Azithromycin Theophylline

Azithromycin Drugs that may interact with azithromycin include antacids, cyclosporine, HMG-CoA reductase inhibitors, pimozide, tacrolimus, theophyllines, and warfarin. Also consider all drug interactions with erythromycin. 

Metabolism Erythromycin is extensively metabolized and is known to inhibit the oxidation of a number of drugs through its interaction with the cytochrome P-450 system (see p. 14). Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity interference with the metabolism of drugs such as theophylline and carbamazepine has been reported. Azithromycin does not undergo metabolism. 

AZITHROMYCIN, CLARITHROMYCIN, ERYTHROMYCIN THEOPHYLUNE 1. t theophylline levels 2. Possibly i eiythromycin levels when given orally 1. Inhibition of CYP2D6-mediated metabolism of theophylline (macrolides and quinolones -isoniazid not known) 2.1 bioavailability uncertain mechanism 1. Monitor theophylline levels before, during and after co-administration 2. Consider an alternative macrolide... 

Macrolide Antibiotics. Erythromycin may significantly increase serum concentrations of medications such as theophylline by inhibiting their hepatic metabolism. Clarithromycin (Biaxin) and troleandomycin appear to interact with other medications in a manner similar to erythromycin, whereas azithromycin (Zithromax) is unlikely to interact with these agents. 

A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including theophylline (1,45). 

In two double-blind, randomized, placebo-controlled studies there was no inhibition of the metabolism of theophylline by azithromycin (53,54). However, there has been a report of reduced theophylline concentrations after withdrawal of azithromycin (55). The authors concluded that the mechanism of interaction was best explained by concomitant induction and inhibition of theophylline metabolism by azithromycin, followed by increased availability of unbound enzyme sites as azithromycin was cleared from the system. 

Gardner M, Coates P, Hilligoss D, Henry E. Lack of effect of azithromycin on the pharmacokinetics of theophylline in man. In Proceedings of the Mediterranean Congress of Chemotherapy, Athens, 1992. 

Poliak PT, Slayter KL. Reduced serum theophylline concentrations after discontinuation of azithromycin evidence for an unusual interaction. Pharmacotherapy 1997 17(4) 827-9. 

The effect of macrohdes on serum theophylline concentration and clearance has been investigated in 53 patients with moderate asthma treated with theophylline (400 mg/day) in a randomized trial reference. Erythromycin (500 mg bd) and roxithromycin (150 mg bd), but not clarithromycin (250 mg bd) or azithromycin (250 mg bd), caused increased serum theophylline concentrations and reduced clearance. 

Azithromycin Early evidence suggests that azithromycin does not inhibit hepatic drug metabolism. It does not appear to interact with carbamazepine, theophylline, or terfenadine. 

Concomitant administration of recombinant human a-interferon decreased theophylline clearance by 15%. Most macrolides are potent inhibitors of CYP3A4. Erythromycin and its salts as well as troleandomycin reduce theophylline Cl concentrahon-dependently 20-40% reduction after 5—7 days of therapy" " with erythromycin, 50% after 10 days with troleandomycin." Results for clarithromycin are similar to those for erythromycin." Azithromycin does not seem to influence theophylline metabolism, although reported results are contradictory. " ... 

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 an analysis of the safety data from clinical studies of azithromycin, there was no evidenee that the plasma levels of theophylline were affeeted in patients given both drugs. Similarly, no adverse effects were reported in another elinieal study of patients taking azithromyein and theophylline. Azithromyein 250 mg twiee daily did not affeet the elearanee or serum levels of theophylline in patients with asthma. However, a 68-year-old man had a marked but transient fall in his serum theophylline level when azithromyein was withdrawn, and this was eonfirmed on reehal-lenge. The same authors eondueted a study in 4 healthy subjeets given azithromyein 500 mg on day 1 then 250 mg daily for 4 days and sustained-release theophylline 200 mg twiee daily. Theophylline levels were slightly elevated during the use of azithromyein, and a transient drop oeeurred 5 days after azithromyein was stopped. ... 

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. 

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