In one study 
theophylline clearance was reduced by 19% after 6 weeks of treatment with 
intramuscular methotrexate 15 mg weekly. A few patients complained of nausea and the 
theophylline dosage had to be reduced in one. 
 The 
clinical significance of this interaction is unclear as reductions of this 
 magnitude are rarely significant. It seems most likely to affect those patients with 
theophylline levels at the top of the therapeutic range.