Methotrexate causes a modest reduction in theophylline clearance. Theophylline may reduce methotrexate-induced neurotoxicity, but there is possibility that it may also reducemethotrexate efficacy.
The apparent clearance of theophylline (given as oral aminophylline,choline theophyllinate or theophylline) was reduced by 19 % in 8 patients with severe, steroid-dependent asthma after 6 weeks of treatment with intramuscular methotrexate 15mg weekly. Three patients complained of nausea and theophylline dosage was reduced in one of them as theophylline level was more than 20 micrograms/mL (See reference number 1).
Four of 6 patients aged 3 to 16 years with acute lymphoblastic leukaemia and high-dose methotrexate-induced neurotoxicity had a complete resolution of their symptoms when they were given a 2.5-mg/kg aminophylline infusion over 1 hour. The other 2 had some improvement in symptoms. One patient also had symptom relief with rapid-release theophylline (See reference number 2). Similar results were reported for another child who developed neurotoxicity after receiving high-dose methotrexate. In this case,aminophylline was reported not to alter methotrexate levels (See reference number 3). A patient with methotrexate-induced leukoencephalopathy recovered after being given a combination of intravenous folinic acid with intravenous aminophylline 145mg daily for 7days (See reference number 4).
Theophylline is a competitive antagonist for adenosine receptors at serum concentrations within therapeutic range used in respiratory disease (See reference number 2)
The clinical importance of small reduction in theophylline clearance is uncertain, although it may be worth bearing this in mind in patients maintained at higher end of therapeutic levels for theophylline, as they may be more likely to develop toxicity. Aminophylline may reduce methotrexate-induced neurotoxicity, and, although there is some evidence that theophylline does not alter cytotoxic effects of methotrexate, this requires confirmation.(See reference number 2) One UK manufacturer of methotrexate (licenced for rheumatoid arthritis) recommends avoiding excessive consumption of caffeine and theophylline-containing drinks, however this recommendation appears to be based on studies and surveys which looked at effects of caffeine intake in patients taking low-dose, weekly methotrexate for rheumatoid arthritis or psoriasis,(See reference number 5,6) see Methotrexate + Caffeine interaction.
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