Clinical relevance of the substitution of different brands of sustained-release theophylline.

In order to assess whether clinically important changes in serum theophylline concentrations occur when patients switch their brand of slow-release (SR) theophylline, 10 subjects with asthma were administered the same dose of four different SR theophylline formulations for 2-week periods in a random, double-blinded, crossover manner. Analysis of the data revealed significant differences in mean peak-to-trough fluctuations of serum theophylline concentrations between the formulations of SR theophylline, which varied from 60% to 106% of trough concentration (p less than 0.0001, analysis of variance). On at least one occasion in every subject, switching between brands of SR theophylline was responsible for raising the serum theophylline concentrations outside the accepted therapeutic range, and this was associated with symptoms of toxicity in five of the subjects. Worsening pulmonary functions were observed in two of the subjects whose switching resulted in lowered theophylline concentrations. Many of the formulation-related changes in theophylline concentrations appeared to be idiosyncratic and could not be predicted by the overall bioavailability differences between the drugs. These results argue against the open substitution of these formulations and suggest that if patients are switched between different brands of SR theophylline, their serum theophylline concentrations need to be closely monitored.