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Introduction

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Generic Name(s):

Methotrexate, a folic acid antagonist, is an antineoplastic agent and immunosuppressant.

Uses

[Section Outline]

Trophoblastic Neoplasms !!navigator!!

Methotrexate is used in the treatment of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens, and hydatidiform mole) in women except in those with impaired renal or hepatic function or who have failed to respond to previous therapy with methotrexate. These latter patients may be treated with dactinomycin. Methotrexate therapy is most effective in patients who have had the disease for only a short period prior to initiation of chemotherapy, who have low initial gonadotropin concentrations, and who do not have metastases. Complete remissions have been attained in about 75% of patients with metastases and in a higher percentage of patients without metastases. Methotrexate has also been used prophylactically against malignant trophoblastic disease in patients with hydatidiform mole.

In contrast to uterine choriocarcinoma, testicular choriocarcinomas are usually resistant to methotrexate alone. In patients with metastatic tumors of the testes, combination therapy utilizing methotrexate, dactinomycin, and chlorambucil has produced objective responses, as evidenced by decrease in size of metastases and tumor masses and/or lowered urinary chorionic gonadotropin concentrations in approximately 33-50% or more of patients treated. Following initial treatment, repeated courses of therapy at 1- to 3-month intervals for several years appear to be necessary in order to suppress tumor growth. In a few patients there has been an apparently permanent remission but control of tumor growth is often of only short duration.

Leukemias !!navigator!!

Methotrexate also is used as a component of various chemotherapeutic regimens in the palliative treatment of acute leukemias. Present regimens are most effective in the treatment of acute lymphocytic (lymphoblastic) leukemia and have been reported to produce remissions in 90% of patients treated. Methotrexate has been used with corticosteroids to induce remissions, but the drug is now most frequently used alone or in combination with other antineoplastic agents for maintenance therapy following induction of remission with vincristine sulfate and prednisone. Combination chemotherapy usually produces longer remissions than use of a single drug. Methotrexate alone rarely is effective in the treatment of acute myeloblastic leukemia; remissions are short with relapses common and resistance develops rapidly. Methotrexate, however, may produce remissions in adults who have responded initially to mercaptopurine and who have become resistant to this drug. In addition, methotrexate has been used in combination regimens in induction of remissions of acute myeloblastic leukemia.

Leukemic infiltration into the meninges and CSF has been relieved temporarily by intrathecal administration of methotrexate. The drug may be effective in patients whose systemic disease has become resistant to methotrexate since leukemic cells in the CNS usually retain their original degree of sensitivity to methotrexate; however, poor responses generally occur in patients with initial methotrexate resistance. Focal leukemic involvement of the CNS may not respond to intrathecal methotrexate and usually responds best to radiation therapy. Methotrexate is also used prophylactically against meningeal leukemia.

Osteosarcoma !!navigator!!

High-dose methotrexate, 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.262,263,264 These regimens appear to prolong the relapse-free survival in such patients.262 Methotrexate is designated an orphan drug by the US Food and Drug Administration (FDA) for use in osteogenic sarcoma.192

Breast Cancer !!navigator!!

Methotrexate has been used alone or, more commonly, in combination chemotherapy for the treatment of breast cancer.

Combination chemotherapy used as an adjunct to surgery has been shown to increase both disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast cancer.166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,185,187 Adjuvant combination chemotherapy in early breast cancer has produced overall reductions in the annual rates of recurrence and death of 28 and 16%, respectively, with overall 5-year disease-free survival rates of 58.8 versus 49.6% for patients receiving combination chemotherapy versus those who did not.167 Adjuvant combination chemotherapy that includes methotrexate, cyclophosphamide, and fluorouracil has been used most extensively and is considered a regimen of choice.166,167,168,169,170,171,172,173,174,175,178,179,182,185,186,187 Although adjuvant hormonal therapy with tamoxifen (with or without combination chemotherapy) generally is used for node-positive, estrogen-receptor-positive postmenopausal women,166,182 adjuvant combination chemotherapy (with or without tamoxifen) also can be used in such patients,166,167,168,169,170,171,173 but differences in toxicity profiles may influence the choice of regimen.166 For node-positive premenopausal women, adjuvant combination chemotherapy (with or without tamoxifen) generally is used.166,182 Adjuvant therapy with combination chemotherapy and/or tamoxifen has been used in women with node-negative disease.166,172,176,180,181,182

Controversy currently exists regarding which patients with node-negative and estrogen-receptor-negative breast cancer are most likely to benefit from such adjuvant therapy following surgery (see Uses: Breast Cancer, in Fluorouracil 10:00),166,167,172,176,177,178,179,180,181 but such patients with poor prognosis are reasonable candidates for adjuvant chemotherapy with an effective regimen (e.g., 6-12 months of methotrexate, cyclophosphamide, and fluorouracil initiated within 6 weeks of surgery); other node-negative patients also may be suitable candidates, but toxicities, costs, and other quality-of-life considerations should be weighed in assessing potential benefit.166,167,176,177,182,183,184 All patients with node-negative breast cancer are at some risk of recurrence,166,167 and effective adjuvant combination chemotherapy can increase both disease-free and overall survival, albeit less markedly than in patients with node-positive disease.166,167

In patients with node-positive early breast cancer (i.e., stage II), an effective regimen of adjuvant combination chemotherapy (e.g., methotrexate, cyclophosphamide, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; cyclophosphamide and doxorubicin with or without tamoxifen) is used to reduce the rate of recurrence and improve survival in both premenopausal and postmenopausal patients once treatment to control local disease (surgery, with or without radiation therapy) has been undertaken.166,167,168,169,170,171,172,173,174,187 These combinations have been tested and established as providing therapeutic benefit, and are superior to single-agent therapy with conventional agents;166,167,168,169,170,171,172,173,187 numerous other combination regimens providing apparently similar outcomes also have been used but are less common or have been studied less extensively.166,167,185,187 Although long-term (e.g., 6 months or longer) chemotherapy with adjuvant regimens is clinically superior to short-term (e.g., preoperative and perioperative) adjuvant regimens,166,167,187 clinical superiority between 6- versus 12-month regimens has not been demonstrated.166,167 There is some evidence that the addition of doxorubicin to a regimen of methotrexate, cyclophosphamide, and fluorouracil can improve outcome further in patients with more than 3 positive axillary lymph nodes,171,185 and that sequential (i.e., administering several courses of doxorubicin first) regimens are more effective than alternating regimens in such patients;171,185 in patients with fewer positive nodes, no additional benefit from doxorubicin has been demonstrated.171,174 The dose intensity of adjuvant combination chemotherapy also appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; therefore, arbitrary reductions in dose intensity should be avoided.166,170,187 In women with stage II disease and more than 10 positive lymph nodes, high-dose chemotherapy and autologous bone marrow transplant is an option currently being evaluated.166

In stage III (locally advanced) breast cancer, combination chemotherapy (with or without hormonal therapy) is used sequentially following surgery and radiation therapy for operable disease and following biopsy and radiation therapy for inoperable disease; commonly employed effective regimens include methotrexate, cyclophosphamide, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and methotrexate, cyclophosphamide, fluorouracil, and prednisone.166,182 These and other regimens also have been used in the treatment or more advanced (stage IV) and recurrent disease.166,182

Lymphoma !!navigator!!

Methotrexate may also be useful in the treatment of Burkitt's lymphoma, advanced stages (III and IV, Peters' Staging System) of lymphosarcoma, especially in children when used with other drugs, and in advanced cases of mycosis fungoides (cutaneous T-cell lymphoma). Although radiation therapy is generally used for treatment of localized histiocytic lymphoma, lymphosarcoma, and mycosis fungoides, chemotherapy may be useful in the treatment of generalized stages of these diseases. Hodgkin's disease responds poorly to methotrexate therapy.

Psoriasis !!navigator!!

Methotrexate is used in carefully selected patients in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy; however, the drug is not curative. Methotrexate should be used in the treatment of psoriasis only after the diagnosis has been definitely established, as by biopsy and/or after dermatologic consultation. Although methotrexate has been reported to produce beneficial effects in up to 75% of patients with psoriasis, there has been only one brief controlled study and the long-term effects of the drug and optimal dosage have not been established. Prior to initiation of methotrexate therapy, patients should be carefully screened to exclude pregnant women and patients with renal, hepatic or hematopoietic disease, or infections. The potential benefit to the patient must be carefully weighed against the possible risks involved and patients should be informed of potential toxicity.

Methotrexate has also been used topically in the treatment of psoriasis; however, results of one study indicated that the drug had little visible effect on the psoriatic lesions and another reported that the usefulness of topical methotrexate was limited by adverse effects on the surrounding skin.

Rheumatoid Arthritis !!navigator!!

Methotrexate is used for the management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of nonsteroidal anti-inflammatory agents (NSAIAs).111,112,113,114,115,116,127,128,138,139,140,141,142,143,144,145,146,147,148,149,152,153,154 Methotrexate is one of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.220,224

Pharmacologic therapy for rheumatoid arthritis usually consists of combinations of nonsteroidal anti-inflammatory agents (NSAIAs), DMARDs, and/or corticosteroids.220,222,224 The ultimate goal in managing rheumatoid arthritis is to prevent or control joint damage, prevent loss of function, and decrease pain.220 Although NSAIAs may be useful for initial symptomatic treatment of rheumatoid arthritis, these drugs do not alter the course of the disease or prevent joint destruction.220,224 DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy.220 DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs.220 DMARDs commonly used in the treatment of rheumatoid arthritis include methotrexate, etanercept, hydroxychloroquine, infliximab, leflunomide, and sulfasalazine.220 Less frequently used DMARDs include azathioprine, cyclosporine, minocycline, penicillamine, and/or oral or injectable gold compounds.220 The role of anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, in the management of rheumatoid arthritis remains to be established.236

While many factors influence the choice of a DMARD, methotrexate has substantially greater long-term efficacy than other DMARDs and is used as the initial or anchor DMARD in many patients with rheumatoid arthritis.220,222,224,225,226 Because residual inflammation generally persists in patients receiving maximum dosages of a single DMARD, many rheumatoid arthritis patients are candidates for combination therapy to achieve optimum control.220,222,224,227 Although the most effective combination regimen of DMARDs has not been determined, regimens that have been found efficacious in clinical studies220,222 include combinations of methotrexate and cyclosporine,228 etanercept,225 hydroxychloroquine,229 infliximab,230,231,232 leflunomide,233 or sulfasalazine.229,234

Low-dose oral corticosteroids and local injection of corticosteroids are effective in relieving symptoms in patients with active rheumatoid arthritis.220 In addition, limited evidence indicates that low-dose corticosteroids slow the rate of joint damage.220

Several international groups of rheumatologists have issued consensus reports that address the role of tumor necrosis factor (TNF) blocking agents (e.g., etanercept, infliximab) in the management of rheumatoid arthritis.237,238,239,240 These groups state that use of TNF blocking agents is most appropriate in patients with active disease (5 swollen joints and elevated acute-phase response [ESR of 28 mm/hour or greater, or CRP level of 2 mg/dL or greater]) despite adequate exposure to methotrexate or other effective DMARD.239,240 A course of methotrexate in a dosage of at least 20 mg weekly (or lower dosage if toxicity develops) for 3 months is considered an adequate course of DMARD therapy, and failure with such a course should prompt consideration of modification of the therapeutic regimen (e.g., initiation of a TNF blocking agent).240,220,238,239 Other factors to consider when deciding whether to use a TNF blocking agent in the treatment of rheumatoid arthritis are differences in the aggressiveness of the disease, extent of structural damage, effects of the disease on quality of life, and toxicity of previously used DMARDs.

Once therapy with a TNF blocking agent has been started, patients should be assessed for therapeutic response (e.g., a 20% reduction in swollen joint count with a 20% reduction in acute-phase response).240 While therapy should be continued indefinitely in those who have responded to therapy and are not experiencing substantial adverse effects, therapy with the TNF blocking agent should be discontinued in patients who have not responded after 12 weeks.240

Administration of methotrexate alone is not a complete treatment for rheumatoid arthritis, and the drug should be used only as part of a comprehensive treatment program, including nondrug therapies such as rest and physical therapy.127 Most patients with active rheumatoid arthritis will show some benefit from methotrexate therapy,111,112,113,114,115,116,127,128,138,139,140,141,142,143,144,145,146,147,148,149,152,153,154 although improvement often plateaus during the first 6 months of therapy with the drug127,128,138,139,141,143,144,147,148,149 (occasionally being maintained for 2 years or longer)114,115,127,128,138,139,140,141,143,144,147,152,153,154 and may wane during continued use.114,138,139,141,143,148,152,153,154 There is no substantial evidence that methotrexate permanently arrests or reverses the underlying disease process,127,128,138,140,144,147,153 although the drug slows its progression in some patients.138,140,143,144,160,220 NSAIA and/or low-dose corticosteroid therapy may be continued when methotrexate therapy is initiated;111,112,113,114,115,138,140,144,146 however, the possible increased risk of toxicity with concomitant use of methotrexate and NSAIAs should be considered.127,128,138,139 (See Drug Interactions: Protein Bound Drugs and Weak Organic Acids, and also Nonsteroidal Anti-inflammatory Agents.) Depending on the patient's response to methotrexate, corticosteroid dosage may be gradually reduced.111,114,115,127,128,140,144,152,154 The manufacturer of methotrexate states that combined use of methotrexate and gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, or other antirheumatic cytotoxic or immunosuppressive agents has not been adequately studied to date and may increase the risk of adverse effects.127

Head and Neck Cancer !!navigator!!

Methotrexate is used alone and in combination therapy for the palliative treatment of recurrent or metastatic head and neck carcinoma.182,210,211,212 When used alone, at a dosage of 40-60 mg/m2 once weekly, methotrexate produces an average objective response rate of 30%.210,211 Duration of response is short at an average of 4 months.210

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 In patients with recurrent or metastatic head and neck cancer who cannot tolerate combination therapy with cisplatin and fluorouracil, weekly low-dose methotrexate may be used.210

Methotrexate frequently is used in combination regimens with other antineoplastic agents (e.g., bleomycin, fluorouracil, vincristine).210 Combination therapy with cisplatin, methotrexate, bleomycin, and vincristine has been used for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.212 Further study is needed to establish the comparative benefit of methotrexate-containing regimens in the treatment of advanced head and neck cancer.210,212

Crohn's Disease !!navigator!!

Methotrexate has been used for its anti-inflammatory effects in the management of Crohn's disease.241,242,243,244 245,246,247,248,249,251,258,259,260,250 Results of several open-label, and double-blind, placebo-controlled studies in adults indicate that use of methotrexate can result in clinical response (including clinical remission) in patients with chronically active Crohn's disease who have not responded to prior therapies (e.g., corticosteroids, other immunosuppressants),241,242,244 245,248 although efficacy of orally administered methotrexate has not been consistently reported in placebo-controlled clinical studies.242,251,258,259

Safety and efficacy of parenteral methotrexate in the management of active Crohn's disease was evaluated in a double-blind placebo-controlled multicenter 16-week study that included 141 adults with chronically active Crohn's disease who had inadequate response to a corticosteroid (i.e. , prednisone).241,242,248,251 To be included in the study, patients had to have a chronically active disease unresponsive to a minimum of 3-months of therapy with prednisone (12.5 mg daily) with at least one attempt to discontinue the corticosteroid.241 At baseline, patients had a median Crohn's Disease Activity Index (CDAI) of 181-190.241 The CDAI score is based on subjective observations by the patient (e.g., the daily number of liquid or very soft stools, severity of abdominal pain, general well-being) and objective evidence (e.g., number of extraintestinal manifestations, presence of an abdominal mass, use or nonuse of antidiarrheal drugs, the hematocrit, body weight).257 Patients were randomized to receive IM methotrexate (94 patients; 25 mg once weekly) or placebo (47 patients).241,243,244,245,250,253 Patients continued to receive prednisone, which was tapered over 10 weeks (starting 2 weeks after randomization), unless their condition worsened; however, no other drugs used for management of Crohn's disease (e.g., oral or topical derivatives of 5-aminosalicylic acid, budesonide, other immunosuppressive agents, topical corticosteroids) were allowed.241 The primary outcome was clinical remission (defined as a CDAI index of 150 points or less and discontinuance of prednisone) at the end of the trial (16 weeks).241 Clinical remission at the end of the study was reported in 39 or 19% of patients receiving methotrexate or placebo, respectively.241 In addition, patients receiving methotrexate used less prednisone overall and had a lower mean average CDAI score than those receiving placebo (170 points for methotrexate versus 193 points for placebo).241 Many patients in this study who entered remission after 16-24 weeks of treatment with IM methotrexate (25 mg weekly) were enrolled in a new trial which evaluated the safety and efficacy of parenteral methotrexate for maintenance therapy of Crohn's disease.252 In this multicenter, double-blind, placebo-controlled trial, 76 patients with chronically active Crohn's disease in remission were randomized to receive 15 mg of IM methotrexate once weekly (40 patients) or placebo (36 patients) for 40 weeks; no other treatment for Crohn's disease was allowed.252 After 40 weeks, a greater proportion of patients receiving methotrexate were free of relapse (defined as an increase of baseline CDAI of 100 points or more, or the need to initiate therapy for active disease) than those receiving placebo (65% for methotrexate versus 39% for placebo); in addition, a smaller proportion of patients receiving methotrexate required prednisone therapy for relapse when compared with those receiving placebo (28% for methotrexate versus 58% for placebo). 245,252,253

Safety and efficacy of oral methotrexate in the management of chronically active Crohn's disease was evaluated in 2 other randomized double-blind, placebo-controlled trials in 59 corticosteroid-dependent adults.242,251,258,259 Patients received a weekly oral methotrexate dosage of 12.5 mg for 9 months251,259 in one trial and 15-22.5 mg for up to 1 year251,258 in the other. Efficacy (measured by reduction of dosage of corticosteroids, reduction in CDAI, or reduction in Harvey Bradshaw index) of oral methotrexate was similar to that of oral mercaptopurine (50 mg daily) in one of the studies and to placebo259 in both studies.251,258,259

Some clinicians state that pediatric patients with corticosteroid-dependent or corticosteroid-resistant, moderately to severely active Crohn's disease who had an inadequate response to or were intolerant of azathioprine or mercaptopurine, may receive methotrexate (10-15 mg/m2 weekly) for the management of such disease.256 (See Cautions: Pediatric Precautions.)

For further information on the management of Crohn's disease, see Uses: Crohn's Disease, in Mesalamine 56:36.

Other Uses !!navigator!!

Methotrexate is used in combination regimens with cisplatin and vinblastine, with or without doxorubicin, for the treatment of invasive and advanced bladder cancer.182,205,206,207,208,209 (See Uses: Bladder Cancer, in Cisplatin 10:00.) Because methotrexate is 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.205,206 Because elimination of methotrexate may be impaired and risk of toxicity increased in patients with renal dysfunction, edema, pleural fluid collections, or ascites, 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 such patients.205

Methotrexate has been used in second-line therapy for the treatment of recurrent small cell lung cancer.235 Although methotrexate is labeled for use in the treatment of the squamous cell type of non-small cell lung cancer,127 other agents are preferred for the treatment of this neoplasm.182

Methotrexate has been used in treating a variety of solid tumors. In some studies, the drug has been administered by intra-arterial infusion alone or in conjunction with IM leucovorin calcium in the palliative management of carcinomas capable of being infused via a single artery. Low-dose oral methotrexate has been used in patients with chronic progressive multiple sclerosis.201,202,203,204 Results of several clinical studies indicate that low-dose methotrexate (7.5 mg weekly for up to 2 years) reduces both disease activity (as assessed by magnetic resonance imaging [MRI]) and sustained progression of disability (as assessed by the Expanded Disability Status Scale, the Ambulation Index, and standardized tests of upper extremity function).201,202,203,204 Patients with secondary progressive multiple sclerosis benefited the most from methotrexate therapy.201,202,203

Methotrexate has been used for its immunosuppressive and/or anti-inflammatory effects in the treatment of psoriatic arthritis,109,110 systemic lupus erythematosus, vasculitis, dermatomyositis, polymyositis,Wegener's granulomatosis, and a variety of dermatologic and chronic refractory ocular diseases. Controlled studies have shown that oral or parenteral methotrexate therapy is effective in the short-term management of psoriatic arthritis;109,110 however, because of its potential toxicities, methotrexate is generally used in the management of this condition only in patients whose disease is severe and/or unresponsive to conventional therapy.109,110

Dosage and Administration

[Section Outline]

Reconstitution and Administration !!navigator!!

Methotrexate is administered orally. Methotrexate sodium is administered by IM, IV, or intrathecal injection; the drug may also be administered intra-arterially.

Methotrexate sodium injection and powder for injection should be reconstituted according to the manufacturers' directions.

For the treatment of meningeal leukemia, methotrexate must be administered intrathecally since passage of the drug from the blood to CSF is minimal. Prior to intrathecal administration of methotrexate, a volume of CSF approximately equivalent to the volume of methotrexate solution to be injected (e.g., 5-15 mL) is usually removed. If a lumbar puncture is traumatic, methotrexate should not be administered intrathecally. Two days should elapse before again attempting the injection. Methotrexate should be injected intrathecally only if there is easy flow of blood-free spinal fluid. Some clinicians recommend that the entire volume of methotrexate injection be injected intrathecally in 15-30 seconds. Aspiration should not be performed. For intrathecal injection, preservative-free methotrexate solutions containing 1 mg/mL are used ; solutions may be prepared using preservative-free 0.9% sodium chloride injection as a diluent. Methotrexate formulations or diluents containing preservatives must not be used for intrathecal administration or high-dose methotrexate therapy. 127

Methotrexate sodium solutions should be inspected visually for particulate matter and discoloration whenever solution and container permit.

Dosage !!navigator!!

Methotrexate should only be used under the supervision of a clinician who is experienced in cancer chemotherapy and in the use of antimetabolites.262,265 (See Cautions: Precautions and Contraindications.) Dosage of methotrexate sodium is expressed in terms of methotrexate. Various dosage schedules for methotrexate therapy alone and in combination with other antineoplastic agents and/or radiation therapy have appeared in the literature; dosage, route of administration, and duration of therapy must be individualized according to the disease being treated, other therapy being employed, and the condition, response, and tolerance of the patient. In patients in whom discontinuance of methotrexate has been required, therapy should be reinstituted with caution, giving complete consideration to further need for the drug and the possibility of recurrence of toxicity. Clinicians should consult published protocols for additional dosages of methotrexate and other chemotherapeutic agents and the method and sequence of administration.

Careful review of the intended use for methotrexate should be undertaken to ensure that inadvertent overdosage (e.g., administering antineoplastic rather than anti-inflammatory dosages) does not occur.309 Dosages used in rheumatic conditions (e.g., rheumatoid arthritis, psoriasis) and certain inflammatory GI conditions (e.g., Crohn's disease) are substantially lower than those used to treat cancer, and intermittent dosing rather than daily dosing is used for such inflammatory conditions.309 It is essential that any order for daily dosing of the drug be reviewed carefully to ensure that the intended use is an antineoplastic one.309 Inadvertent daily administration of the drug for non-cancer uses can prove fatal.309 Regimens for rheumatic conditions and certain inflammatory GI conditions employ intermittent dosing, usually once weekly as a single dose or once weekly as 3-divided doses at 12-hour intervals.309 Clinicians also should ensure that printed materials (e.g., discharge instructions) patients and/or their caregivers receive describe the correct dosing regimen for their condition, and they should be instructed carefully about their prescribed regimen, paying particular attention to the frequency of administration.309

Trophoblastic Neoplasms

For the treatment of trophoblastic neoplasms, the usual dosage of methotrexate is 15-30 mg daily, administered orally or IM for 5 days. A repeat course may be given after a period of one or more weeks provided all signs of residual toxicity have disappeared. Three to five courses of therapy are usually employed. Therapy is usually evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin which should return to normal or less than 50 IU/24 hours, usually after the third or fourth course. Complete resolution of measurable lesions usually occurs 4-6 weeks later. One or two courses of methotrexate therapy are usually given after normalization of urinary chorionic gonadotropin hormone concentrations is achieved. In the treatment of trophoblastic disease in women, regimens alternating courses of methotrexate therapy and dactinomycin therapy or combining administration of methotrexate and mercaptopurine or methotrexate, dactinomycin, and chlorambucil have also been used. In the treatment of trophoblastic disease in women, 10-15 mg of methotrexate daily has also been administered via the hypogastric artery until toxicity or therapeutic response occurred. Combination chemotherapy with methotrexate, chlorambucil, and dactinomycin has been used in the treatment of metastatic testicular tumors in men.

Leukemia

Although methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukemia, oral methotrexate dosage of 3.3 mg/m2 daily and prednisone 60 mg/m2 daily for 4-6 weeks have been used.127 After a remission is attained, maintenance therapy with methotrexate is administered twice weekly, orally or by IM injection, for a total weekly dose of 30 mg/m2.127 Administration of the drug in twice-weekly doses appears to be more effective than daily drug administration. Alternatively, 2.5 mg/kg has been administered IV every 14 days.127

For the treatment of meningeal leukemia, an intrathecal methotrexate dosage of 12 mg/m2 or an empiric dose of 15 mg, administered at 2- to 5-day intervals until CSF cell counts return to normal, has been suggested; this is then followed by one additional dose of the drug. Alternatively, 12 mg/m2 has been administered once weekly for 2 weeks and then once monthly thereafter. For prophylaxis against meningeal leukemia, a methotrexate dose of 12 mg/m2 or 15 mg has been used; the intervals for administration differ from the regimen used in the treatment of meningeal leukemia, and specialized references and the medical literature should be consulted for specific recommendations. However, because the volume of CSF is related to age and not body surface area, dosage regimens based on body surface area may result in inadequate CSF concentrations in children and high, potentially neurotoxic CSF concentrations in adults; therefore, some clinicians recommend that intrathecal dosage be based on the patient's age.106,107,108,127 Clinical studies indicate that intrathecal methotrexate dosage regimens based on age may be more effective and less neurotoxic than dosage regimens based on body surface area.107,108,127 The suggested intrathecal doses based on age are 6 mg for children younger than 1 year of age, 8 mg for children 1 year of age, 10 mg for children 2 years of age, and 12 mg for children 3 years of age or older and for adults;107,108,127 geriatric patients may require reduced doses because of reduced CSF turnover and decreasing brain volume.107,127 Regardless of the method used to determine intrathecal methotrexate dosage, the dose should be carefully checked prior to administration to minimize the risk of inadvertent intrathecal overdosage .106 Because methotrexate appears in systemic circulation following intrathecal administration, systemic administration of the drug should be appropriately adjusted, reduced, or discontinued. Systemic administration of leucovorin calcium simultaneously with intrathecal methotrexate may prevent systemic toxicity without abolishing the activity of the antimetabolite in the CNS. The manufacturers state that focal leukemic involvement of the CNS may not respond to intrathecal methotrexate therapy and may be best treated with radiation therapy.

Osteosarcoma

The recommended initial dose for high-dose methotrexate treatment of nonmetastatic osteosarcoma is 12 g/m2 administered by IV infusion over 4 hours (followed by leucovorin or levoleucovorin rescue) 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]). 262 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.262

Leucovorin and levoleucovorin are used as rescue therapy following a high-dose methotrexate regimen to prevent acute toxicity.262,263,264 Leucovorin is administered orally, IM, or by IV injection starting 24 hours after the beginning of the methotrexate infusion. 262,263 If the patient experiences GI toxicity (e.g., nausea, vomiting), leucovorin should be administered parenterally.262,263 The usual dosage of leucovorin is 15 mg (approximately 10 mg/m2) orally, IM, or by IV injection every 6 hours for a total of 60 hours or a total of 10 doses.262,263 (See Leucovorin Calcium 92:12.)

Levoleucovorin is administered as an IV infusion at a rate no faster than 160 mg of levoleucovorin per minute every 6 hours for a total of 60 hours or a total of 10 doses, starting 24 hours after the beginning of the methotrexate infusion.264 (See Levoleucovorin Calcium 92:12.)

Patients receiving high-dose methotrexate regimens must be well hydrated and carefully monitored.262 (See Cautions: Precautions and Contraindications.) For specific information on dosage modifications, cautions, and precautions associated with high-dose methotrexate therapy, the manufacturer's prescribing information should be consulted.262

Breast Cancer

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.168,169,170,171,172,173,174,176,180,181,183,185,187 The 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; therefore, arbitrary reductions in dose intensity should be avoided.166,170,187

One commonly employed regimen for the treatment of early breast cancer includes a methotrexate dosage of 40 mg/m2 (administered IV) on days 1 and 8 of each cycle combined with cyclophosphamide 100 mg/m2168,169,187 on days 1 through 14 of each cycle and fluorouracil 600 mg/m2 on days 1 and 8 of each cycle.168,169,187 In patients older than 60 years of age, the initial methotrexate dosage was reduced to 30 mg/m2 and the initial fluorouracil dosage was reduced to 400 mg/m2.169 Dosage also was reduced if myelosuppression developed.168,169 Cycles generally were 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).168,169,187 Clinical superiority between 6- versus 12-month regimens has not been demonstrated.166,167

There is some evidence that the addition of doxorubicin to a regimen of cyclophosphamide, methotrexate, and fluorouracil can improve outcome further in patients with early breast cancer and more than 3 positive axillary lymph nodes,171 and that sequential (i.e., administering several courses of doxorubicin first) regimens are more effective than alternating regimens in such patients;171 in patients with fewer positive nodes, no additional benefit from doxorubicin has been demonstrated.171,174 In the sequential regimen, 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.171,185 If myelosuppression developed with this sequential regimen, the subsequent cycle generally was delayed rather than reducing dosage.171,185

Burkitt's Lymphoma and Lymphosarcoma

The usual dosage of methotrexate for the treatment of stages I or II of Burkitt's lymphoma is 10-25 mg/day orally for 4-8 days. Methotrexate is commonly given concomitantly with other antineoplastic agents in the treatment of stage III Burkitt's lymphoma and lymphosarcomas. In all stages, several courses of drug therapy 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.

Mycosis Fungoides

Clinical response occurs in up to 50% of patients receiving single-agent therapy with methotrexate for mycosis fungoides (cutaneous T-cell lymphoma).241 In early stages of the disease, the usual dosage is 5-50 mg orally once weekly.241 The need for dosage reduction or discontinuance of therapy is determined by response to therapy and hematologic monitoring.241 Methotrexate also has been administered twice weekly in doses of 15-37.5 mg in patients with disease that has responded poorly to once-weekly dosing.241 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.241

Psoriasis

For the management of psoriasis, a single 5- to 10-mg dose of methotrexate should be given 1 week prior to initiation of methotrexate therapy to detect idiosyncratic reactions. Optimum dosage has not been established and dosage must be based on individual requirements and response. Dosage must be constantly supervised by a physician who is experienced in the use of antineoplastic agents.

There are 2 dosage schedules suggested by the manufacturers. To avoid potentially lethal overdosage, patients should be instructed carefully about their dosage regimen, paying particular attention to the frequency of administration.

The divided oral dosage schedule, which is based on cellular kinetic studies, consists of 2.5 mg of methotrexate administered orally at 12-hour intervals for 3 doses each week; in this regimen, dosage may be increased gradually by 2.5 mg/week, but weekly dosage should usually not exceed 25 mg and should not exceed 30 mg.

In the weekly single-dosage schedule, the manufacturers suggest that 10-25 mg may be administered orally, IM, or IV as a single dose once weekly. The usual oral dose in the weekly single-dosage schedule is 7.5-25 mg, with an occasional patient requiring up to 37.5 mg; dosage may be increased gradually by 2.5-5 mg/week. The usual IM or rapid IV dose in the weekly single-dosage schedule is 7.5-50 mg, with an occasional patient requiring up to 100 mg; dosage may be increased gradually. The manufacturers state that the oral, IM, or IV dose in the weekly single-dosage schedule should usually not exceed 50 mg.

In most patients, substantial improvement usually occurs within 4 weeks and optimum results occur in 2-3 months. Cessation of methotrexate usually results in a recurrence of symptoms in 2 weeks to 6 months. After optimal response is achieved, each schedule should be reduced to the lowest possible dose with the longest possible rest period. Conventional topical therapy should be resumed as soon as possible.

Psoriatic Arthritis

The optimum dosage of methotrexate in the management of psoriatic arthritis has not been clearly established, although oral and parenteral dosage regimens similar to those used in the management of psoriasis have been employed.109,110 Clinicians should consult specialized references for detailed information on specific dosage regimens.

Rheumatoid Arthritis

For the management of rheumatoid arthritis, a single test dose of methotrexate may be given prior to initiation of therapy to detect possible sensitivity to adverse effects associated with the drug. Optimum dosage has not been fully established and dosage must be based on individual requirements and response. Patients receiving methotrexate therapy for rheumatoid arthritis must be constantly supervised by a physician who is experienced in the use of antineoplastic agents. The mnemonic dispensing packages (Rheumatrex® Dose Pack) may be used for initial methotrexate therapy and are suitable for maintenance therapy in patients receiving weekly methotrexate doses of 5-20 mg; however, use of these dispensing packages is not recommended for titration to weekly doses higher than 20 mg.265 To avoid potentially lethal overdosage, patients should be instructed carefully about their dosage regimen, paying particular attention to the frequency of administration.

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 orally once weekly. This dosage may be administered either in a single-dosage schedule consisting of a single 7. 5-mg oral dose once weekly or in a divided-dosage schedule consisting of 2.5 mg of methotrexate administered orally at 12-hour intervals for 3 doses each week. Dosage in either the single- or divided-dosage schedule may be gradually increased until an optimum therapeutic response is achieved. 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). After an optimum response to the drug is achieved, the weekly dosage should be reduced to the lowest possible effective level. 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. The optimum duration of therapy is unknown; however, limited data from long-term clinical studies indicate that initial clinical improvement may be maintained for prolonged periods (e.g., 2 years or longer) with continued methotrexate therapy. Following discontinuance of the drug, rheumatoid arthritis usually worsens within 3-6 weeks.

Parenteral methotrexate regimens in the management of rheumatoid arthritis are variable, but have often consisted of 7.5-15 mg given IM once weekly in adults.113,114,115,138,139

Crohn's Disease

For the management of Crohn's disease, methotrexate has been administered in low-dose, intermittent (i.e., weekly rather than daily) regimens.241,242,243,244,245,250,251,252,253,258,259 For the management of chronically active, refractory Crohn's disease, methotrexate has been administered once weekly either IM in a dosage of 25 mg for 16 weeks241,243,244,250,251 or orally in a dosage of 12.5-22.5 mg for up to 1 year. 242,251,258,259 For maintenance therapy of Crohn's disease, an IM methotrexate dosage of 15 mg weekly has been used.252

Cautions

[Section Outline]

The major toxic effects of methotrexate are on normal, rapidly proliferating tissues, particularly of the bone marrow and lining of the GI tract. These adverse effects generally are dose related and are reversible if detected early. Ulcerations of the oral mucosa are usually the earliest signs of toxicity, but in some patients bone marrow depression coincides with or precedes the appearance of mouth lesions.

Hematologic Effects !!navigator!!

Leukopenia, thrombocytopenia, anemia, and hemorrhage from various sites may result from methotrexate therapy and may develop rapidly. In one study using single IV doses of methotrexate, the nadir of hemoglobin concentrations occurred in 6-13 days and was followed by recovery; reticulocytes reached their nadir in 2-7 days followed by recovery with rebound between 9 and 19 days. Leukocytes generally had two periods of depression; the first occurred in 4-7 days with recovery in 7-13 days and the second in 12-21 days with recovery in 15-29 days. Platelets reached their minimum in 5-12 days and recovered in number in 15-27 days.

Thrombocytopenia has been reported in approximately 5%, leukopenia and pancytopenia in approximately 1.5%, and decreased hematocrit and epistaxis in less than 1% of patients receiving 12-18 weeks of methotrexate for the management of rheumatoid arthritis.127,128

GI Effects !!navigator!!

Toxic effects of methotrexate on oral and GI mucosa are manifested by gingivitis, glossitis, pharyngitis, stomatitis, enteritis, ulcerations and bleeding of the mucous membranes of the mouth or other portions of the GI tract, abdominal distress, anorexia, nausea, vomiting, hematemesis, diarrhea, and melena. If ulcerative stomatitis or diarrhea occurs, methotrexate therapy must be interrupted in order to prevent hemorrhagic enteritis and death from intestinal perforation.

Pancreatitis also has been reported in patients receiving methotrexate.127

Hepatic Effects !!navigator!!

Methotrexate therapy has been associated with both acute and chronic hepatotoxicity.127,128,131,155,164 Acutely, elevations in serum aminotransferase (transaminase) concentrations frequently occur 1-3 days after a dose of the drug.100,127,128,131 Such elevations generally are transient, asymptomatic, and do not appear to be predictive of subsequent hepatic damage.127,128,131,138,141,142,147,148 Elevated liver function test results reportedly occurred in approximately 15% of patients receiving 12-18 weeks of methotrexate for the management of rheumatoid arthritis.127

Hepatotoxicity manifested as hepatic fibrosis or cirrhosis or other histologic changes in the liver has occurred during long-term methotrexate therapy; such hepatotoxicity may require hepatic allotransplantation and can be fatal.127,128,131,150,155,164,165 In patients with psoriasis, when such changes occur, they often may not be preceded by symptoms of hepatotoxicity or abnormal liver function test results;116,127,131,138,141,142,147,148 in patients with rheumatoid arthritis, prolonged, substantial abnormalities in liver function test results may precede appearance of hepatic fibrosis or cirrhosis.127 Chronic hepatotoxicity generally has been associated with prolonged (2 years or longer) methotrexate therapy and cumulative doses of 1.5 g or more.127,128,131,164 Although accurate estimates of the incidence of chronic hepatotoxicity currently are not available,127 the incidence appears to be greater in patients receiving frequent (e.g., daily), small doses of the drug (such as the daily-dosage regimen used for psoriasis)128,131,155,160 than in those receiving intermittent regimens (such as those used for neoplastic disease and possibly rheumatoid arthritis).128,131,150,155,160 The risk of developing chronic hepatotoxicity in patients receiving methotrexate therapy for the management of psoriasis appears to be related to the cumulative dose of the drug, and presence of concurrent conditions such as alcoholism, obesity, or diabetes as well as advanced age appear to contribute to this risk.116,127,131,141,142,150,158,160 Although clinical experience is limited,127,131,150 these risk factors also may apply to patients receiving methotrexate therapy for the management of rheumatoid arthritis.127,150 In one retrospective analysis in a limited number of patients with rheumatoid arthritis who underwent periodic percutaneous liver biopsy as routine monitoring for potential hepatotoxicity while receiving intermittent methotrexate regimens for an average of 32 months, progressive hepatic changes, principally progression to mild to moderate fatty infiltration with portal inflammation, occurred in about 20% of these patients; alterations in liver function test results were not predictive of such changes.150 In this study, fibrosis that developed in patients with rheumatoid arthritis was considered mild and no patient with rheumatoid arthritis developed cirrhosis; however, the drug was discontinued in most patients when fibrosis was evident and additional study and experience are necessary to better elucidate the potential risk of hepatotoxicity associated with methotrexate therapy for arthritis.150

Although various pathologic hepatic changes including atrophy, necrosis, fatty changes, fibrosis, and cirrhosis have been observed in patients with methotrexate-induced hepatotoxicity, no specific pathologic finding appears to be characteristic of methotrexate hepatotoxicity. The rate of progression of hepatic lesions with continued therapy and the potential reversibility of such lesions following discontinuance of the drug currently are not known.127,131 (See Cautions: Precautions and Contraindications.)

Respiratory Effects !!navigator!!

Pulmonary toxicity, which can progress rapidly119,129,130 and is potentially fatal,119,127,154 has been associated with methotrexate therapy.117,118,119,127,128,129,130,152,154 Adverse pulmonary effects, including pulmonary fibrosis and acute or chronic interstitial pneumonitis, appear to occur at any time during therapy at any dosage of the drug, including low dosages.117,118,119,127,128,129,130,242 Although the clinical presentation of methotrexate-induced pulmonary toxicity is variable, manifestations commonly include fever, cough (especially one that is dry and nonproductive), dyspnea, chest pain, hypoxemia (which can be severe), and/or radiographic evidence of pulmonary infiltrates (usually diffuse and/or alveolar).117,118,119,127,128,129,130,159,160 Lung biopsies have revealed variable degrees of interstitial inflammation, granulomatous inflammation, and/or fibrosis.119,128,129,130,159 Because patients with rheumatoid arthritis may have underlying interstitial pulmonary changes associated with their disease, it may be difficult to differentiate such changes from potential methotrexate-induced changes;119,129,159,160 however, rheumatoid changes generally progress more slowly.119 In addition, a potential association between preexisting rheumatoid pulmonary changes and susceptibility to methotrexate-induced pulmonary toxicity has been suggested but requires further elucidation.129,159

The possibility of methotrexate-induced pulmonary toxicity should be considered in any patient who develops pulmonary manifestations (e.g., dry, nonproductive cough; dyspnea) while receiving the drug.119,127,128,129,130,160 If such manifestations occur, methotrexate should be discontinued and careful clinical evaluation of the patient performed, including exclusion of possible infectious causes.119,127,128,129,130 Management of methotrexate-induced pulmonary toxicity mainly is supportive and may include mechanical ventilation;119,128,129,130 limited evidence suggests that administration of relatively high dosages of corticosteroids may provide some benefit, but additional experience is necessary.119,128,129,130,141,159 In addition, pulmonary toxicity induced by the drug may not be fully reversible and fatalities have been reported.119,127,128,242

Dermatologic and Sensitivity Reactions !!navigator!!

Severe, occasionally fatal cutaneous or sensitivity reactions (e.g., toxic epidermic necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme) have been reported in pediatric and adult patients within days of receiving single or multiple oral, IM, IV, or intrathecal doses of methotrexate.193 These reactions occurred following high-, intermediate-, or low-dose methotrexate therapy in patients with neoplastic or non-neoplastic diseases.193 Recovery has been reported after discontinuance of the drug.193 Other adverse dermatologic effects of methotrexate include erythematous rashes, pruritus, dermatitis, urticaria, folliculitis, photosensitivity, depigmentation, hyperpigmentation, petechiae, ecchymoses, telangiectasia, acne, and furunculosis. Alopecia occasionally occurs. Regrowth of hair usually occurs after methotrexate is discontinued but may require several months. Burning and erythema may occur in psoriatic areas for 1-2 days following each dose of the drug and psoriatic lesions may be aggravated by concomitant exposure to ultraviolet radiation. In addition, painful plaque erosions rarely have been reported in patients receiving methotrexate for the treatment of psoriasis.127

Effects following Intrathecal Administration !!navigator!!

Following intrathecal administration of methotrexate, 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 (which may be progressive and even fatal) manifested by confusion, irritability, somnolence, ataxia, dementia, and occasionally seizures and coma; and increased CSF pressure have occurred.127 Systemic toxicity also may occur following intrathecal and intra-arterial administration. Leukoencephalopathy, manifested by mental confusion, tremors, ataxia, irritability, somnolence, and seizures, and rarely progressing to coma and death, has been reported in patients receiving simultaneous oral and intrathecal methotrexate therapy. Leukoencephalopathy also has occurred following IV administration of methotrexate to patients who had received craniospinal irradiation.127 In addition, chronic leukoencephalopathy also has been reported in patients receiving repeated high doses of methotrexate with leucovorin rescue, but without cranial irradiation.127 Discontinuance of methotrexate may not be associated with complete recovery.127

Inadvertent intrathecal overdosage of methotrexate has occurred rarely.101,102,103,104,105 In cases in which the inadvertent intrathecal dose was less than 100 mg and the error was usually rapidly recognized and appropriate therapy promptly instituted, the patients experienced no or only mild neurotoxicity.101,102,105 In cases in which the dose exceeded 100 mg, severe neurotoxicity occurred, manifested as prompt burning or numbness in the lower extremities, stupor, agitation, seizures, and/or respiratory insufficiency;103,104,105 in some cases, brain damage105 or fatal necrotizing leukoencephalopathy103 resulted despite prompt treatment, but complete recovery following prompt and aggressive therapy has been reported.104

Inadvertent intrathecal overdosage of methotrexate constitutes a medical emergency, requiring prompt treatment and management.103,104,105,106 Although data are limited, management may be guided by the dose administered, time elapsed since administration, and anticipated severity of neurotoxicity.103,104,105,106 Regardless of the dose administered, as soon as the overdose is recognized, a repeat lumbar puncture should be performed immediately and CSF allowed to drain to gravity.103,104,105,106

The efficacy of CSF drainage alone as a means for removing the drug is a function of the dose administered and time elapsed since administration, and decreases as these factors increase.105 If the dose exceeds 100 mg, prompt neurosurgical intervention with ventriculolumbar perfusion following immediate CSF drainage should be considered;104,105,106 continuous CSF drainage or multiple CSF exchanges may also be considered but are not likely to be as effective.105

Other treatment measures may include high-dose parenteral leucovorin calcium therapy to minimize systemic toxicity, corticosteroids to minimize CNS inflammatory reactions, and other supportive therapy as necessary.102,103,104,105,106 Efficacy of carboxypeptidase G2 (glucarpidase) has not been established in the management of severe overdoses of intrathecal methotrexate; however, successful use of the drug in this setting has been reported.217,218 Successful treatment with intrathecal glucarpidase in a 6-year-old patient who received a 600-mg dose of methotrexate intrathecally has been reported; the patient also was treated with CSF drainage, ventriculolumbar perfusion, IV dexamethasone, IV leucovorin calcium, and hydration and alkalinization.218 While the addition of leucovorin to the ventriculolumbar perfusion fluid has been suggested and employed,103,104 its value is not known and the possibility that it may be epileptogenic via this route of administration should be considered.106 Intrathecal administration of leucovorin is contraindicated, 127 and the drug has contributed to at least one death when administered by this route.217 The possible benefits of prophylactic anticonvulsant therapy are probably outweighed by the potential for obscuring acute neurologic symptoms and causing additional adverse effects.104,106

Cardiovascular Effects !!navigator!!

Pericarditis, pericardial effusion, hypotension, and thromboembolic complications (e.g., thrombophlebitis; pulmonary embolism; arterial, cerebral, deep vein, or retinal vein thrombosis) have been reported in patients receiving methotrexate therapy.193

Other Adverse Effects !!navigator!!

Headaches, drowsiness, blurred vision, eye discomfort, conjunctivitis, severe visual changes of unknown etiology, tinnitus, malaise, undue fatigue, and dizziness may occur in patients receiving methotrexate. A transient acute neurologic syndrome manifested by confusion, hemiparesis, seizures, and coma has been reported in patients receiving high-dose methotrexate therapy.127 The exact cause of this stroke-like encephalopathy is not known; however, it has been suggested that the syndrome may have been related to hemorrhage or complications from intra-arterial catheterization. Other reported complications from intra-arterial infusion techniques include arterial spasm, thrombosis, hemorrhage, infection at the catheter site, and thrombophlebitis. Transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy have been reported in some patients receiving low-dose methotrexate therapy.127,193

Other reported adverse effects of methotrexate include chills and fever, sweating, arthralgia, myalgia, decreased resistance to infection, septicemia, upper respiratory infection, osteoporosis including aseptic necrosis of the femoral head, hypogammaglobulinemia, cystitis, dysuria, vaginal discharge, gynecomastia, loss of libido, impotence, diabetes, abnormal tissue cell changes, and even sudden death.

Severe nephropathy manifested by azotemia, hematuria, and renal failure may occur in patients receiving methotrexate; fatalities have been reported. In one study, postmortem examination revealed extensive necrosis of the epithelium of the convoluted tubules. In patients with renal impairment, methotrexate accumulation and increased toxicity or additional renal damage may occur.

Soft tissue necrosis and osteonecrosis have been reported rarely in patients receiving methotrexate.127 The risk of soft tissue necrosis and osteonecrosis associated with methotrexate may be elevated in patients receiving concomitant radiotherapy.127

Elevations in serum uric acid concentrations may occur in patients receiving methotrexate as a result of cell destruction and hepatic and renal damage. In some patients, uric acid nephropathy and acute renal failure may result. Tumor lysis syndrome associated with other cytotoxic drugs (e.g., fludarabine, cladribine),194,195,196,197,198 also has been reported in patients with rapidly growing tumors who were receiving methotrexate.193 Pharmacologic and appropriate supportive treatment may prevent or alleviate this complication.193,198 Methotrexate also was reported to precipitate acute gouty arthritis in two patients being treated for psoriasis. Administration of large volumes of fluids, alkalinization of the urine, and/or administration of allopurinol may be useful in preventing acute attacks of hyperuricemia and uric acid nephropathy.

Nodulosis, vasculitis, and reversible lymphomas (see Precautions and Contraindications) have been reported rarely in patients receiving methotrexate.127 Sometimes fatal opportunistic infections have been reported in patients receiving methotrexate for neoplastic or non-neoplastic diseases.193 The most frequent infection was Pneumocystis carinii pneumonia; however, other infections (e.g., nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, herpes simplex hepatitis, disseminated herpes simplex) also were reported.193

Precautions and Contraindications !!navigator!!

Methotrexate is a highly toxic drug with a very low therapeutic index and a therapeutic response is not likely to occur without some evidence of toxicity. The drug can produce hepatotoxicity, severe hematologic toxicity, and GI hemorrha severe infection and even death may result. When methotrexate is used in combination with other antineoplastic agents and/or radiation therapy, toxic reactions may be more severe than would occur with methotrexate therapy alone. Concomitant use of methotrexate and radiation therapy may result in an increased risk of soft tissue necrosis and osteonecrosis (see Cautions: Other Adverse Effects).127 Although doses of methotrexate used in the management of psoriasis and rheumatoid arthritis are usually lower than those used in antineoplastic chemotherapy, severe toxicity may occur in any patient receiving the drug and deaths have been reported with the use of methotrexate in the management of malignancy, psoriasis, and rheumatoid arthritis.

Since methotrexate may produce severe toxicity, which may be fatal, the manufacturer states that the drug should only be used in patients with life-threatening neoplastic diseases or in those with severe, recalcitrant, disabling psoriasis or rheumatoid arthritis that is not adequately responsive to other forms of therapy.127

The use of high-dose methotrexate regimens employed in the adjunctive treatment of osteosarcoma requires a meticulous understanding of the risks associated with such therapy and of leucovorin rescue. Particular attention to leukocyte counts, serum bilirubin and ALT (SGPT) concentrations, presence of mucositis or persistent pleural effusions, renal function, hydration, urinary alkalinization, fluid and electrolyte balance, and pharmacokinetic monitoring must be ensured when such regimens are used. The manufacturer's labeling and published protocols should be consulted for specific recommendations, including dosage guidelines based on these findings.

Methotrexate must be used only under constant supervision by a clinician who is experienced in the use of antimetabolites. Patients should be fully informed of the risks involved and should be instructed to report promptly any symptoms of toxicity. Because methotrexate is a highly toxic drug, the manufacturers recommend that patients be given no more than a 7-day supply of the drug at one time or, if an intermittent regimen is used (i.e., weekly rather than daily doses), no more than a 1-month supply (e.g., using a mnemonic dispensing package); refills should be only by direct order (i.e., written or oral) of the prescribing clinician. In addition, patients receiving intermittent regimens consisting of weekly rather than daily doses of the drug for the management of rheumatic conditions (e.g., rheumatoid arthritis, psoriasis) and certain inflammatory GI conditions (e.g., Crohn's disease) should be carefully instructed about their regimen and the frequency of methotrexate administration since mistaken daily use of the drug has resulted in fatalities; patients should be provided with and encouraged to read a copy of the patient instructions supplied by the manufacturer.309

Patients receiving methotrexate should be closely monitored for hematologic, renal, hepatic, and pulmonary toxicities, with complete hematologic studies, urinalysis, renal function tests, liver function tests, and chest radiographs. Liver biopsy and bone marrow aspiration studies may be advisable, especially in patients receiving high-dose or prolonged methotrexate therapy. Particular attention to close monitoring is recommended for patients with renal impairment or with pleural effusions or other third-space compartments (e.g., ascites) since elimination of the drug may be impaired. In addition, consideration should be given to evacuating accumulated fluid if possible in patients with substantial compartmental third-spacing prior to methotrexate therapy; monitoring serum concentrations of the drug, reducing drug dosage, or, occasionally, discontinuance of methotrexate also is recommended. Dehydrated patients also are at risk of increased serum methotrexate concentrations. The patient's bleeding time, coagulation time, blood group, and blood type should be on record in case the need for transfusion or surgery arises. If toxic effects or adverse reactions occur, dosage should be reduced or the drug discontinued and appropriate corrective measures taken; however, it should be considered that serious toxic reactions may occur in the absence of abnormal laboratory test results. Severe, occasionally fatal cutaneous reactions have been reported in patients receiving single or multiple oral, IM, IV, or intrathecal doses of methotrexate.193 These reactions usually occur within days of administration of the drug and recovery has been reported after discontinuance of methotrexate.193 (See Cautions: Dermatologic and Sensitivity Reactions.)

Hematologic studies must be performed prior to and at frequent intervals during methotrexate therapy. Complete blood cell counts, including differential and platelet counts, generally should be determined at least once weekly in patients receiving the drug for the treatment of neoplastic disease, and at least once monthly in patients receiving the drug for psoriasis or rheumatoid arthritis. If a profound drop in blood cell count occurs, the drug must be immediately discontinued and appropriate alternative therapy instituted. If profound leukopenia and fever occur, the patient should be closely observed and antibiotic therapy should be initiated if there are signs of infection. Blood or platelet transfusions may be necessary in patients with severe bone marrow depression.

There is poor correlation between liver function test results and chronic hepatotoxicity in patients receiving methotrexate, and liver scans are of minimal value in detecting methotrexate hepatotoxicity; liver biopsy is currently the only reliable measure of hepatotoxicity. Nonetheless, hepatic function must be determined prior to initiation of methotrexate and liver function tests, including serum albumin concentrations, should be repeated periodically throughout therapy (at 1- to 2-month intervals in patients treated for psoriasis or rheumatoid arthritis). In patients being treated for psoriasis, liver biopsy should be performed before instituting methotrexate or shortly thereafter (i.e., 2-4 months after).127 Repeat liver biopsies are recommended after a total cumulative dose of 1.5 g and after additional cumulative doses of 1-1.5 g.127,163 In patients with psoriasis, a relationship between abnormal liver function test results and hepatic fibrosis or cirrhosis has not been established, and prolonged, substantial abnormalities in liver function test results may not precede appearance of hepatic fibrosis or cirrhosis in such patients.127 When a pre-methotrexate liver biopsy is not feasible, a liver scan might be useful to detect occult liver disease.163 Because some patients may discontinue methotrexate after 2-4 months of therapy (due to adverse effects or lack of efficacy), pre-methotrexate liver biopsy might be postponed in patients with psoriasis until this initial period is completed; if long-term methotrexate therapy is anticipated, liver biopsy should then be performed.163,165 Abnormal liver function test results frequently occur 1-2 days following a dose of methotrexate, and it is recommended that liver function tests be performed at least 1 week after the last dose of the drug.163 Because these tests generally return to normal within a few days, repeat tests should be done before performing a liver biopsy. If substantial abnormal liver function test results develop and persist, methotrexate therapy should be withheld for 1-2 weeks and liver function tests repeated.163 Liver function test results should generally return to normal within 1-2 weeks following discontinuance of the drug; however, if substantial abnormal liver function test results persist, a liver biopsy is recommended.163

The decision to perform liver biopsies during methotrexate therapy for rheumatoid arthritis must be carefully individualized.131,138,139 Age at first use of methotrexate and duration of therapy reportedly are risk factors for methotrexate-induced hepatotoxicity.127 Although unconfirmed to date, it is not known if other risk factors similar to those observed in patients with psoriasis also are present in patients with rheumatoid arthritis.127 In patients with a history of excessive alcohol consumption, those with prolonged, substantial abnormal liver function test results, or those with chronic hepatitis B or C, liver biopsy should be performed before instituting methotrexate therapy.127 In patients with rheumatoid arthritis, prolonged, substantial abnormal liver function test results may precede appearance of fibrosis or cirrhosis.127 In patients with normal liver function, history and physical examination, and no other risk factors (obesity, diabetes mellitus, impaired renal function, history of liver disease, history of IV drug abuse, family history of inheritable liver disease, history of significant exposure to known hepatotoxic drugs), a liver biopsy is recommended after a cumulative methotrexate dosage of approximately 1.5 g.116,127,131,138,139,142,145,163,164 In addition, a liver biopsy should be performed during therapy in patients with prolonged, substantial abnormal liver function test results or with serum albumin concentration below normal values (but whose rheumatoid arthritis is under control).127 If pre-methotrexate and the first post-methotrexate therapy biopsies show no serious abnormalities and the patient has no risk factors, repeat liver biopsies are recommended every 2-3 years or after additional cumulative dosages of 1-1.5 g.131,138,139,142 Patients with grade I, II, or IIIA pathologic changes may continue to receive methotrexate therapy, but some clinicians state that those with grade IIIA changes should have a repeat liver biopsy after approximately 6 months of continuous methotrexate therapy.163 Patients with prolonged, substantial abnormal liver function test results who refuse liver biopsy or those with grade IIIB or IV pathologic changes should not receive further methotrexate therapy; however, occasional patients may require additional therapy with careful follow-up liver biopsies.127,150,163 Concomitant administration of methotrexate and other drugs with hepatotoxic potential including alcohol should be avoided.

Renal function tests should be performed prior to and periodically during methotrexate therapy (at 1- to 2-month intervals in patients with psoriasis or rheumatoid arthritis; more frequent monitoring usually is necessary in patients receiving methotrexate for the treatment of neoplastic disease). If renal impairment develops during methotrexate therapy, dosage should be reduced or the drug discontinued until renal function is improved or restored. In addition, tumor lysis syndrome associated with other cytotoxic drugs (e.g., fludarabine, cladribine)194,195,196,197,198 also has been reported in patients with rapidly growing tumors who were receiving methotrexate.193 Pharmacologic and appropriate supportive treatment may prevent or alleviate this complication.193,198

Malignant lymphomas may occur in patients receiving low-dose methotrexate therapy; such lymphomas may regress following withdrawal of the drug and therefore may not require cytotoxic therapy.262,265 However, if lymphomas do not regress following discontinuance of methotrexate, appropriate therapy should be instituted.262,265 The manufacturers state that the potential benefits of methotrexate therapy (alone or in combination with other drugs) should be weighed against these potential risks, especially in children or young adults.262,265

Since potentially fatal opportunistic infections (e.g., Pneumocystis carinii pneumonia) have been reported in patients receiving methotrexate therapy, the possibility of P. carinii pneumonia should be considered in patients who develop pulmonary symptoms.127,193 In addition, pulmonary function tests may be useful if methotrexate-induced pulmonary toxicity is suspected, particularly if baseline values are available.127,130 For other precautions associated with the potential toxic effects of the drug on the lungs, see Cautions: Pulmonary Effects.

The immunosuppressive action of methotrexate must be considered when evaluating use of the drug in patients in whom immune responses may be important or essential. In patients at high risk for acquired immunodeficiency syndrome (AIDS), an HIV antibody determination should be considered because of the potential for additive immunosuppression and increased risk of opportunistic infections. Two psoriatic patients developed tuberculosis while receiving methotrexate and it has been suggested that, in addition to a chest radiograph, a tuberculin skin test should be performed prior to initiation of methotrexate therapy. If the initial tuberculin test is positive, isoniazid preventive therapy (see 8:16.04) should be initiated concomitantly with methotrexate therapy. Since an accurate evaluation of the tuberculin test is not possible in patients receiving methotrexate, chest radiographs should be repeated every 6 months during therapy in these patients.

Methotrexate should be used with extreme caution in patients with infection, peptic ulcer, ulcerative colitis, or debility, and in very young or geriatric patients. Methotrexate should be used with extreme caution, if at all, in patients with malignant disease who have preexisting liver damage or impaired hepatic function, preexisting bone marrow depression, aplasia, leukopenia, thrombocytopenia, or anemia; the drug is usually contraindicated in patients with impaired renal function. In the management of psoriasis or rheumatoid arthritis, methotrexate is contraindicated in patients with preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or clinically important anemia; those with overt or laboratory evidence of immunodeficiency syndromes; and those with excessive alcohol consumption, alcoholic liver disease, or chronic liver disease.127

Pediatric Precautions !!navigator!!

The manufacturer states that safety and efficacy of methotrexate in pediatric patients for the management of any conditions other than cancer chemotherapy or polyarticular-course juvenile rheumatoid arthritis have not been established.127,262,265 Severe neurotoxic effects, manifested mainly by focal or generalized seizures, have been reported with increased frequency in pediatric patients with acute lymphoblastic leukemia who were receiving intermediate-dose IV methotrexate (1 g/m2).193 Leukoencephalopathy and/or microangiopathic calcifications usually were observed in diagnostic imaging procedures of symptomatic patients.193

Mutagenicity and Carcinogenicity !!navigator!!

Methotrexate has been reported to cause chromosome damage. Although patients who had previously received methotrexate have conceived and borne normal children, both men and women should be advised to avoid conception during and immediately following methotrexate therapy so that normal production of germinal cells may be reestablished. (See Cautions: Pregnancy, Fertility, and Lactation.) It has been suggested that methotrexate may be carcinogenic; however, extensive epidemiologic studies are required before its carcinogenicity can be confirmed or refuted. Malignant lymphomas (e.g., non-Hodgkin's lymphoma) may occur in patients receiving low-dose oral methotrexate therapy; such lymphomas may regress following withdrawal of the drug and, therefore, may not require cytotoxic therapy.127 However, if lymphomas do not regress following discontinuance of methotrexate, appropriate therapy should be instituted.127 Therefore, the manufacturers state that the potential benefits of methotrexate therapy (alone or in combination with other drugs) should be weighed against these potential risks, especially in children or young adults.127

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Abortion, fetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of psoriasis or rheumatoid arthritis in pregnant women. Women of childbearing potential should not receive methotrexate until pregnancy is excluded. For the management of psoriasis or rheumatoid arthritis, methotrexate therapy in women should be started immediately following a menstrual period and appropriate measures should be taken in men or women to avoid conception during and for at least 12 weeks following methotrexate therapy. Both men and women receiving methotrexate should be informed of the potential risk of adverse effects on reproduction.127,128 Women of childbearing potential should be fully informed of the potential hazard to the fetus should they become pregnant during methotrexate therapy.127,128 In cancer chemotherapy, methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the fetus.

Fertility

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving methotrexate.

Lactation

Methotrexate is distributed into breast milk.127,161,162 Because of the potential for serious adverse reactions to methotrexate in nursing infants, the drug is contraindicated in nursing women.127

Drug Interactions

[Section Outline]

Protein-bound Drugs and Weak Organic Acids !!navigator!!

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, phenylbutazone, tetracyclines, chloramphenicol, and aminobenzoic acid. Until the clinical importance of these findings is established, these drugs should be given cautiously in patients receiving methotrexate. In addition, the possibility that weak organic acids, including salicylates, may delay renal excretion of methotrexate and increase accumulation should be considered.

Nonsteroidal Anti-inflammatory Agents !!navigator!!

Severe, sometimes fatal, toxicity (including hematologic and GI toxicity) has occurred following administration of a NSAIA (e.g., indomethacin, ketoprofen) concomitantly with methotrexate (particularly with high-dose therapy) in patients with various malignant neoplasms, psoriasis, or rheumatoid arthritis.120,121,122,123,124,125,126,127,128 The toxicity was associated with elevated and prolonged serum concentrations of methotrexate.120,121,122,123,124,125,126,127 The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination.120,121,122,123,124,125,126

NSAIAs should be avoided in patients receiving relatively high dosages of methotrexate (e.g., those used in the treatment of neoplastic disease).127,128,155 The risk of concomitant low-dose, intermittent (e.g., 5-15 mg weekly) methotrexate therapy and NSAIAs has not been fully elucidated, but the drugs have been used concomitantly in many patients receiving methotrexate for the management of rheumatoid arthritis.127,128 However, in clinical studies in which the drugs were used concomitantly, the patients often were monitored closely and were receiving relatively stable dosages of NSAIAs; in addition, those with conditions that might predispose to methotrexate toxicity generally were excluded from the studies.128 NSAIAs should be used with caution in patients receiving low-dose methotrexate regimens such as those employed in the management of rheumatoid arthritis, and the possibility of increased and prolonged serum methotrexate concentrations and resultant toxicity should be considered.127,128,138,139 Although intermittent regimens also are used in the management of psoriasis, methotrexate dosages in such regimens usually are higher than those used in the management of rheumatoid arthritis and therefore are more likely to result in toxicity during concomitant NSAIA therapy;127,128 serious toxicity, including at least one death, has been reported in several patients with psoriasis receiving combined therapy with the drugs.128 Further study is needed to evaluate the interaction between NSAIAs and methotrexate.121,122,123,124,125,126,127

Penicillins !!navigator!!

Concomitant use of penicillins (e.g., amoxicillin, carbenicillin) may decrease renal clearance of methotrexate,127 presumably by inhibiting renal tubular secretion of the drug.188,190 Increased serum concentrations of methotrexate, resulting in GI or hematologic toxicity, have been reported in patients receiving low- or high-dose methotrexate therapy concomitantly with penicillins, and patients receiving the drugs concomitantly should be carefully monitored.127,188,189,190

Proton-Pump Inhibitors !!navigator!!

Although no formal drug interaction studies have been conducted with methotrexate and proton-pump inhibitors, data from case reports, population pharmacokinetic studies, and retrospective analyses suggest that concomitant use of methotrexate (particularly at high dosages) with proton-pump inhibitors (e.g., esomeprazole, omeprazole, pantoprazole) may decrease methotrexate clearance, resulting in elevated and prolonged serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate and possibly leading to methotrexate toxicities.301,302,303,304,305,306,307,308 Increased concentrations of methotrexate and/or hydroxymethotrexate with or without associated adverse effects (e.g., renal toxicity, adverse hematologic effects, severe mucositis, myalgia) have been reported when methotrexate dosages ranging from 300 mg/m2 to 12 g/m2 were administered concomitantly with proton-pump inhibitors.302 Although the majority of reported cases occurred in patients receiving high dosages of methotrexate,302,303,304,305,306,307,308 methotrexate toxicity also has been reported following concomitant administration of low dosages of methotrexate (15 mg per week) with a proton-pump inhibitor.302 Therefore, the manufacturers of proton-pump inhibitors state that temporary discontinuance of proton-pump inhibitor therapy may be considered in some patients receiving high-dose methotrexate.303,304,305,306,307,308 Some clinicians specifically recommend withholding proton-pump inhibitor therapy for several days before, during, and for several days after methotrexate administration;301 in patients in whom acid suppression is clinically indicated during methotrexate therapy, substitution of a histamine H2-receptor antagonist (e.g., ranitidine) for the proton-pump inhibitor may be considered.301,302 Pending further evaluation, some clinicians state that these recommendations should extend to patients receiving low-dose methotrexate.301

Other Drugs !!navigator!!

Drugs with similar pharmacologic activity such as pyrimethamine should not be given to patients receiving methotrexate.

Concomitant use of other potentially hepatotoxic drugs (e.g., retinoids, azathioprine, sulfasalazine) and methotrexate may increase the risk of hepatotoxicity;127 patients receiving concomitant therapy with these drugs should be closely monitored.127

Although concomitant use of methotrexate with cisplatin exhibits possible synergistic antineoplastic effects,288 cisplatin may alter renal elimination of methotrexate.279 Caution is advised if high-dose methotrexate is administered in conjunction with cisplatin for the treatment of osteosarcoma.262

Co-trimoxazole should be used with caution in patients receiving methotrexate, since sulfonamides can displace methotrexate from plasma protein-binding sites resulting in increased free methotrexate concentrations.

It has been suggested that folic acid preparations including vitamin products may decrease the effectiveness of methotrexate therapy and should not be given to patients receiving methotrexate; however, there have been no clinical studies to support or refute this hypothesis.

Methotrexate increases plasma mercaptopurine concentrations;262,299 dosage adjustment may be necessary.262

Probenecid diminishes renal tubular transport of methotrexate; patients should be carefully monitored during concomitant use of these agents.262,265

Methotrexate may decrease clearance of theophylline; serum theophylline concentrations should be monitored in patients receiving theophylline concomitantly with methotrexate.127,191

Vaccination with live virus vaccines generally should not be performed in patients receiving methotrexate. Disseminated vaccinia infection has been reported following smallpox vaccination in at least one patient receiving methotrexate.127,128,151 Although the antibody response to killed virus vaccines is not normal, partial or complete protection may still be attained and these vaccines may be used if necessary in patients receiving methotrexate.

Other Information

[Section Outline]

Acute Toxicity

Treatment !!navigator!!

Treatment of toxicity resulting from impaired elimination or an inadvertent overdosage of methotrexate consists of administration of a folic acid antidote (i.e., leucovorin, levoleucovorin) with or without a carboxypeptidase G2 (i.e., glucarpidase);263,264,266 however, glucarpidase is indicated only for the treatment of toxic plasma methotrexate concentrations (exceeding 0.454 mcg/mL [1 µ M ]) in patients with delayed methotrexate clearance due to renal impairment.266 Because of the potential for subtherapeutic concentrations of methotrexate, glucarpidase should not be used in patients who exhibit the expected clearance of methotrexate or in those with normal or mildly impaired renal function.266

In cases of inadvertent overdosage of methotrexate, leucovorin or levoleucovorin should be administered as soon as possible.127,263,264 In patients with impaired elimination of methotrexate, leucovorin or levoleucovorin should be administered within 24 hours of methotrexate administration when there is delayed methotrexate excretion.127,263,264 Leucovorin or levoleucovorin should not be administered intrathecally.127,263,264 As the time interval between methotrexate administration and rescue therapy with leucovorin or levoleucovorin increases, the effectiveness of either drug in counteracting methotrexate toxicity may decrease.263,264,265 Serum creatinine and methotrexate concentrations should be determined at 24-hour intervals.262,263,264,265 The optimal dose of leucovorin or levoleucovorin should be determined based on serum methotrexate concentrations.127,262,263,264,265 (See Leucovorin Calcium 92:12 and Levoleucovorin Calcium 92:12.)

If glucarpidase is used, rescue therapy with leucovorin or levoleucovorin should be continued following administration of the drug;266 however, because leucovorin is a substrate for glucarpidase (and the pharmacokinetics of levoleucovorin and leucovorin are comparable), leucovorin and levoleucovorin should not be administered within 2 hours before or after a dose of glucarpidase.266,300 During the first 48 hours following administration of glucarpidase, leucovorin or levoleucovorin should be administered at the dose utilized prior to administration of glucarpidase.266 After 48 hours, the dose of leucovorin or levoleucovorin should be determined based on plasma methotrexate concentrations.266 (See Glucarpidase 92:12.)

For specific information on dosage modifications, cautions, and precautions associated with impaired methotrexate elimination or an inadvertent overdosage, the manufacturer's prescribing information should be consulted.262

If accidental overdosage of intrathecal methotrexate occurs, intensive systemic supportive therapy (e.g., administration of high-dose leucovorin calcium, alkaline diuresis, rapid CSF drainage, ventriculolumbar perfusion) may be required (see Cautions: Effects following Intrathecal Administration).127

In case of severe overdosage of methotrexate, hydration and urinary alkalinization may be needed to prevent precipitation of the drug and/or its metabolites in the renal tubules.127 Hemodialysis and peritoneal dialysis generally have been ineffective in improving the elimination of methotrexate.127,213 However, effective clearance of methotrexate has been reported with the use of acute, intermittent hemodialysis with a high-flux polysulfone dialyzer (the F-80B Fresenius Dialyzer) in a small number of patients with acute renal failure secondary to methotrexate or with end-stage renal disease unrelated to methotrexate therapy.127,213

For additional information on the treatment of intrathecal methotrexate overdosage, see Cautions: Effects following Intrathecal Administration.

Pharmacology

Methotrexate and its polyglutamate metabolites reversibly inhibit dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one-carbon fragments necessary for synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The affinity of dihydrofolate reductase for methotrexate is far greater than its affinity for folic acid or dihydrofolic acid and, therefore, even very large doses of folic acid given simultaneously will not reverse the effects of methotrexate. Leucovorin calcium, a derivative of tetrahydrofolic acid, may block the effects of methotrexate if given shortly after the antineoplastic agent. Results of one study indicate that methotrexate 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 such as neoplasms, psoriatic epidermis, bone marrow, the lining of the GI tract, hair matrix, and fetal cells are most sensitive to the effects of methotrexate.

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), and decreased intracellular concentrations of polyglutamylated metabolites of methotrexate; however, the precise mechanism of this resistance development has not been established.

Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effects.113,116,127,128,138,141,142,144,145

Pharmacokinetics

Absorption !!navigator!!

Oral absorption of methotrexate appears to be highly variable and dose dependent.127,214,215 While older studies demonstrated good absorption from the GI tract with relatively low oral doses of methotrexate, more recent studies indicate that the oral bioavailability of the drug may be below 50% even at relatively low doses (i.e., 15 mg/m2 or lower).215 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/m2.127,214,215 Studies investigating the use of divided doses of methotrexate in an attempt to improve the oral bioavailability of the drug have shown conflicting results.215 It has been suggested that poor bioavailability should be assumed with oral methotrexate doses of 100 mg/m2 or greater, regardless of the dosage schedule used.215 Food delays absorption and decreases peak serum concentrations of the drug.127,214 Peak serum concentrations of methotrexate generally are achieved in 1-2 hours following oral administration in adults.127

Oral administration of methotrexate in pediatric patients with leukemia reportedly results in wide variability in the rate and extent of oral absorption.127,215 Oral bioavailability of 23-95%, with a 20-fold difference between the highest and lowest peak serum concentration measurements (range: 0.11-2.3 µ M ), has been reported in pediatric patients receiving oral methotrexate 20 mg/m2 for the treatment of leukemia.127 Substantial variability in the time to peak serum concentration also has been observed; in patients receiving methotrexate at an oral dose of 15 mg/m2, the time to peak serum concentration ranged from 0.67-4 hours.127

Methotrexate appears to be completely absorbed following IM administration at doses of up to at least 100 mg.127,215 Peak serum concentrations are achieved 30-60 minutes after IM administration of the drug.127 Serum concentrations following intra-arterial administration are similar to those achieved following IV administration.

Distribution !!navigator!!

Methotrexate is actively transported across cell membranes. At serum methotrexate concentrations exceeding 0.1 µmol/mL, passive diffusion becomes a major means of intracellular transport of the drug.127,215 The drug is widely distributed into body tissues with highest concentrations in the kidneys, gallbladder, spleen, liver, and skin. Following systemic administration of a single dose of methotrexate, the drug inhibits DNA synthesis in psoriatic epidermis for 12-16 hours. Following oral127 or IV128,132,133 administration of the drug to animals, synovial fluid methotrexate concentrations are higher in inflamed than in uninflamed joints; concurrent administration of salicylates did not affect distribution of methotrexate into joints, but pretreatment with prednisone reduced the amount of drug distributed into inflamed joints relative to that into normal joints.127,128,132,133 In patients receiving long-term, oral methotrexate therapy for rheumatoid arthritis, the ratio of synovial fluid to serum concentrations of methotrexate ranged from 0.9-1.2.128,134 Methotrexate distributes into third space fluids, and the presence of pleural effusions or ascites can substantially alter the disposition of the drug (see Pharmacokinetics: Elimination).215,216 Slow release of methotrexate from third space accumulations may prolong the terminal half-life and may increase the risk of drug toxicity with high doses (i.e., exceeding 250 mg/m2).215,216

Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation of methotrexate may result from repeated daily doses. Following IV administration, an initial volume of distribution of approximately 0.18 L/kg and a steady-state volume of distribution of approximately 0.4-0.8 L/kg have been reported.127,215 According to the manufacturer, the drug does not reach therapeutic concentrations in the CSF when given orally or parenterally. However, high-dose systemic methotrexate therapy can result in peak CSF concentrations above the therapeutic threshold of 0.001 µmol/mL216,219 and has been used to prevent meningeal leukemia and lymphoma.216 Following IV administration of methotrexate, CSF drug concentrations are dose related; a CSF concentration of 0.0001 µmol/mL was reported after a dose of 500 mg/m2y 24-hour IV infusion, and CSF concentrations exceeding 0.01 µmol/mL were observed following an IV bolus dose of 7500 mg/m2.215 Intrathecal administration of methotrexate may result in potentially cytotoxic serum drug concentrations that can persist for 24-48 hours.215

Methotrexate crosses the placental barrier. Methotrexate is distributed into breast milk;127,161,162 the highest reported breast milk plasma concentration ratio, which occurred 10 hours after administration of a 22.5-mg oral dose, was 0.08:1.127,162 (See Cautions: Pregnancy, Fertility, and Lactation.)

At serum concentrations of 0.001-0.1 µmol/mL, about 50% of the drug is bound to plasma proteins (primarily albumin).127,215

Elimination !!navigator!!

In patients receiving methotrexate for the treatment of psoriasis or rheumatoid arthritis, or as low-dose antineoplastic therapy (i.e., less than 30 mg/m2), a terminal half-life of about 3-10 hours has been reported.127 Higher doses of methotrexate have been associated with a longer elimination half-life of about 8-15 hours.127

Plasma concentrations of methotrexate following high-dose IV infusion appear to decline in a biphasic manner.215 The half-life of the initial phase (t½α) averages 1.5-3.5 hours in patients with normal total body clearance and the half-life in the terminal phase (t½β) is about 8-15 hours.215

After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamates, metabolites which by hydrolysis may be converted back to methotrexate.127 Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase.127 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.127 In addition, small amounts of methotrexate polyglutamates may be converted to 7-hydroxymethotrexate; 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.127 Following oral administration of methotrexate, the drug also is partially metabolized by the intestinal flora.127

The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the feces, probably via the bile. Methotrexate has a biphasic excretion pattern. Up to 92% of a single dose is excreted within 24 hours following IV administration followed by excretion of 1-2% of the retained dose daily. In one study, 58-92% of an IV methotrexate dose of 0.1-10 mg/kg was excreted in the urine within 24 hours. Only slightly less urinary excretion occurred following oral administration of 0.1 mg/kg. Following oral administration of 10 mg/kg, however, only 15% of the dose was excreted in the urine within 24 hours and 48% within 5 days. About 39% of the larger oral dose was recovered in the feces as compared to 7-9% following 0.1 mg/kg administered orally and 2-5% of 0.1-10 mg/kg administered IV. Enterohepatic recirculation of methotrexate may occur.127,215 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 addition, simultaneous administration of other weak organic acids such as salicylates may suppress methotrexate clearance.

Chemistry and Stability

Chemistry !!navigator!!

Methotrexate is a mixture containing at least 85% 4-amino-10-methylfolic acid, calculated on the anhydrous basis, and small amounts of related compounds. Methotrexate is a folic acid antagonist. Structurally, the primary constituent of methotrexate differs from folic acid in the substitution of an amino group for a hydroxyl group in the pteridine nucleus and in the addition of a methyl group on the amino nitrogen between the pteroyl and benzoyl groups. Methotrexate is a weak acid that occurs as an orange-brown, crystalline powder and is practically insoluble in water and in alcohol. Great care should be taken to prevent inhaling particles of the chemical and exposing the skin to it. Methotrexate sodium occurs as a yellow powder and is soluble in water. Methotrexate sodium injection has a pH of 7.5-9. Commercially available injections of methotrexate sodium are available with benzyl alcohol as a preservative or without a preservative.

Stability !!navigator!!

Methotrexate sodium tablets should be protected from light and stored in well-closed containers at 20-25°C.265,269 Methotrexate sodium injection and powder for injection should be protected from light and stored at 20-25°C.262 Stability and compatibility of methotrexate sodium solutions depend on several factors including the formulation of methotrexate sodium used, presence of preservatives, concentration of drug(s), specific diluents used, resulting pH, and temperature; the manufacturers' labeling and specialized references should be consulted for specific information.

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]. 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.

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.

Methotrexate Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mg (of methotrexate)*

Methotrexate Sodium Tablets (scored)

Rheumatrex® Dose Pack (scored)

Dava

Tablets, film coated

5 mg (of methotrexate)

Trexall® (scored)

Duramed

7.5 mg (of methotrexate)

Trexall® (scored)

Duramed

10 mg (of methotrexate)

Trexall® (scored)

Duramed

15 mg (of methotrexate)

Trexall® (scored)

Duramed

Parenteral

For injection

1 g (of methotrexate)*

Methotrexate Sodium for Injection

Injection

10 mg (of methotrexate) per mL*

Methotrexate Sodium Injection Isotonic

25 mg (of methotrexate) per mL*

Methotrexate Sodium Injection Isotonic

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

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Roenigk HH Jr, Auerbach R, Maibach HI et al. Methotrexate guidelines—revised. J Am Acad Dermatol . 1982; 6:145-55. [PubMed 7037877]

101. Lampkin BC, Higgins GR, Hammond D. Absence of neurotoxicity following massive intrathecal administration of methotrexate. Cancer . 1967; 20:1780-1. [PubMed 5299295]

102. Ettinger LJ, Freeman AI, Creaven PJ. Intrathecal methotrexate overdose without neurotoxicity. Cancer . 1978; 41:1270-3. [PubMed 346194]

103. Ettinger LJ. Pharmacokinetics and biochemical effects of a fatal intrathecal methotrexate overdose. Cancer . 1982; 50:444-50. [PubMed 6178493]

104. Spiegel RJ, Cooper PR, Blum RH et al. Treatment of massive intrathecal methotrexate overdose by ventriculolumbar perfusion. N Engl J Med . 1984; 311:386-8. [PubMed 6610829]

105. Addiego JE Jr, Ridgway D, Bleyer WA. The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr . 1981; 98:825-8. [PubMed 6971923]

106. Poplack DG. Massive intrathecal overdose: “check the label twice!” N Engl J Med . 1984; 311:400-2. Editorial.

107. Bleyer WA. Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics. Cancer Treat Rep . 1977; 61:1419-25. [PubMed 579164]

108. Bleyer WA, Coccia PF, Sather HN et al. Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncol . 1983; 1:317-25. [PubMed 6366138]

109. Black RL, O'Brien WM, Van Scott EJ et al. Methotrexate therapy in psoriatic arthritis. JAMA . 1964; 189:743-7. [PubMed 14174051]

110. Willkens RF, Williams HJ, Ward JR et al. Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum . 1984; 27:376-81. [PubMed 6712754]

111. Weinblatt ME, Coblyn JS, Fox DA et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med . 1985; 312:818-22. [PubMed 3883172]

112. Williams HJ, Willkens RF, Samuelson CO Jr et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. Arthritis Rheum . 1985; 28:721-30. [PubMed 3893441]

113. Andersen PA, West SG, O'Dell JR et al. Weekly pulse methotrexate in rheumatoid arthritis: clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med . 1985; 103:489-96. [PubMed 4037555]

114. Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med . 1983; 75(Suppl 6A):69-73. [PubMed 6660241]

115. Weinstein A, Marlowe S, Korn J et al. Low-dose methotrexate treatment of rheumatoid arthritis. Am J Med . 1985; 79:331-7. [PubMed 4036984]

116. Klippel JH, Decker JL. Methotrexate in rheumatoid arthritis. N Engl J Med . 1985; 312:853-4. [PubMed 3974665]

117. Sostman HD, Matthay RA, Putman CE et al. Methotrexate-induced pneumonitis. Medicine (Baltimore) . 1976; 55:371-88. [PubMed 957997]

118. Cannon GW, Ward JR, Clegg DO et al. Acute lung disease associated with low-dose methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum . 1983; 26:1269-74. [PubMed 6626285]

119. St Clair EW, Rice JR, Snyderman R. Pneumonitis complicating low-dose methotrexate therapy in rheumatoid arthritis. Arch Intern Med . 1985; 145:2035-8. [PubMed 4062454]

120. Thyss A, Milano G, Kubar J et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet . 1986; 1:256-8. [PubMed 2868265]

121. Ellison NM, Servi RJ. Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration. Cancer Treat Rep . 1985; 69:342-3. [PubMed 3978662]

122. Singh RR, Malaviya AN, Pandey JN et al. Fatal interaction between methotrexate and naproxen. Lancet . 1986; 1:1390. [PubMed 2872507]

123. Day RO, Graham GG, Champion GD et al. Anti-rheumatic drug interactions. Clin Rheum Dis . 1984; 10:251-75. [PubMed 6150784]

124. Daly HM, Scott GL, Boyle J et al. Methotrexate toxicity precipitated by azapropazone. Br J Dermatol . 1986; 114:733-5. [PubMed 3718865]

125. Hansten PD, Horn JR. Methotrexate interactions: ketoprofen (Orudis). Drug Interact Newsl . 1986; 6(Updates):U5-6.

126. Hansten PD, Horn JR. Methotrexate and nonsteroidal anti-inflammatory drugs. Drug Interact Newsl . 1986; 6:41-3.

127. Immunex. Methotrexate sodium tablets, methotrexate sodium and methotrexate LPF®sodium parenteral prescribing information. Pearl River, NY; 1999 Feb.

128. Lederle Laboratories. Rheumatrex® (methotrexate) product monograph. Pearl River, NY; 1988 Nov.

129. Ridley MG, Wolfe CS, Mathews JA. Life threatening acute pneumonitis during low dose methotrexate treatment for rheumatoid arthritis: a case report and review of the literature. Ann Rheum Dis . 1988; 47:784-8. [PubMed 3052323][PubMedCentral]

130. Green L, Schattner A, Berkenstadt H. Severe reversible interstitial pneumonitis induced by low dose methotrexate: report of a case and review of the literature. J Rheumatol . 1988; 15:110-2. [PubMed 3280790]

131. Kevat S, Ahern M, Hall P. Hepatotoxicity of methotrexate in rheumatic diseases. Med Toxicol Adverse Drug Exp . 1988; 3:197-208. [PubMed 3041245]

132. Stewart CF, Christensen ML, Evens RP et al. Influence of concomitant aspirin or prednisone on methotrexate synovial fluid concentration. J Pharmacol Exp Ther . 1987; 243:131-7. [PubMed 3668846]

133. Evens RP, Christensen ML, Stewart CF et al. Influence of prednisone on synovial fluid concentrations of methotrexate. Clin Pharmacol Ther . 1985; 37:194.

134. Furst DE, Herman R, Hoffman J et al. Serum kinetics, synovial fluid levels and liver concentrations of methotrexate in 41 RA patients given methotrexate. Arthritis Rheum . 1988; 31:S116.

135. Tsukada W, Akimoto T, Mizushima Y. Some aspects of anti- inflammatory action of immunosuppressive drugs. Jpn J Pharmacol . 1974; 24:583-8. [PubMed 4455967]

136. Welles WL, Silkworth WL, Oronsky AL et al. Studies on the effect of low dose methotrexate on rat adjuvant arthritis. J Rheumatol . 1985; 12:904-6. [PubMed 4087270]

137. Ridge SC, Rath N, Galivan J et al. Studies of D- penicillamine, gold thioglucose, and methotrexate on streptococcal cell wall arthritis. J Rheumatol . 1986; 13:895-8. [PubMed 3102727]

138. Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis: indications, contraindications, efficacy, and safety. Ann Intern Med . 1987; 107:358-66. [PubMed 3304050]

139. Health and Public Policy Committee, American College of Physicians. Methotrexate in rheumatoid arthritis. Ann Intern Med . 1987; 107:418-9. [PubMed 3619228]

140. Nordstrom DM, West SG, Andersen PA et al. Pulse methotrexate therapy in rheumatoid arthritis: a controlled prospective roentgenographic study. Ann Intern Med . 1987; 107:797-801. [PubMed 3688672]

141. Furst DE, Kremer JM. Methotrexate in rheumatoid arthritis. Arthritis Rheum . 1988; 31:305-14. [PubMed 2965875]

142. Scott DGI. Methotrexate and rheumatoid arthritis. J Clin Pharm Ther . 1988; 13:85-9. [PubMed 3292551]

143. Kremer JM, Lee JK. A long-term prospective study of the use of methotrexate in rheumatoid arthritis: update after a mean of fifty-three months. Arthritis Rheum . 1988; 31:577-84. [PubMed 3288222]

144. Weinblatt ME, Trentham DE, Fraser PA et al. Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum . 1988; 31:167-75. [PubMed 3279962]

145. Willkens RF, Watson MA. Methotrexate: a perspective of its use in the treatment of rheumatic diseases. J Lab Clin Med . 1982; 100:314-21. [PubMed 7108346]

146. Suarez-Almazor ME, Fitzgerald A, Grace M et al. A randomized controlled trial of parenteral methotrexate compared with sodium aurothiomalate (Myochrysine®) in the treatment of rheumatoid arthritis. J Rheumatol . 1988; 15:753-6. [PubMed 3139877]

147. Tishler M, Caspi D, Rosenbach TO et al. Methotrexate in rheumatoid arthritis: a prospective study in Israeli patients with immunogenetic correlations. Ann Rheum Dis . 1988; 47:654-9. [PubMed 3415364][PubMedCentral]

148. Steinsson K, Weinstein A, Korn J et al. Low dose methotrexate in rheumatoid arthritis. J Rheumatol . 1982; 9:860- 6. [PubMed 7161777]

149. Boerbooms AMT, Jeurissen MEC, Westgeest AAA et al. Methotrexate in refractory rheumatoid arthritis. Clin Rheumatol . 1988; 7:249-56. [PubMed 3416568]

150. Shergy WJ, Polisson RP, Caldwell DS et al. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. Am J Med . 1988; 85:771-4. [PubMed 3195601]

151. Allison J. Methotrexate and smallpox vaccination. Lancet . 1968; 2:1250. [PubMed 4177233]

152. Pullman SW, Solomon SD. Observations on long-term effects of methotrexate in rheumatoid arthritis. Arthritis Rheum . 1988; 31:R12.

153. Calvin M, Iobst W, Spencer-Green G et al. Five year follow-up of rheumatoid arthritis treated with low-dose pulse methotrexate. Arthritis Rheum . 1988; 31:S115.

154. Hall S, Buchbinder R, Harkness A et al. Safety and efficacy of low dosage long term methotrexate in rheumatoid arthritis assessed by life table analysis of treatment terminations. Arthritis Rheum . 1988; 31:S116.

155. Dahl MGC, Gregory MM, Scheuer PJ. Methotrexate hepatotoxicity in psoriasis—comparison of different dose regimens. Br Med J . 1972; 1:654-6. [PubMed 5015292][PubMedCentral]

156. Hansten PD, Horn JR. Drug interactions: clinical significance of drug-drug interactions. 6th ed. Lea & Febiger; 1989:273-81.

157. Dahl MGC, Gregory MM, Scheuer PJ. Liver damage due to methotrexate in patients with psoriasis. Br Med J . 1971; 1:625- 30. [PubMed 5548839][PubMedCentral]

158. Zachariae H, Kragballe K, Sogaard H. Methotrexate induced liver cirrhosis: studies including serial liver biopsies during continued treatment. Br J Dermatol . 1980; 102:407-12. [PubMed 7387883]

159. Bell MJ, Geddie WR, Gordon DA et al. Pre-existing lung disease in patients with rheumatoid arthritis may predispose to methotrexate lung. Arthritis Rheum . 1986; 29(Suppl):S75.

160. Tugwell P, Bennett K, Bell M et al. Methotrexate in rheumatoid arthritis: feedback on American College of Physicians guidelines. Ann Intern Med . 1989; 110:581-3. [PubMed 2648921]

161. American Academy of Pediatrics: Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics . 1989; 84:924-36. [PubMed 2677964]

162. Johns DG, Rutherford LD, Leighton PC et al. Secretion of methotrexate into human milk. Am J Obstet Gynecol . 1972; 112:978-80. [PubMed 5042796]

163. Roenigk HH Jr, Auerbach R, Maibach HI et al. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol . 1988; 19:145-56. [PubMed 3042816]

164. Gilbert SC, Klintmalm G, Menter A et al. Methotrexate-induced cirrhosis requiring liver transplantation in three patients with psoriasis: a word of caution in light of the expanding use of this “steroid-sparing” agent. Arch Intern Med . 1990; 150:889-91. [PubMed 2327848]

165. Roenigk HH Jr. Methotrexate and liver biopsies: is it really necessary? Arch Intern Med . 1990; 150:733-4. Editorial.

166. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.

167. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet . 1992; 339:1-15,71-85. [PubMed 1345950]

168. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med . 1976; 294:405-10. [PubMed 1246307]

169. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med . 1995; 332:901-6. [PubMed 7877646]

170. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med . 1994; 330:1253-9. [PubMed 8080512]

171. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA . 1995; 273:542-7. [PubMed 7837388]

172. Fisher B, Redmond C, Dimitrov NV et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med . 1989; 320:473-8. [PubMed 2644531]

173. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol . 1990; 8:1483-96. [PubMed 2202791]

174. Moliterni A, Bonadonna G, Valagussa P et al. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive nodes. J Clin Oncol . 1991; 9:1124-30. [PubMed 2045854]

175. Fisher B, Redmond C, Wickerman DL et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol . 1989; 7:572-82. [PubMed 2651576]

176. McGuire WL. Adjuvant therapy of node-negative breast cancer. N Engl J Med . 1989;320:525-7. Editorial. [PubMed 2915655]

177. De Vita VT Jr. Breast cancer therapy: exercising all our options. N Engl J Med . 1989; 320:527-9. [PubMed 2915656]

178. National Institutes of Health Office of Medical Applications of Research. Consensus conference: treatment of early-stage breast cancer. JAMA . 1991; 265:391-5. [PubMed 1984541]

179. Early Breast Cancer Trialists' Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality on early breast cancer: and overview of 61 randomized trials among 28,896 women. N Engl J Med . 1988; 319:1681-92. [PubMed 3205265]

180. The Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med . 1989; 320:491-6. [PubMed 2644533]

181. Mansour EG, Gray R, Shatila AH et al. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an intergroup study. N Engl J Med . 1989; 320:485-90. [PubMed 2915651]

182. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther . 2000; 42:83-92. [PubMed 10994034]

183. Rosen PP, Groshen S, Saigo PE et al. Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 16 years. J Clin Oncol . 1989; 7:1239-51. [PubMed 2549203]

184. Reviewers' comments (personal observations).

185. Buzzoni R, Bonadonna G, Valagussa P et al. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol . 1991; 9:2134-40. [PubMed 1960555]

186. Tallman MS, Gray R, Bennett JM et al. Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience. J Clin Oncol . 1995; 13:1557-63. [PubMed 7602344]

187. Goldhirsch A, Gelber RD, Price KN et al. Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet . 1994; 343:377-81. [PubMed 7905550]

188. Penicillin interactions: methotrexate (Mexate). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc, 1993:245.

189. Methotrexate (Mexate) interactions: mezlocillin. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc, 1994:800.

190. Methotrexate (Mexate) interactions: amoxicillin (Amoxil). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc, 1994:775-6.

191. Methotrexate (Mexate) interactions: theophylline. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc, 1993:419-20.

192. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

193. Food and Drug Administration. Methotrexate tablets and injection [May 20, 1997: Lederle]. MedWatch drug labeling changes. Rockville, MD; August 1997. From FDA website ([Web]).

194. Dann EJ, Gillis S, Polliack A et al. Brief report: tumor lysis syndrome following treatment with 2-chlorodeoxyadenosine for refractory chronic lymphocytic leukemia. N Engl J Med . 1993; 329:1547-8. [PubMed 8105383]

195. Ortho Biotech. Leustatin (cladribine) injection for intravenous infusion only prescribing information (dated 1995 Dec). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996 (Suppl A):A122-5.

196. Berlex Laboratories. Fludara (fludarabine phosphate) for injection prescribing information. Richmond, CA: 1994 Jun.

197. List AF, Kummet TD, Adams JD et al. Tumor lysis syndrome complicating treatment of chronic lymphocytic leukemia with fludarabine phosphate. Am J Med . 1990; 89:388-90. [PubMed 1697447]

198. Gucalp R, Dutcher J. Oncologic emergencies. In: Harrison's principles of internal medicine. 14th ed. Fauci AS, Braunwald E, Isselbacher KJ et al, eds. New York: McGraw-Hill Book Co; 1998:627-34.

199. Gorlick R, Goker E, Trippett T et al. Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med . 1996; 335:1041-8. [PubMed 8793930]

201. Rudick RA, Cohen JA, Weinstock-Guttman B et al. Management of multiple sclerosis. N Engl J Med . 1997;337:1604-11. [PubMed 9371858]

202. Goodkin DE, Rudick RA, VanderBrug Medendorp S et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol . 1995; 37:30-40. [PubMed 7818255]

203. Goodkin DE, Rudick RA, VanderBrug Medendorp S et al. Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology . 1996; 47:1153-7. [PubMed 8909421]

204. Hauser SL, Goodkin DE. In: Harrison's principles of internal medicine. 14th ed. Fauci AS, Braunwald E, Isselbacher KJ et al, eds. New York: McGraw-Hill Book Co; 1998:2409-18.

205. Scher HI, Shipley WU, Herr HW. Cancer of the bladder. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997:1300-22.

206. Thrasher JB, Crawford ED. Current management of invasive and metastatic transitional cell carcinoma of the bladder. J Urol . 1993; 149:957-72. [PubMed 8483247]

207. Bladder cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Oct.

208. Vogelzang NJ, Moormeier JA, Awan AM et al. Methotrexate, vinblastine, doxorubicin and cisplatin followed by radiotherapy or surgery for muscle invasive bladder cancer: the University of Chicago experience. J Urol . 1993; 149:753-7. [PubMed 8455237]

209. Roth BJ. Chemotherapy for advanced bladder cancer. Semin Oncol . 1996; 23:633-44. [PubMed 8893874]

210. Catimel G. Head and neck cancer: guidelines for chemotherapy. Drugs . 1996; 51:73-88. [PubMed 8741233]

211. Forastiere AA, Metch B, Schuller DE et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol . 1992; 10:1245-51. [PubMed 1634913]

212. Clavel M, Vermorken JB, Cognetti F et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol . 1994; 5:521-6. [PubMed 7522527]

213. Wall SM, Johansen MJ, Molony DA et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis . 1996; 28:846-54. [PubMed 8957036]

214. Godfrey C, Sweeney K, Miller K et al. The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis. Br J Clin Pharmacol . 1998; 46:369-76. [PubMed 9803986][PubMedCentral]

215. Crom WR, Evans WE. Methotrexate. In: Evans WE, Schentag JJ, Jusko WJ, eds. Principles of therapeutic drug monitoring. 3rd ed. Vancouver, WA: Applied Therapeutics, Inc; 1992:29-1-29-42.

216. Allegra CJ, Grem JL. Antimetabolites. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997:432-52.

217. Jardine LF, Ingram LC, Bleyer WA. Intrathecal leucovorin after intrathecal methotrexate overdose. J Ped Hematol Oncol . 1996; 18:302-4.

218. O'Marcaigh AS, Johnson CM, Smithson WA et al. Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc . 1996; 71:161-5. [PubMed 8577190]

219. Glantz MJ, Cole BF, Recht L et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol . 1998; 16:1561-7.

220. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum . 2002; 46:328-46. [PubMed 11840435]

221. Immunex, Seattle, WA: Personal communication.

222. Pincus T, O'Dell JR, Kremer JM. Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy. Ann Intern Med . 1999; 131:768-74. [PubMed 10577301]

223. Reviewer comments on etanercept 92:36 (personal observations).

224. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther . 2000; 42:57-64. [PubMed 10887424]

225. Weinblatt ME, Kremer JM, Bankhurst AD et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med . 1999; 340:253-9. [PubMed 9920948]

226. The North American Rheumatoid Arthritis Study Group. Selection of DMARD therapy in early rheumatoid arthritis. Arthritis Rheum . 1998; 41(Suppl 9):S269. [PubMedCentral]

227. Breedveld F. New tumor necrosis factor-alpha biologic therapies for rheumatoid arthritis. Eur Cytokine Netw . 1998; 9:233-8. [PubMed 9831171]

228. Tugwell P, Pincus T, Yocum D et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med . 1995; 333:137-41. [PubMed 7791814]

229. O'Dell JR, Haire CE, Erikson N et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med . 1996; 334:1287-91. [PubMed 8609945]

230. Maini RN, Breedveld FC, Kalden JR et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum . 1998; 41:1552-63. [PubMed 9751087]

231. Maini R, St Clair EW, Breedveld F et al. Infliximab (chimeric anti-tumor necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet . 1999; 364:1932-9.

232. Kavanaugh A, St Clair EW, McCune WJ et al. Chimeric anti-tumor necrosis factor-α monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol . 2000; 27:841-50. [PubMed 10782805]

233. Weinblatt ME, Kremer JM, Coblyn JS et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum . 1999; 42:1322-8. [PubMed 10403258]

234. Boers M, Verhoeven AC, Markusse HM et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet . 1997; 350:309-18. [PubMed 9251634]

235. Small cell lung cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Oct.

236. Anon. Anakinra (Kineret) for rheumatoid arthritis. Med Lett Drugs Ther . 2002; 44:18-19. [PubMed 11856953]

237. Furst DE, Keystone E, Maini RN et al. Recapitulation of the round-table discussion—assessing the role of anti-tumor necrosis factor therapy in the treatment of rheumatoid arthritis. Rheumatology (Oxford) . 1999; 38(Suppl 2):50-3. [PubMed 10646494]

238. Working Party of the British Society for Rheumatology. Guidelines for prescribing TNF-α-blockers in adults with RA. London; British Society for Rheumatology: 2000 Apr 14.

239. Furst DE, Breedveld FC, Burmester GR et al. Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis (May 2000). Ann Rheum Dis . 2000; 59(suppl 1):11-12.

240. Emery P, Reginster JY, Appelboom T et al. WHO collaborating centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis. Rheumatology . 2001; 40:699-702. [PubMed 11426031]

241. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Methotrexate Tablets & Injection [May 8, 2001: Lederle]. From FDA web site [Web].

242. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Methotrexate Sodium for Injection, Methotrexate Sodium Injection [Jan 2004]. From FDA web site [Web].

243. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults: Practice Guidelines. Am J Gastroenterol . 2001; 96:635-43. [PubMed 11280528]

244. Scribano M, Pantera C. Review article: medical treatment of moderate to severe Crohn's disease. Aliment Pharmacol Ther . 2003; 17(Suppl. 2):23-30. [PubMed 12786609]

245. Biancone L, Tosti V, Fina D et al. Review article: maintenance treatment of Crohn's disease. Aliment Pharmacol Ther . 2003; 17(Suppl. 2):31-37. [PubMed 12786610]

246. Korelitz BI, Present DH. Methotrexate for Crohn's disease. N Engl J Med . 1995; 333:600-1. [PubMed 7623920]

247. Rutgeers P. Modern therapy for inflammatory bowel disease. Scand J Gastroenterol . 2003 (Suppl 237):30-3.

248. Hanauer SB, Present DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord . 2003; 3:81-92. [PubMed 12776005]

249. Podolsky DK. Inflammatory bowel disease. N Engl J Med . 2002; 347:417-29. [PubMed 12167685]

250. Hanauer SB. Inflammatory bowel disease. N Engl J Med . 1996; 334:841-8. [PubMed 8596552]

251. Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database Syst Rev . 2003;(1):CD003459. [PubMed 12535475]

252. Feagan BG, Fedorak RN, Irvine EJ et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. N Engl J Med . 2000; 342: 1627-1632. [PubMed 10833208]

253. Feagan BG. Maintenance therapy for inflammatory bowel disease. Am J Gastroenterol . 2003 Dec; 98(12 Suppl): S6-S17.

254. Fraser AG, Morton D, McGovern DA et al. The efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther . 2002; 16:693-7. [PubMed 11929386]

255. Lemann M, Zenjari T, Bouhnik Y et al. Methotrexate in Crohn's disease: long-term efficacy and toxicity. Am J Gastroenterol . 2000; 95:1730-4. [PubMed 10925976]

256. Kirschner BS. Differences in the management of inflammatory bowel disease in children and adolescents compared to adults. Neth J Med . 1998; 53:S13-8. [PubMed 9883009]

257. Best WR, Becktel JM, Singleton JW et al. Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study. Gastroenterology . 1976; 70:439-44. [PubMed 1248701]

258. Arora S, Katkov W, Cooley J et al. Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology . 1999; 46:1724-9. [PubMed 10430331]

259. Oren R, Moshkowitz M, Odes S et al. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. Am J Gastroenterol . 1997; 92:2203-9. [PubMed 9399753]

260. Mahadevan U, Marion JF, Present DH. Fistula response to methotrexate in Crohn's disease: a case series. Aliment Pharmacol Ther . 2003; 18:1003-8. [PubMed 14616166]

261. Markowitz J, Grancher K, Mandel F et al, for the Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Am J Gastroenterol . 1993; 88:44-8. [PubMed 8420272]

262. Bedford Laboratories. Methotrexate injection and methotrexate for injection prescribing information. Bedford, OH: 2012 April.

263. Bedford Laboratories. Leucovorin calcium for injection prescribing information. Bedford, OH: 2000 Sept.

264. Spectrum Pharmaceuticals, Inc. Levoleucovorin (Fusilev®) for injection prescribing information. Irvine, CA; 2008 July.

265. Dava Pharmaceuticals, Inc. Rheumatrex® (methotrexate tablets) prescribing information. Fort Lee, NJ: 2009 Jul.

266. BTG International Inc. Glucarpidase (Voraxaze®) prescribing information. Brentwood, TN: 2012 Jan

267. Anon. Drugs of choice for cancer. Treatment Guidelines from the Medical Letter . 2003; 1:41-52. [PubMed 15529105]

268. Gestational trophoblastic tumors. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jun 5.

269. Duramed Pharmaceuticals Inc. Methotrexate sodium (Trexall®) prescribing information. Pomona, NY: 2005 Oct.

270. Osteosarcoma/malignant fibrous histiocytoma of bone. From: PDQ: Physician data query (database). Bethesda, MD: National Cancer Institute; 2004 Apr 20.

271. American College of Obstetricians and Gynecologists. Medical management of tubal pregnancy. ACOG Practice Bulletin 3 . Washington, DC: ACOG; 1998.

272. American College of Emergency Physicians Clinical Policies Committee and the Clinical Policies Subcommittee on Early Pregnancy. Clinical policy: critical issues in the initial evaluation and management of patients presenting to the emergency department in early pregnancy. Ann Emerg Med . 2003; 41:123-33. [PubMed 12514693]

273. Barnhart KT, Gosman G, Ashby R et al. The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens. Obstet Gynecol . 2003; 101:778-84. [PubMed 12681886]

274. Breast cancer treatment. From: PDQ: Physician data query (database). Bethesda, MD: National Cancer Institute; 2004 Mar 19.

275. GlaxoSmithKline. Daraprim® (pyrimethamine) tablets prescribing information. Research Triangle Park, NC; 2003 Mar.

276. Small cell lung cancer treatment. From PDQ: Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Sep 29.

277. Mycosis fungoides and the Sézary syndrome treatment. From PDQ: Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Dec 12.

278. Fung MA, Murphy MJ, Hoss DM et al. Practical evaluation and management of cutaneous lymphoma. J Am Acad Dermatol . 2002; 46:325-57. [PubMed 11862169]

279. Crom WR, Pratt CB, Green AA et al. The effect of prior cisplatin on the kinetics of methotrexate. Clin Pharmacol Ther. 1983; 33:220.

280. Abbott Laboratories. Humira® (adalimumab) injection prescribing information. North Chicago, IL; 2011 Sep.

281. Pfizer. Cordarone® (amiodarone hydrochloride) tablets prescribing information. New York, NY; 2011 Oct.

282. Baxter. Nexeterone® (amiodarone hydrochloride) injection prescribing information. Deerfield, IL; 2012 Jan.

283. Amgen Inc. Kineret® (anakinra) injection prescribing information. Thousand Oaks, CA; 2006 Dec 15

284. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al., Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum1998; 41:2196-204

285. Cohen S, Hurd E, Cush J, Schiff M et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum2002;46:614-24.

286. Amgen Inc,Thousand Oaks, CA: Personal communication.

287. Lundbeck Inc. Elspar® (asparaginase) prescribing information. Deerfield, IL; 2010 Feb

288. Schabel FM, Trader MW, Laster WR et al. cis-Dichlorodiammineplatinum(II): combination chemotherapy and cross-resistance studies with tumors of mice. Cancer Treat Rep. 1979; 63:1459-73.

289. Sandoz. Neoral® (cyclosporine for microemulsion) soft gelatin capsules and oral solution prescribing information. East Hanover, NJ; 1997 Jun

290. Maini RN, Breedveld FC, Kalden JR et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41:1552-63.

291. Markham A, Lamb HM. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs. 2000;59:1341-59.

292. Janssen Biotech, Inc. Remicade® (infliximab) for IV injection prescribing information. Horsham, PA; 2011 Sep.

293. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35.

294. Antoni C; Kalden JR. Combination therapy of the chimeric monoclonal anti-tumor necrosis factor α antibody (infliximab) with methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol. 1999. 17(Suppl 18):S73-7.

295. Elliott MJ, Maini RN, Feldmann M et al. Repeated therapy with monoclonal antibody to tumour necrosis factor α (cA2) in patients with rheumatoid arthritis. Lancet. 1994;344:1125-7.

296. Feldman M, Charles P, Taylor P et al. Biological insights from clinical trials with anti-TNF therapy. Sem Immunopathol. 1998; 20:211-28.

297. Rezaian MM. Do infliximab and methotrexate act synergistically in the treatment of rheumatoid arthritis? Arthritis Rheum. 1999; 42:1779. Letter.

298. Maini RN, Feldmann M, Schaible T. Do infliximab and methotrexate act synergistically in the treatment of rheumatoid arthritis? Arthritis Rheum. 1999; 42:1779-81. Reply.

299. Innocenti F, Danesi R, Di Paolo A et al. Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate. Cancer Chemother Pharmacol . 1996; 37:409-14. [PubMed 8599862]

300. BTG International Inc. West Conshohocken, PA : Personal communication.

301. Pharmacy Times. Methotrexate and Proton Pump Inhibitors. [April 9, 2012: Horn]. Plainsboro, NJ; April 2012. [Web]

302. Bezabeh S, Mackey AC, Kluetz P et al. Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors. Oncologist . 2012; 17:550-4. [PubMed 22477728][PubMedCentral]

303. Takeda Pharmaceuticals America, Inc. Dexilant® (dexlansoprazole) delayed-release capsules prescribing information. Deerfield, IL; 2012 May.

304. AstraZeneca. Nexium® I.V. (esomeprazole sodium) for injection prescribing information. Wilmington, DE; 2012 Jan.

305. AstraZeneca. Nexium® (esomeprazole magnesium) delayed-release capsules and packets for delayed-release oral suspension prescribing information. Wilmington, DE; 2012 Jan.

306. Eisai Inc. and Janssen Pharmaceuticals Inc. AcipHex® (rabeprazole sodium) delayed-release tablets prescribing information. Woodcliff Lake and Titusville, NJ; 2012 May.

307. AstraZeneca. Prilosec® (omeprazole) delayed-release capsules and for delayed-release oral suspension prescribing information. Wilmington, DE; 2012 Jan.

308. Takeda Pharmaceuticals America, Inc. Prevacid® (lansoprazole) delayed-release capsules and Prevacid® SoluTab (lansoprazole) delayed-release oral disintegrating tablets prescribing information. Deerfield, IL; 2012 May.

309. Institute for Safe Medication Practices. 2018-2019 Targeted Medication Safety Best Practices for Hospitals. From ISMP website. Accessed 2018 Aug 6 [Web]