Methotrexate dosing

PO/IM BID for 4 doses, starting 24 h after first methotrexate dose IV day 8... 

Leucovorin rescue after high-dose methotrexate therapy The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 g/m administered by IV infusion over 4 hours. Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m ) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of Gl toxicity, nausea, or vomiting, administer leucovorin parenterally. 

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. 

For immunosuppressive effects methotrexate is most frequently used in RA but also azathioprine and cyclosporin are employed. Methotrexate doses for this indication can be lower than those used for cancer chemotherapy but significant toxicity such as nausea, cytopenias and mucosal lesions, and with longterm therapy slowly progressive hepatotoxicity may still be seen. 

In contrast to administration in earlier treatment elements applied in childhood ALL protocols (e.g., consolidation or extra-compartment therapy) where thiopurines are given at fixed doses, in maintenance both 6-MP and methotrexate doses are adjusted according to absolute leukocyte or neutrophil and platelet counts. Current BFM dose modification guidelines for maintenance treatment in childhood ALL call for an absolute leukocyte count in a target range of 2-3 x 10 /L (2, 57). Minimal requirements for starting maintenance treatment are an absolute leukocyte count of > 1 x 10 /L with at least 0.2 X 10 /L neutrophils and 50 x 10 /L thrombocytes (counts not decreasing). 

Although the most common methotrexate dosing regimens for the treatment of rheumatoid arthritis are 15 or 17.5 mg weekly, there is an increased effect up to 30 or 35 mg weekly. The drug decreases the rate of appearance of new erosions. Evidence supports its use in juvenile chronic arthritis, and it has been used in psoriasis, psoriatic arthritis, polymyositis, dermatomyositis, Wegener s granulomatosis, giant cell arteritis, subacute lupus erythematosus, and vasculitis. 

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. 

Probable association Duration of methotrexate treatment (over 2 years) Cumulative methotrexate dose (over 1500 mg) Prior treatment with arsenicals Obesity with diabetes mellitus... 

Collectively, the available data suggest that methotrexate rarely causes significant serious hver damage in patients who have been otherwise carefully selected, who present no risk factors for methotrexate-induced hepatotoxicity, and who have received lower weekly dosages with strict monitoring of liver function (for example transaminases) in order to reduce methotrexate doses when liver enzymes are persistently raised (48). 

Methotrexate is readily filtered by the kidneys, and renal clearance is influence by both tubular secretion [139, 140, 141, 142] and tubular reabsorption [142]. Intravenous administration of methotrexate 140-350 mg/kg [<6h infusion] results in 70-94% of the dose appearing in the urine over 24 h [143]. In contrast, when methotrexate is administered as a 24-h continuous infusion, 60% of the dose is excreted in the mine during the 24-h infusion [144]. Approximately 10% of the dose is excreted in the urine as 7-hydroxymethotrexate [143,144]. The 7-hydroxy metabohte is important since it may contribute to the renal toxicity of methotrexate [148] and this moiety becomes a significant metabolite when methotrexate doses are 50 mg/kg or greater [145]. Following oral administration of methotrexate a lesser fraction of the dose is recovered in the urine than following intravenous administration [141]. This may reflect the dose-dependent incomplete absorption of methotrexate [141,146,147]. Methotrexate is highly bound to plasma proteins. 

The starting methotrexate dose is 7.5 to 15 mg per week, and this is increased incrementally by 2.5 mg every 2 to 4 weeks until a response is evident. Maximal doses are typically about 25 mg per... 

Low-dose methotrexate therapy decreases theophylline Cl by 19%, probably due to CYP isoenzyme inhibition.Higher methotrexate doses might have a greater effect. 

Wall AM, Gajjar A, Link A, Mahmoud H, Pui C-H, Relling MV. Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia. Leukemia (2000) 14, 221-5. 

Swanson DL, Barnes SA, Mengden Koon SJ, el-Azhary RA. Caffeine consumption and methotrexate dosing requirement in psoriasis and psoriatic arthritis. IntJ Dermatol (2001) 46, 157-9. 

Parshuram CS, Dupuis LL, To T et al (2006) Occurrence and impact of anticipated variation in intravenous methotrexate dosing. Ann Pharmacother 40 805-811... 

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