Interactions : אינטראקציות

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction
In animal experiments non-steroidal anti-inflammatory drugs (NSAIDs) including salicylic acid caused reduction of tubular methotrexate secretion and consequently increased its toxic effects. However, in clinical studies, where NSAIDs and salicylic acid were given as concomitant medication to patients with rheumatoid arthritis, no increase of adverse reactions was observed. Treatment of rheumatoid arthritis with such drugs can be continued during methotrexate therapy but only under close medical supervision.
Regular alcohol consumption and administration of additional hepatotoxic medicinal products increase the probability of hepatotoxic effects of methotrexate.
Patients taking potentially hepatotoxic medicinal products during methotrexate therapy (e.g., leflunomide, azathioprine, sulfasalazine, and retinoids) should be closely monitored for possibly increased hepatotoxicity. Alcohol consumption should be avoided during treatment with Methotrexat "Ebewe" .
Be aware of pharmacokinetic interactions between methotrexate, anticonvulsant drugs (reduced methotrexate blood levels), and 5-fluorouracil (increase of 5-fluorouracil).
Salicylates, phenylbutazone, phenytoin, barbiturates, tranquillisers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulfonamides and p-aminobenzoic acid displace methotrexate from serum albumin binding and thus increase bioavailability (indirect dose increase).
Probenecid and mild organic acids may also reduce tubular methotrexate secretion, and thus cause indirect dose elevations, too.
Antibiotics, like penicillins, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastrointestinal toxicity may occur.
Oral antibiotics like tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics may reduce intestinal methotrexate absorption or interfere with enterohepatic circulation by inhibition of the intestinal flora or suppression of the bacterial metabolism.
Under (pre-)treatment with substances that may have adverse reactions affecting the bone marrow (e.g., sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine), the risk of pronounced haematopoietic disorders during methotrexate therapy must be considered.
Concomitant administration of drugs that cause folate deficiency (e.g., sulfonamides, trimethoprim/sulfamethoxazole) may lead to increased methotrexate toxicity. Therefore, particular caution must be exercised in patients with existing folic acid deficiency. On the other hand, concomitant administration of folinic acid-containing drugs or of vitamin preparations, which contain folic acid or derivatives, may impair methotrexate efficacy.
Under concomitant administration of Methotrexat "Ebewe" and basic treatments (e.g., gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), increased toxic effects of methotrexate are generally not to be expected.
Proton-pump inhibitors
Concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.
Though the combination of methotrexate and sulfasalazine may enhance methotrexate efficacy by sulfasalazine-related inhibition of folic acid synthesis, and thus may lead to an increased risk of side effects, these were only observed in single patients within several trials.
Methotrexate may reduce theophylline clearance. Therefore, theophylline blood levels should be monitored under concomitant methotrexate administration.
Excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing beverages, black tea) should be avoided during methotrexate therapy, since the efficacy of methotrexate may be reduced due to possible interaction between methotrexate and methylxanthines at adenosine receptors.
The combined use of methotrexate and leflunomide may increase the risk for pancytopenia. Methotrexate leads to increased plasma levels of mercaptopurines. Therefore, the combination of these may require dosage adjustment.
Particularly in the case of orthopaedic surgery where susceptibility to infection is high, a combination of methotrexate with immune-modulating agents must be used with caution.
Delayed methotrexate clearance should be considered in combination with other cytostatic agents. On account of its possible effect on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to record the immune reaction). During methotrexate therapy concurrent vaccination with live vaccines must not be carried out (see section 4.3).