Methotrexate dosage

Percutaneous Hver biopsy after each 1.5 g of total accumulated methotrexate dosage to detect hepatic fibrosis or cirrhosis not rehably predicted by semm aminotransferase tests are recommended (1,50). Concurrent use of NSAIDs may increase toxicity of methotrexate, although toxicity may be avoided if the dmgs are separated by 12 h. 

Bleyer WA, Coccia PF, Sather HN, Level C, Lukens J, Niebrugge DJ et al. Reduction in central nervous system leukemia with a pharmacokinetically dervived intrathecal methotrexate dosage regimen. J Clin Oncol 1983 1 317-25. 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

With methotrexate - Use the same initial dose and dosage range if Neoral is combined with the recommended dose of methotrexate. Most patients can be treated with Neoral 6oses of 3 mg/kg/day or less when combined with methotrexate doses of 15 mg/week or less. 

Hypersensitivity to polyoxyethylated castor oil (injection only see Warnings and Administration and Dosage), cyclosporine, or any component of the products Gengraf and Neoral in psoriasis or RA patients with abnormal renal function, uncontrolled hypertension, or malignancies Gengraf and A/eora/concomitantly with PUVA or DVB, methotrexate or other immunosuppressive agents, coal tar or radiation therapy in psoriasis patients. 

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and Gl toxicity have occurred with coadministration of methotrexate (usually in high dosage) along with some NSAIDs (see Precautions. Drug Interactions). 

Renal use Use methotrexate in patients with impaired renal function with extreme caution, and at reduced dosages, because renal dysfunction will prolong elimination. Gl Diarrhea and ulcerative stomatitis require interruption of therapy hemorrhagic enteritis and death from intestinal perforation may occur. 

Loehrer PJ, Elson P, Dreicer R, et al. Escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced urothelial carcinoma an Eastern Cooperative Oncology Group trial. J Clin Oncol 1994 12 483-488. 

Trimethoprim has been reported to decrease the therapeutic effect of cyclosporine with a concomitant increased risk of nephrotoxicity. Increased levels of dapsone, warfarin, methotrexate, zidovudine, and sul-fonylureas may occur when given together with trimethoprim dosages of these drugs should be modified and the patient monitored accordingly. 

Methotrexate is well absorbed orally and at usual dosages is 50% bound to plasma proteins. The plasma decay that follows an intravenous injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tissues. The major routes of drug excretion are glomerular filtration andl active renal tubular secretion. 

Plasma methotrexate concentrations as a therapeutic guide to high-dose methotrexate therapy with leucovorin rescue continue leucovorin until plasma methotrexate concentrations are <5 X 10 M (see dosage)... 

Adalimumab is given subcutaneously and has a half-life of 10-20 days. Its clearance is decreased by more than 40% in the presence of methotrexate, and the formation of human antimonoclonal antibody is decreased when methotrexate is given at the same time. The usual dose in rheumatoid arthritis is 40 mg every other week, although increased responses may be evident at higher dosages. In psoriasis, 80 mg is given at week 0, 40 mg at week 1, and then 40 mg every other week thereafter. 

At higher dosage, methotrexate may cause bone marrow depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in the treatment of inflammatory bowel disease, these events are uncommon but warrant dose reduction if they do occur. Folate supplementation reduces the risk of these events without impairing the antiinflammatory action. 

The compound is indicated for the treatment of rheumatoid arthritis and decreases the rate of formation of new erosions. It is effective both as monotherapy and in combination with methotrexate. The usual dose is 40 mg every other week, though increased responses may be evident at higher dosages. Adalimumab is presently being tested in psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile chronic arthritis. 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

Infliximab leads to symptomatic improvement in two thirds and disease remission in one third of patients with moderately severe or fistulizing Crohn s disease, including patients who have been dependent on glucocorticoids or who have not responded to 6-mercaptopurine or methotrexate. The median time to clinical response is 2 weeks. Infliximab induction therapy is generally given in a dosage of 5 mg/kg at 0, 2, and 6 weeks. Patients who respond may be treated with repeat infusions every 6-12 weeks to maintain remission with or without other therapies. 

Methotrexate inhibits folic acid, so leucovorin (folinic acid) is prescribed in adequate dosage to prevent excessive toxicity to the bone marrow, mucosae and liver. 

Bleyer WA. Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics. Cancer Treat Rep 1977 61 1419-25. 

Aspirin displaces methotrexate from its binding sites and also inhibits its renal tubular elimination, so that the dosage of concurrently used methotrexate should be reduced (except once-a-week low-dose treatment in rheumatoid arthritis) (110). 

Methotrexate is a foUc acid antagonist that acts by inhibiting dihydrofolate reductase. Owing to its immunosuppressive and anti-inflammatory properties, low-dosage methotrexate (7.5-15 mg/week) has been extensively investigated for other therapeutic purposes characterized by inflammation or cellular proliferation. Since the mid-... 

Pulmonary endoalveolar hemorrhage was a possible complication of pneumonitis in a 57-year-old woman who voluntarily increased her dosage of methotrexate from 7.5 mg once a week to 7.5 mg/day for 15 days (17). 

Significant hematological abnormalities occur in 10-24% of patients who take methotrexate. Mild to moderate leukopenia is the most frequent, followed by thrombocytopenia. Isolated thrombocytopenia and anemia are uncommon (SEDA-22, 416) (36). In a retrospective study in 315 patients, 13 had thrombocytopenia, two of whom also had pancytopenia (37). Thrombocytopenia correlated with the weekly dosage of methotrexate administered on the same day as NSAIDs, and methotrexate was safely reintroduced in patients who developed thrombocytopenia as a result of concomitant administration of... 

Pancytopenia is a rare but potentially fatal complication, and numerous reports have been published. The characteristics and incidence of pancytopenia have been carefully re-evaluated from case reports and clinical trials published from 1980 to 1995 (38). Of 70 reported cases, 12 patients died (17%). Impaired renal function was the most important contributing factor (54%), particularly in fatal cases (10/12). Other important susceptibility factors included advanced age (over 65 years), hypoalbuminemia, concurrent infection, and/or concomitant multiple medications (particularly co-trimoxazole). The mean cumulative dosage was 675 (10-4800) mg, and the minimal cumulative methotrexate dose leading to fatal pancytopenia was 10 mg. This confirms that pancytopenia can occur at any time during treatment, even in the absence of known susceptibility factors. Bone marrow biopsy showed megaloblastosis and hypocellularity. Eosinophilia and increased mean corpuscular volume were rarely observed. In an overall review of five long-term prospective studies (511 patients), the calculated incidence of methotrexate-induced pancytopenia was 1.4%. Although severe myelo-suppression sometimes required folinic acid, there are as yet no data to determine whether prophylactic folate supplementation can reduce the incidence of pancytopenia. 

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