What is the evidence for the possibility of severe adverse effects on coadministration of methotre

Fråga: What is the evidence for the possibility of severe adverse effects on coadministration of methotrexate at anti-rheumatic doses (7.5mg/week) and trimethoprim, without concomitant sulfamethoxazole?

The case concerns a patient with methotrexate treatment who developed an exanthema when treated with trimethoprim for a urinary tract infection (UTI).

Sammanfattning: The causal link between a trimethoprim-methotrexate interaction and bone marrow suppression in these cases seems relatively strong (temporal association and possible mechanistic explanation). The phenomenon of adverse effects of such an interaction seems, however, unlikely. Risk factors could be old age, co-morbidity, folate deficiency and lowered renal function. When therapeutic alternatives are available, it might be prudent to avoid the combination.

Svar: The mechanism of action of methotrexate is through inhibition of folic-acid dependent metabolic processes in eukaryotic cells. Trimethoprim and sulfamethoxazole are folic acid antagonists on prokaryotic metabolism, and generally affect eukaryotes at manifold higher concentrations than those achieved in therapeutic use, which is the rationale for their use as an antimicrobial agent (1).

The concomitant use of trimethoprim and methotrexate has been stated to be counter-indicated (2,3). This is due to an elevated risk of pancytopenia. The bulk of the evidence for this, however, is based on case reports concerning co-administration of methotrexate and co-trimoxazole (trimethoprim and sulfamethoxazole). This has been reviewed in several Drugline documents (4,5,6) Since sulfamethoxazole is known for its hematotoxicity, however, it is not obvious to what extent conclusions concerning co-trimoxazole might be inferred upon trimethoprim alone.

Most of the haematological side-effects reported for trimethoprim have been in combination with sulfamethoxazole. Rare cases of agranulocytosis in severely folate-depleted patients have been reported on treatment with trimethoprim alone (7). Few published cases have been found where the combination of methotrexate and trimethoprim alone have been associated with serious clinical consequences.

The first one concerns an 80-year-old woman with methotrexate treatment due to psoriasis. During medication with trimethoprim 200mg b.i.d due to a UTI, she developed severe neutropenia and skin ulcerations. Blood folate was in the normal range. The patient were reported to have normal s-urea and creatinine. However, during the episode she was also taking naproxen 250 mg b.i.d. (1).

The second case concerns an 81-year-old woman with methotrexate treatment due to polyarthritis. She also had a bladder carcinoma. Due to repeated UTI she was treated prophylactically with trimethoprim 100 mg/d. Two months later this was increased to 200 mg/d due to symptoms of UTI. One week later the patient developed septicemia and pancytopenia. Her blood folate level was found to be low (8).

A further two patients are reported, one concerning a 48-year-old woman with systemic lupus erythematosus and methothrexate treatment, who developed bone marrow failure after treating an UTI with trimethoprim. On bone marrow biopsy, infiltration of a previously unknown metastatic tumor was found. A further 58-year-old woman with RA and methotrexate, developed bone marrow failure while on trimethoprim because of a UTI. In her case, folic acid supplementation had been discontinued for unspecified reasons after admission to an orthopaedic surgery ward, due to a fracture (9).

There are two suggested mechanisms for the possibility of a methotrexate-trimethoprim interaction underlying these cases. One is pharmacodynamic, involving a synergetic effect on folate dependent metabolic processes. The other one is pharmakokinetic, concerning the possibility that trimethoprim might interfere with methotrexate elimination (1,4,8). Theoretically the second and fourth case might be examples of a pharmacodynamic interaction, in the presence of a folate deficiency, whereas renal elimination might have been impaired in the elderly subject coadministering naproxen. There are, however, no data for serum concentrations of methotrexate in the given case. Ng HW, Macfarlane AW, Graham RM, Verbov JL. Near fatal drug interactions with methotrexate given for psorias. Br Med J 1987;295:752-3. FASS 2003 Methotrexate. Drugdex(R) System; Micromedex, Inc., Englewood, Colorado (Edition expires (date)) Drugline nr 18826 (år 2002) Drugline nr 13855 (år 1996) Drugline nr 11323 (år 1994) Dukes MNG, Aronson JK, editor. Meyler´s Side effects of drugs. 14th ed. Amsterdam: Elsevier; 2000 Steuer A, Gumpel JM. Methotrexate and trimethoprim: a fatal interaction. Br J Rheumatol 1997;37(1):105-6. Saravana S, Lalukotta K. Myelotoxicity due to methotrexate - an iatrogenic cause. Eur J Haematol 2003;71:315-6.