Renal impairment methotrexate

Methotrexate is an antimetabolite drug that is excreted primarily by the kidney. It is contraindicated in significant renal impairment and in hepatic impairment. It is nephrotoxic and accumulation may occur in renal impairment. Dose should be reduced in renal impairment that is not severe and drug should be avoided if creatinine clearance is less than 20 mL/minute. 

Monitoring Periodic monitoring for toxicity, including CBC with differential and platelet counts, and liver and renal function testing is mandatory. Periodic liver biopsies may be indicated in some situations. Monitor patients at increased risk for impaired methotrexate elimination (eg, renal dysfunction, pleural effusions, ascites) more frequently (see Precautions). 

METHOTREXATE PROCARBAZINE t risk of renal impairment if methotrexate infusion is given within 48 hours of procarbazine administration. Also t risk of methotrexate toxicity, particularly to the kidneys Procarbazine has a transient effect on the kidneys, and this will delay the renal elimination of methotrexate Do not start methotrexate infusion less than 72 hours after the last dose of procarbazine. Hydrate patients aggressively (plenty of oral fluids or intravenous fluids), alkalinize the urine to pH>7 and closely monitor renal function, e.g. blood urea and creatinine, before and after methotrexate infusion until methotrexate blood levels are <0.05 xmol/L... 

Antimetabolites cause gastrointestinal toxicity including stomatitis and diarrhoea as well as bone marrow depression renal impairment potentiates the toxicity of methotrexate. Active excreHon of methotrexate by the renal tubule is blocked by salicylate, which also displaces it from plasma protein, increasing the risk of toxicity. Hepatic dysfunction potentiates the toxicity of 5-fluorouracil, since it is primarily metabolised by the liver. 

Price P, Thompson H, BesseU EM, Bloom HJ. Renal impairment following the combined use of high-dose methotrexate and procarbazine. Cancer Chemother Pharmacol 1988 21(3) 265-7. 

An interaction between triamterene and methotrexate (also an inhibitor of dihydrofolate reductase), leading to pancytopenia, has been reported (16). Dehydration due to diuretic treatment may have contributed to renal impairment and reduced clearance of methotrexate, further increasing the risk of bone marrow suppression. 

Abelson HT, Fosburg MT, Beardsley GP. Methotrexate-induced renal impairment. J Clin Oncol 1983.1 208-216. 

Methotrexate, cisplatin Renal impairment In proportion to lowered creatinine clearance (normal = 60 mL/min per m ) CIcr <10 mL/min, contraindicated... 

An elderly woman who had been treated with low-dose methotrexate 5 mg weekly and loxoprofen for one month developed acute pyelonephritis. Intravenous eefotiam was started, and on day 7 she developed severe watery diarrhoea. Analysis showed pancytopenia and Clostridium difficile infection. Methotrexate and cefotiam were stopped, and vancomycin started, and the patient reeovered. It was suggested that the combination of the antineoplastic drug and antibacterial increased the risk of Clostridium difficile diarrhoea. In addition, the NSAID (see Methotrexate + NSAIDs , p.649) and renal impairment from the pyelonephritis could have eontrib-uted to the methotrexate toxicity. This appears to be an isolated ease, and any interaetion with cefotiam is not established. 

When 2 patients with osteosarcoma, treated with high-dose methotrexate 12 give per course, were given ciprofloxacin 500 mg twice daily, either during or 2 days before the start of the methotrexate course, methotrexate elimination was delayed, resulting in raised serum levels, severe cutaneous toxicity and renal impairment. The first patient also had hepatic injury and haematological toxicity. Following increased folinic acid rescue, methotrexate levels normalised after several days. In earlier courses without ciprofloxacin in the first patient and subsequent courses without ciprofloxacin in the second patient, methotrexate elimination was normal. This preliminary report has subsequently been published in full. ... 

A 57 year-old woman who had been treated for several years with daily doses of dielofenae 150 mg, atenolol 50 mg and triamterene with hydrochlorothiazide 50/25 mg, for rheumatoid arthritis and hypertension, additionally started treatment with methotrexate 5 mg weekly. After 2 months she was admitted to hospital with pancytopenia, extensive mu-eosal uleeration and renal impairment. The authors point out that triamterene is structurally similar to folate and has anti-folate activity, which may therefore have been additive with the effects of methotrexate, but the diclofenac may also have contributed (see Methotrexate + NSAIDs , p.649). In 1998, the manufacturer noted there were two other reports of pancytopenia in patients taking methotrexate and triamterene, but again the patients were also taking NSAIDs. ... 

A three to fourfold increase in serum methotrexate levels at 24 hours was also seen in 4 patients given probenecid. Pretreatment with probenecid (500 mg every 6 hours for 5 doses) doubled the serum methotrexate levels of another 4 patients. Severe and life-threatening pancytopenia occurred when a woman taking low-dose methotrexate 7.5 mg weekly for rheumatoid arthritis was given probenecid. She also had renal impairment, hy-poalbuminaemia and was taking salsalate (a salicylic acid derivative). ... 

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. 

Methotrexate (Rheumatrex Dose Pack, Trexall) [Antineoplastic, Antirheumatic (DMARDs), Immunosuppressant/ Antimetabolite] WARNING Administration only by experienced healthcare provider do not use in women of childbearing age unless absolutely necessary (teratogenic) impaired elimination w/ impaired renal Fxn, ascites, pleural effusion severe myelosuppression if used w/ NSATDs hepatotox can induce lung Dz ... 

As more than 80% of methotrexate is excreted unchanged in the kidneys, a minor decrease in renal function can have a profound effect on the renal clearance of methotrexate and lead to significant toxicity, When drugs that impair the renal clearance of methotrexate are used concurrently, it is mandatory to measure methotrexate levels. 

These include mesalazine, metformin, NSAIDs, tetracyclines (except doxycycline and minocycline), chloramphenicol, lithium, methotrexate, chloroquine, fibrates, chlorpropamide and glibenclamide, Clinically, it is useful to measure urine output per hour or per 24 hours as a fall in urine output in the presence of adequate fluid intake often indicates or warns of some impairment of renal function. Furthermore, it is neither expensive nor time-consuming to perform a quick test for albumin, casts and red cells in the urine, and to measure pH. Creatinine clearance values are often used to determine the safe doses for several drugs (e.g. NSAIDs, ciclosporin). 

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. 

Impaired renal fnnction is a susceptibility factor for methotrexate-induced pancytopenia. 

Kremer JM, Hamilton RA The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol 1995 22(ll) 2072-7. 

Beta-lactams are weak organic acids that compete with the renal tubular secretion of methotrexate and its metabolites and reduce their clearance, leading to methotrexate toxicity (250,251). Consecutive aplastic crises have been described, particularly in patients with impaired... 

Methotrexate is often prescribed for the management of rheumatoid arthritis, and some NSAIDs have been reported to interact with it, causing increased plasma methotrexate concentrations, associated with impaired renal function. The safety of concurrent rofecoxib and oral methotrexate has been studied for 3 weeks in 25 patients with rheumatoid arthritis (7). Rofecoxib 12.5-50 mg/day had no effect on the plasma concentrations or renal clearance of methotrexate, but supratherapeutic doses of rofecoxib (75 and 250 mg) caused a significant increase in the plasma methotrexate AUC and reduced its renal clearance. 

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