Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction
Methotrexate is immunosuppressive and may therefore reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently.

Methotrexate is extensively protein bound and may displace or be displaced by other acidic drugs. The concurrent administration of agents such as p-aminobenzoic acid, chloramphenicol, penicillins, ciprofloxacin, diphenylhydantoins, phenytoin, acidic anti-inflammatory agents, salicylates, sulphonamides, tetracyclines, thiazide diuretics, probenicid, sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity. Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should generally be avoided, unless considered clinically justified, in which case the patient should be closely monitored.

Administration of additional haemotoxic medicinal products (e.g., metamizole) increase the probability of severe haemotoxic effects of methotrexate.

Renal tubular transport is also diminished by probenecid and penicillins; use of methotrexate with these drugs should be carefully monitored.

NSAIDs should not be administered prior to, or concomitantly with, high dose methotrexate as fatal methotrexate toxicity has been reported. Caution is also advised when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and thereby may enhance its toxicity. It is recommended that methotrexate dosage be carefully controlled during treatment with NSAIDs.
Concomitant administration of folate antagonists, such as co-trimoxazole, trimethoprim and nitrous oxide should be avoided.

Vitamin preparations containing folic acid, or its derivatives may alter response to methotrexate.

Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics may reduce intestinal methotrexate absorption or interfere with the enterohepatic circulation, due to inhibition of the intestinal flora or suppression of bacterial metabolism.

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.

Co-administration of proton-pump inhibitors such as omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to a delay in the renal elimination of methotrexate. In combination with pantoprazole, inhibited renal elimination of the 7-hydroxymethotrexate metabolite, with myalgia and shivering, was reported in one case.

Methotrexate may reduce theophylline clearance. Therefore, theophylline blood levels should be monitored under concomitant methotrexate administration.

Excessive consumption of beverages containing caffeine or theophylline (coffee, soft drinks containing caffeine, 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 dose 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.

Anaesthetics on nitric oxide base potentiate the effect of methotrexate on the folic acid metabolism and lead to severe unpredictable myelosuppression and stomatitis. This can be reduced by administering calcium folinate.

Colestyramine can increase the non-renal elimination of methotrexate by interrupting the enterohepatic circulation.

Delayed methotrexate clearance should be considered in combination with other cytostatic agents.

Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis 
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 and 4.4).

Existing data suggest that etretinate is formed from acitretin after ingestion of alcoholic beverages.
However, the formation of etretinate without concurrent alcohol intake cannot be excluded. Serum levels of methotrexate may be increased by etretinate, and severe hepatitis has been reported following concurrent use.

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis and in case of intrathecal administration increased severe, unpredictable neurotoxicity. Whilst this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided.