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Pharmacodynamic interactions: Hepatotoxic agents: Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate. If concomitant administration cannot be avoided, patients should be monitored closely for signs and symptoms of liver toxicity including closer monitoring of liver enzymes. Consumption of alcohol should be avoided or minimised.
Potentially hepatotoxic agents include e.g. retinoids (e.g. acitretin, etretinate), azathioprine and leflunomide.
Hematotoxic agents: Hematotoxic medicinal products should not be taken during treatment with methotrexate. If concomitant administration cannot be avoided, patients should be monitored closely for signs and symptoms of hematotoxicity including close monitoring of blood count and platelets.
Administration of additional hematotoxic medicinal products (e.g. metamizole) increases the probability of severe hematotoxic effects of methotrexate. Concomitant administration with leflunomide increases the risk for pancytopenia.
In the case of (pre-) treatment with medicinal products, which may have adverse reactions on the bone marrow (e.g. sulfonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause acute megaloblastic pancytopenia in rare instances.
Medicinal products that affect folate levels and folic acid-containing vitamin products: The concomitant administration of products that cause folate deficiency (e.g. sulfonamides, trimethoprim sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore advisable in the presence of existing folic acid deficiency.
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.
Although the combination of methotrexate and sulfasalazine can cause an increase in the efficacy of methotrexate and as a result, more undesirable effects due to the inhibition of folic acid synthesis through sulfasalazine, such undesirable effects have only been observed in rare individual cases in the course of several studies.
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.
Ciclosporin: Ciclosporin may potentiate methotrexate efficacy and toxicity. There is a risk of excessive immunosuppression with a risk of lymphoproliferation when the combination is used.
Pharmacokinetic interactions: Interactions that may increase methotrexate levels: Frequent patient monitoring is necessary especially if high methotrexate doses are administered concomitantly with medicinal products, which reduce methotrexate protein binding, eliminate of methotrexate, or cause kidney damage. If concomitant use cannot be avoided, consider dose adjustment of methotrexate. Monitoring of methotrexate serum levels may be useful.
Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the elimination of methotrexate and higher serum concentrations may be assumed to induce higher hematological toxicity.
Methotrexate is plasma protein bound and certain drugs such as oral hypoglycaemics, thiazide diuretics, sulfonamides, phenytoin, barbiturates, tranquilizers, oral contraceptives, amidopyrine derivatives, doxorubicin, p-aminobenzoic acid, some antibiotics such as penicillin, tetracyclines, chloramphenicol decrease this binding, which can lead to increased toxicity when used concurrently.
There is also a possibility of increased toxicity when low-dose methotrexate and non-steroidal anti-inflammatory medicinal products or salicylates are combined. NSAIDs may cause kidney damage.
Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.
A 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.
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 hematological and gastrointestinal toxicity may occur.
The application of procarbazine during high-dose methotrexate therapy increases the risk of impairment of renal function. Delayed methotrexate clearance should also be considered in combination with other cytostatic medicinal products.
Interactions that may reduce methotrexate levels: Concomitant use of enzyme-inducing anticonvulsants (carbamazepine, phenytoin, phenobarbital, primidone) may decrease the methotrexate exposure and impair its therapeutic effect. If used concomitantly, dose adjustment of methotrexate should be considered. Monitoring of methotrexate serum levels may be useful.
Cholestyramine can increase the non-renal elimination of methotrexate by interrupting the enterohepatic circulation. If cholestyramine administration cannot be avoided doses of cholestyramine and methotrexate should be separated as much as possible.
Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the bacterial metabolism.
Methotrexate effects on other medicinal products: Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.
One should be aware of pharmacokinetic interactions between methotrexate and 5-fluorouracil (increased t½ of 5-fluorouracil). If coadministration is necessary, the patient should be monitored for 5-fluorouracil toxicity and dose adjustments should be considered if necessary.
Theophylline and caffeine: An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing soft drinks, 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.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.
Infection risk and vaccinations: Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections. 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.
Particularly in the case of orthopedic surgery where susceptibility to infection is high, a combination of methotrexate with immune-modulating medicinal products must be used with caution.
Radiotherapy: Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis.