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Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 24%. In patients receiving both azithromycin and antacids, the medicinal products should not be taken simultaneously, but with an interval of about 2 hours.
Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine (dideoxyinosine): Co-administration of 1,200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.
Digoxin and colchicine (P-gp substrates): Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.
It is necessary to perform clinical checks during the azithromycin treatment and possibly to measure serum digoxin levels.
Ergot derivatives: Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see Precautions).
Zidovudine: Single 1,000 mg doses and multiple 1,200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Pharmacokinetic studies have been conducted between azithromycin and the following medicinal products known to undergo significant cytochrome P450 mediated metabolism.
Atorvastatin: Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.
Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.
Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.
Coumarin-type oral anticoagulants: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.
Cyclosporin: In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these medicinal products. If co-administration of these medicinal products is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz: Co-administration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole: Co-administration of a single dose of 1,200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
Indinavir: Co-administration of a single dose of 1,200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.
Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
Midazolam: In healthy volunteers, co-administration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.
Nelfinavir: Co-administration of azithromycin (1,200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.
Rifabutin: Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either medicinal product.
Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see Adverse Reactions).
Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
Terfenadine: Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.
Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers.
Triazolam: In 14 healthy volunteers, co-administration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.
Trimethoprim/sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.
Other antibiotics: On a possible co-resistance between macrolide antibiotics and azithromycin (e.g. erythromycin) as well as lincomycin and clindamycin is to look at. Concomitant use of several medicinal products from the same group of substances is not recommended.
Medicinal products known to prolong the QT interval: Azithromycin should not be co-administered with other medicinal products, known to prolong the QT interval (see Precautions).
