Dirithromycin Theophylline

Drug interactions with dirithromycin have rarely been reported, since it does not interact with cytochrome P450. Nevertheless, in 13 healthy volunteers 500mg/day for 10 days caused a significant 18% fall in the average steady-state plasma theophylline concentration and a 26% fall in peak concentration, with a 14-15% increase in clearance (4). In contrast, the steady-state pharmacokinetics of theo-phylhne did not change in 14 patients with chronic obstructive airways disease who took dirithromycin for 10 days (5). 

Bachmann K, Nunlee M, Martin M, Sullivan T, Jauregui L, DeSante K, Sides GD. Changes in the steady-state pharmacokinetics of theophylline during treatment with dirithromycin. J Clin Pharmacol 1990 30(ll) 1001-5. Bachmann K, Jauregui L, Sides G, Sullivan TJ. Steady-state pharmacokinetics of theophylline in COPD patients treated with dirithromycin. J Clin Pharmacol 1993 33(9) 861-5. 

Troleandomycin can increase serum theophylline levels, causing toxicity if the dosage is not reduced. Azithromycin, clarithromycin, dirithromycin, josamycin, midecamycin, rokitamycin, spiramycin, and telithromycin normally only cause modest changes in theophylline levels or do not interact at all. There are unexplained and isolated case reports of theophylline toxicity with josamycin and clarithromycin. Roxithromycin usually has no relevant interaction but a significant increase in theophylline levels was seen in one study. See also Theophylline + Macrolides Erythromycin , p.ll87. 

In one study, 13 healthy subjects had a fall in their steady-state trough theophylline level of 18%, and a fall in their peak serum level of 26% while taking dirithromycin 500 mg daily for 10 days, although this was not considered clinically relevant. No significant changes in theophylline pharmacokinetics were seen in 14 patients with COPD who were given dirithromycin 500 mg daily for 10 days. This is supported by a similar single-dose study in 12 healthy subjects. ... 

It is believed that troleandomycin forms inactive cytochrome P450-metab-olite complexes within the liver, the effect of which is to reduce the metabolism (A/-demethylation and 8-hydroxylation) of theophylline, thereby reducing its clearance and increasing its levels. Clarithromycin, josamycin, midecamycin, and roxithromycin are thought to rarely form complexes, and azithromycin, dirithromycin, rokitamycin and spiramycin are not thought to inactivate cytochrome P450. ... 

The interaction between theophylline and troleandomycin is established and well documented. If troleandomycin is given, monitor the levels of theophylline closely and adjust the dose as necessary. Reductions of 25 to 50% may be needed. The situation with roxithromycin is uncertain since only 1 of 4 studies suggested an interaction, but it would be prudent to be alert for the need to reduce the theophylline dosage. Alternative mac-rolides that usually interact only moderately, or not at all are azithromycin, clarithromycin, dirithromycin, josamycin, midecamycin, rokitamycin and spiramycin. Telithromycin may also he a suitable alternative. However, even with these macrolides it would still be prudent to monitor the outcome because a few patients, especially those with theophylline levels at the high end of the range, may need some small theophylline dosage adjustments. In the case of azithromycin, care should be taken in adjusting the dose based on theophylline levels taken after about 5 days of concurrent use, as they may only he a reflection of a transient drop. In addition, acute infection perse may alter theophylline pharmacokineties. 

Bachmann K, Jauregui L, Sides G, Sullivan TJ. Steady-state pharmacc inetics of theophylline in COPD patients treated with dirithromycin. J Clin Pharmacol (1993) 33, 861-5. 

McConnell SA, Nafz er AN, Amsden GW. Lack of effect of dirithromycin on theophylline pharmacokinetics in healthy volunteers. J Antimicrob Chemother (1999) 43,733-6. 

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