of methotrexate injection.1 Carefully monitor patients with renal impairment during treatment with methotrexate.2,3,4,5,6,265,269 Consider reducing the dosage or discontinuing methotrexate in patients with renal impairment as appropriate.1,3,4,5,6,265,269
Use with caution in debilitated patients.2,3,4
The most common adverse effects reported in patients receiving methotrexate injection, powder for injection, oral solution, and tablets include ulcerative stomatitis, leukopenia, nausea, and abdominal distress.1,2,5,6,265,269 Elevated liver function tests are also commonly reported in patients receiving Xatmep® oral solution.6
The most common adverse effects reported in patients receiving methotrexate injection for sub-Q use include nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and "burning of skin lesions."3,4
Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can then be hydrolyzed back to methotrexate.1,2,3,4,5,6,265,269
Protein-bound Drugs and Weak Organic Acids
Because methotrexate is partly bound to serum proteins, its toxicity may be increased as a result of displacement by certain drugs such as salicylates, sulfonamides, sulfonylureas, phenytoin, oral anticoagulants, tetracyclines, and chloramphenicol.1,2,3,4,5,265,269 Coadministration of methotrexate and these drugs may increase plasma concentrations of methotrexate, leading to an increased risk of severe adverse reactions.1,2,5,265,269 If coadministration of methotrexate with protein-bound drugs or weak organic acids cannot be avoided, monitor for adverse reactions from methotrexate during therapy.1,5,265,269
Hepatotoxic and Nephrotoxic Drugs
Coadministration of methotrexate with hepatotoxic (e.g., azathioprine, retinoids, and sulfasalazine) or nephrotoxic drugs may increase plasma concentrations of methotrexate, leading to an increased risk of severe adverse reactions.1,2,3,4,5,6,265,269 Increased organ-specific adverse reactions may also occur.1,2,3,4,5,6,265,269 If coadministration of methotrexate with hepatotoxic or nephrotoxic drugs cannot be avoided, monitor for adverse reactions from methotrexate during therapy.1,2,3,4,5,6,265,269
Coadministration of methotrexate with oral or IV penicillin or sulfonamide antibiotics (e.g., trimethoprim/sulfamethoxazole) may increase plasma concentrations of methotrexate, leading to an increased risk of severe adverse reactions.1,2,3,4,5,6,265,269 If coadministration of methotrexate with penicillin or sulfonamide antibiotics cannot be avoided, monitor for adverse reactions from methotrexate during therapy.1,2,4,6,265,269
Coadministration of methotrexate with oral antibiotics (including neomycin) may increase plasma concentrations of methotrexate, leading to an increased risk of severe adverse reactions.2,3,4,5,6,265,269 If coadministration of methotrexate with oral antibiotics cannot be avoided, monitor for adverse reactions from methotrexate during therapy.5,6,265,269
Coadministration of methotrexate with antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine, and sulfonamides) may increase plasma concentrations of methotrexate, leading to an increased risk of severe adverse reactions.1,2,3,4,5,265,269 If coadministration of methotrexate with antifolate drugs cannot be avoided, monitor for adverse reactions from methotrexate during therapy.1,5,265,269
In patients with neoplastic diseases, coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate.1,2,3,4,5,265,269 When methotrexate is administered with such drugs, it competes with reduced folates for active transport across cell membranes.1,5,265,269 Instruct patients that they should only take folic acid or folinic acid products as directed by their healthcare provider.1,5,265,269
Coadministration of methotrexate with mercaptopurine may increase plasma concentrations of mercaptopurine, leading to an increased risk of severe adverse reactions.1,2,3,4 Dosage adjustment of mercaptopurine may be required.2,3,4
Coadministration of methotrexate and nitrous oxide anesthesia potentiates methotrexate's effects on folate-dependent metabolic pathways, which increases the risk for severe adverse reactions from methotrexate.1,2,3,4,5,6,265,269 Avoid use of nitrous oxide anesthesia in patients taking methotrexate.1,2,3,4,5,6,265,269 Consider alternative therapies in patients who previously received nitrous oxide anesthesia.1,2,5,265,269
Nonsteroidal Anti-inflammatory Agents
Severe, sometimes fatal, hematologic and/or GI toxicity has occurred following administration of aspirin or other NSAIAs concomitantly with methotrexate (particularly with high-dose therapy).1,2,3,4,5,6,265,269 If coadministration of methotrexate with NSAIAs cannot be avoided, monitor for adverse reactions from methotrexate during therapy.1,5,6,265,269
Coadministration of methotrexate and probenecid may increase plasma concentrations of methotrexate, leading to an increased risk of severe adverse reactions.1,2,3,4,5,6,265,269 Consider alternative drugs.6 If coadministration of methotrexate with probenecid cannot be avoided, monitor for adverse reactions from methotrexate during therapy.1,3,4,5,265,269
Coadministration of methotrexate with proton pump inhibitors (e.g., omeprazole, esomeprazole, pantoprazole) may increase plasma concentrations of methotrexate, leading to an increased risk of severe adverse reactions.1,2,3,4,5,265,269 If coadministration of methotrexate with proton pump inhibitors cannot be avoided, monitor for adverse reactions from methotrexate during therapy.1,5,265,269
Coadministration of methotrexate and theophylline increases plasma concentrations of theophylline, which may increase the risk of adverse reactions from theophylline.1,2,3,4,6 If methotrexate and theophylline are given concomitantly, monitor theophylline levels and adjust the dosage according to the approved product labeling.1,2,3,4,6
Methotrexate and its polyglutamate metabolites reversibly inhibit dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid.43 Inhibition of tetrahydrofolate formation limits the availability of one-carbon fragments necessary for synthesis of purines and pyrimidines and various other reactions necessary for the synthesis of DNA and cell reproduction.43 In cancer, malignant cells are unable to synthesize DNA and RNA without these purine and pyrimidine precursors and thus, are unable to proliferate.43 Tissues with high rates of cellular proliferation, such as neoplasms, buccal and intestinal mucosa, bone marrow, the bladder, and fetal cells are most sensitive to the effects of methotrexate.1 The mechanism by which methotrexate works for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and psoriasis is not known; however, it may have effects on the immune system.1,3
Resistance to methotrexate may develop and has been associated with decreased cellular uptake of the drug, increased dihydrofolate reductase activity (associated with increased synthesis of the enzyme), decreased binding of methotrexate to dihydrofolate reductase (because of mutated dihydrofolate reductase protein), increased enzymatic hydrolysis of methotrexate polyglutamates, and decreased intracellular concentrations of polyglutamylated metabolites of methotrexate; however, the precise mechanism of this resistance development has not been established.44
Oral absorption of methotrexate appears to be highly variable and dose dependent.2,3,6 At lower oral doses (i.e., ≤30 mg/m2), methotrexate is well absorbed with a mean bioavailability of approximately 60%.2,3,5,265,269 The bioavailability of methotrexate decreases with increasing oral doses (suggesting the presence of a saturable absorption process) and absorption is substantially reduced at doses exceeding 80 mg/m2.2,3 Food delays absorption and decreases peak serum concentrations of the drug.2,3,4,5,6,265,269 Methotrexate appears to be completely absorbed following parenteral administration.2,3 Peak serum concentrations are achieved within 0.75-6 hours after oral administration2,5,265,269 and 30-60 minutes after IM administration of the drug.2,3,4
Methotrexate is actively transported across cell membranes.1,2,3,4,6 At serum methotrexate concentrations exceeding 0.1 µmol/mL, passive diffusion becomes a major means of intracellular transport of the drug.1,2,3,4,6 According to the manufacturer, the drug does not reach therapeutic concentrations in the CSF when given orally or parenterally.1,2,3,4,5,6,265,269 However, high CSF concentrations can be attained following intrathecal administration.2,3,4 In the serum, about 50% of the drug is bound to plasma proteins.1,2,3,4,5,6,265,269
In adults receiving methotrexate for the treatment of psoriasis or rheumatoid arthritis, or as low-dose antineoplastic therapy (i.e., <30 mg/m2), a terminal half-life of about 3-10 hours has been reported.1,2,3,4,5,6,265,269 Higher IV doses of methotrexate have been associated with a longer elimination half-life of about 8-15 hours in adults.1,2,3,4 In pediatric patients, terminal half-life ranges from 0.7-5.8 hours in those with acute lymphoblastic leukemia or 0.9-2.3 hours in those with polyarticular juvenile idiopathic arthritis.1,3,4,5,6,265,269
After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamates, metabolites which may be converted back to methotrexate by hydrolysis.1,2,3,4,5,6,265,269 Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase.1,2,3,4,6 Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors.1,2,3,4,5,6,265 In addition, small amounts of methotrexate polyglutamates may be converted to 7-hydroxymethotrexate;1,2,3,4,5,6,265,269 accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound.1,2,3,4,5,6 Following oral administration of methotrexate, the drug is also partially metabolized by the intestinal flora.2,3,4,5,6,265,269
The drug is excreted primarily by the kidneys via glomerular filtration and active transport;.1,2,3,4,5,6,265,269 80-90% of an IV dose is excreted unchanged in the urine within 24 hours of administration.1,2,3,4,6 Small amounts (≤10%) are excreted in the feces via the bile.1,2,3,4,5,6,265,269 Enterohepatic recirculation of methotrexate may occur.1,2,3,4,5,6,265,269 Methotrexate excretion is impaired and accumulation occurs more rapidly in patients with impaired renal function, pleural effusions, or those with other third-space compartments (e.g., ascites); in such patients, methotrexate levels may remain elevated for prolonged periods, leading to toxicity.2,3,4,6 Rates of clearance are highly variable and typically lower with higher doses of methotrexate.2,3,4,6
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 2 mg (of methotrexate) per mL | Jylamvo® | |
2.5 mg (of methotrexate) per mL | Xatmep® | |||
Tablets | 2.5 mg (of methotrexate)* | Methotrexate Sodium Tablets (scored) | ||
Tablets, film coated | 5 mg (of methotrexate) | Trexall® (scored) | Teva | |
7.5 mg (of methotrexate) | Trexall® (scored) | Teva | ||
10 mg (of methotrexate) | Trexall® (scored) | Teva | ||
15 mg (of methotrexate) | Trexall® (scored) | Teva | ||
Parenteral | For injection | 1 g (of methotrexate)* | Methotrexate Sodium for Injection | |
Injection | 25 mg (of methotrexate) per mL* | Methotrexate Sodium Injection Isotonic | ||
Injection, for subcutaneous use | 10 mg/0.4 mL | Otrexup® (available as single-dose prefilled auto-injectors) | ||
12.5 mg/0.4 mL | Otrexup® (available as single-dose prefilled auto-injectors) | |||
15 mg/0.4 mL | Otrexup® (available as single-dose prefilled auto-injectors) | |||
17.5 mg/0.4 mL | Otrexup® (available as single-dose prefilled auto-injectors) | |||
20 mg/0.4 mL | Otrexup® (available as single-dose prefilled auto-injectors) | |||
22.5 mg/0.4 mL | Otrexup® (available as single-dose prefilled auto-injectors) | |||
25 mg/0.4 mL | Otrexup® (available as single-dose prefilled auto-injectors) | |||
50 mg/mL | Rasuvo® (available as single-dose prefilled auto-injectors in 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, and 30 mg dosage strengths) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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