Caution is warranted when azithromycin is administered to a patient with a history of a significant cardiac repolarization disorder or who is taking other medicinal products that cause a prolonged QT interval (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 8.5 Post-Market Adverse Reactions).
Concomitant administration of azithromycin with P-glycoprotein substrates may result in increased serum levels of P-glycoprotein substrates. Concomitant administration of P-glycoprotein inhibitors with azithromycin sustained-release form had minimal effect on the pharmacokinetics of azithromycin.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the cytochrome P450-related drug interactions seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inhibition via cytochrome metabolite complex does not occur with azithromycin.
| Proper name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| Antacids Aluminum and magnesium containing antacids (Maalox®) | CT | Reduce the peak serum levels but not the extent of azithromycin absorption | ZITHROMAX and these drugs should not be taken simultaneously |
| Carbamazepine | CT | 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 ZITHROMAX | |
| Cetirizine | CT | In healthy male 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. | |
| Cimetidine | CT | Administration of a single-dose of cimetidine (800 mg) two hours prior to ZITHROMAX had no effect on azithromycin absorption or on azithromycin pharmacokinetics. | |
| Coumarin-Type Oral Anticoagulants | CT | In a pharmacokinetic interaction study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered single 15 mg dose of warfarin Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants | Prothrombin times should be carefully monitored while patients are receiving azithromycin and concomitantly-administered oral anticoagulants. |
| Cyclosporine | CT | 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 cyclosporine, the resulting cyclosporine Cmax and AUC0‑5 were found to be significantly elevated | Caution should be exercised before considering concurrent administration of these drugs. If co administration of these drugs is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly. |
| Didanosine | CT | Daily doses of 1200 mg ZITHROMAX had no effect on the pharmacokinetics of didanosine | |
| Efavirenz | CT | Efavirenz, when administered at a dose of 400 mg for seven days produced a 22% increase in the Cmax of azithromycin administered as a 600 mg single dose. AUC was not affected. Administration of a single 600 mg dose of azithromycin immediate-release had no effect on the pharmacokinetics of efavirenz given at 400 mg doses for seven days. | |
| Fluconazole | CT | A single dose of 1200 mg azithromycin immediate-release did not alter the pharmacokinetics of a single 800 mg oral dose of fluconazole. Total exposure and half-life of 1200 mg azithromycin were unchanged and Cmax had a clinically insignificant decrease (18%) by coadministration with 800 mg fluconazole. | |
| HMG-CoA Reductase Inhibitors | CT | In healthy volunteers, co-administration of atorvastatin (10 mg daily) and azithromycin immediate-release (500 mg daily) did not alter plasma concentrations of atorvastatin (based on HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported. | |
| Indinavir | CT | A single dose of 1200 mg azithromycin immediate-release had no significant effect on the pharmacokinetics of indinavir (800 mg indinavir three times daily for 5 days). | |
| Midazolam | CT | In healthy volunteers (N=12), co-administration of azithromycin immediate-release 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 | CT | Coadministration of a single dose of 1200 mg azithromycin immediate-release with steady-state nelfinavir (750 mg three times daily) produced an approximately 16% decrease in mean AUC0-8 of nelfinavir and its M8 metabolite. Cmax was not affected. Coadministration of nelfinavir (750 mg three times daily) at steady-state with a single dose of 1200 mg azithromycin immediate-release increased the mean AUC0-¥ of azithromycin by 113% and mean Cmax by 136%. | Dose adjustment of ZITHROMAX is not recommended. However, close monitoring for known side effects of azithromycin, when administered in conjunction with nelfinavir, is warranted. |
| P-glycoprotein inhibitors | CT | Co-administration of P-glycoprotein inhibitors (Vitamin E, Poloxamer 407, or Poloxamer 124) with azithromycin sustained release form (1 gram dose) had minimal effect on the pharmacokinetics of azithromycin. | |
| Rifabutin | CT | Co-administration of ZITHROMAX and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment with azithromycin and rifabutin. | Neutropenia has been associated with the use of rifabutin, but it has not been established if concomitantly-administered azithromycin potentiates that effect (see 8 ADVERSE REACTIONS). |
| Sildenafil | CT | In normal healthy male volunteers, there was no evidence of a statistically significant effect of azithromycin immediate-release (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite. | |
| Theophylline | CT | Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. ZITHROMAX did not affect the pharmacokinetics of theophylline administered either as a single intravenous infusion or multiple oral doses at a recommended dose of 300 mg every 12 hours. There is one post-marketing report of supraventricular tachycardia associated with an elevated theophylline serum level that developed soon after initiation of treatment with ZITHROMAX. | Until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving ZITHROMAX and theophylline concomitantly. |
| Trimethoprim/ Sulfamethoxazole | CT | Co-administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin immediate-release 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. | |
| Zidovudine | CT | Single 1 g doses and multiple 1200 mg or 600 mg doses of ZITHROMAX did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of ZITHROMAX increased the concentrations of phosphorylated zidovudine, the clinically active metabolite in peripheral blood mononuclear cells. | |
| Legend: CT = Clinical Trial | |||
The following drug interactions have not been reported in clinical trials with azithromycin and no specific drug interaction studies have been performed to evaluate potential drug-drug interactions. Nonetheless, they have been observed with macrolide products, and there have been rare spontaneously reported cases with azithromycin and some of these drugs, in post marketing experience. Until further data are developed regarding drug interactions, when ZITHROMAX and these drugs are used concomitantly, careful monitoring of patients is advised both during and for a short period following therapy:
Prolongation of QT intervals, palpitations or cardiac arrhythmias have been reported with concomitant administration of azithromycin and astemizole or terfenadine.
Increased serum levels of hexobarbital, cisapride or phenytoin have been reported.
Concomitant administration of some macrolide antibiotics with P-glycoprotein substrates, including 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 digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycn and after its discontinuation are necessary.
Disopyramide: Azithromycin may increase the pharmacologic effect of disopyramide.
Azithromycin and ergot derivatives should not be co-administered due to the possibility that ergot toxicity may be precipitated by some macrolide antibiotics. Acute ergot toxicity is characterized by severe peripheral vasospasm including ischemia of the extremities, along with dysesthesia and possible central nervous system effects.
No data are available on the concomitant clinical use of azithromycin and gentamicin or other amphiphilic drugs which have been reported to alter intracellular lipid metabolism.
Azithromycin may decrease the clearance of triazolam and increase the pharmacologic effect of triazolam.
Azithromycin tablets and powder for oral suspension can be taken with or without food.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
)Caution is warranted when azithromycin is administered to a patient with a history of a significant cardiac repolarization disorder or who is taking other medicinal products that cause a prolonged QT interval (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 8.5 Post-Market Adverse Reactions).
Concomitant administration of azithromycin with P-glycoprotein substrates may result in increased serum levels of P-glycoprotein substrates. Concomitant administration of P-glycoprotein inhibitors with azithromycin sustained-release form had minimal effect on the pharmacokinetics of azithromycin.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the cytochrome P450-related drug interactions seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inhibition via cytochrome metabolite complex does not occur with azithromycin.
| Proper name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| Antacids Aluminum and magnesium containing antacids (Maalox®) | CT | Reduce the peak serum levels but not the extent of azithromycin absorption | ZITHROMAX and these drugs should not be taken simultaneously |
| Carbamazepine | CT | 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 ZITHROMAX | |
| Cetirizine | CT | In healthy male 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. | |
| Cimetidine | CT | Administration of a single-dose of cimetidine (800 mg) two hours prior to ZITHROMAX had no effect on azithromycin absorption or on azithromycin pharmacokinetics. | |
| Coumarin-Type Oral Anticoagulants | CT | In a pharmacokinetic interaction study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered single 15 mg dose of warfarin Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants | Prothrombin times should be carefully monitored while patients are receiving azithromycin and concomitantly-administered oral anticoagulants. |
| Cyclosporine | CT | 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 cyclosporine, the resulting cyclosporine Cmax and AUC0‑5 were found to be significantly elevated | Caution should be exercised before considering concurrent administration of these drugs. If co administration of these drugs is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly. |
| Didanosine | CT | Daily doses of 1200 mg ZITHROMAX had no effect on the pharmacokinetics of didanosine | |
| Efavirenz | CT | Efavirenz, when administered at a dose of 400 mg for seven days produced a 22% increase in the Cmax of azithromycin administered as a 600 mg single dose. AUC was not affected. Administration of a single 600 mg dose of azithromycin immediate-release had no effect on the pharmacokinetics of efavirenz given at 400 mg doses for seven days. | |
| Fluconazole | CT | A single dose of 1200 mg azithromycin immediate-release did not alter the pharmacokinetics of a single 800 mg oral dose of fluconazole. Total exposure and half-life of 1200 mg azithromycin were unchanged and Cmax had a clinically insignificant decrease (18%) by coadministration with 800 mg fluconazole. | |
| HMG-CoA Reductase Inhibitors | CT | In healthy volunteers, co-administration of atorvastatin (10 mg daily) and azithromycin immediate-release (500 mg daily) did not alter plasma concentrations of atorvastatin (based on HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported. | |
| Indinavir | CT | A single dose of 1200 mg azithromycin immediate-release had no significant effect on the pharmacokinetics of indinavir (800 mg indinavir three times daily for 5 days). | |
| Midazolam | CT | In healthy volunteers (N=12), co-administration of azithromycin immediate-release 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 | CT | Coadministration of a single dose of 1200 mg azithromycin immediate-release with steady-state nelfinavir (750 mg three times daily) produced an approximately 16% decrease in mean AUC0-8 of nelfinavir and its M8 metabolite. Cmax was not affected. Coadministration of nelfinavir (750 mg three times daily) at steady-state with a single dose of 1200 mg azithromycin immediate-release increased the mean AUC0-¥ of azithromycin by 113% and mean Cmax by 136%. | Dose adjustment of ZITHROMAX is not recommended. However, close monitoring for known side effects of azithromycin, when administered in conjunction with nelfinavir, is warranted. |
| P-glycoprotein inhibitors | CT | Co-administration of P-glycoprotein inhibitors (Vitamin E, Poloxamer 407, or Poloxamer 124) with azithromycin sustained release form (1 gram dose) had minimal effect on the pharmacokinetics of azithromycin. | |
| Rifabutin | CT | Co-administration of ZITHROMAX and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment with azithromycin and rifabutin. | Neutropenia has been associated with the use of rifabutin, but it has not been established if concomitantly-administered azithromycin potentiates that effect (see 8 ADVERSE REACTIONS). |
| Sildenafil | CT | In normal healthy male volunteers, there was no evidence of a statistically significant effect of azithromycin immediate-release (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite. | |
| Theophylline | CT | Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. ZITHROMAX did not affect the pharmacokinetics of theophylline administered either as a single intravenous infusion or multiple oral doses at a recommended dose of 300 mg every 12 hours. There is one post-marketing report of supraventricular tachycardia associated with an elevated theophylline serum level that developed soon after initiation of treatment with ZITHROMAX. | Until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving ZITHROMAX and theophylline concomitantly. |
| Trimethoprim/ Sulfamethoxazole | CT | Co-administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin immediate-release 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. | |
| Zidovudine | CT | Single 1 g doses and multiple 1200 mg or 600 mg doses of ZITHROMAX did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of ZITHROMAX increased the concentrations of phosphorylated zidovudine, the clinically active metabolite in peripheral blood mononuclear cells. | |
| Legend: CT = Clinical Trial | |||
The following drug interactions have not been reported in clinical trials with azithromycin and no specific drug interaction studies have been performed to evaluate potential drug-drug interactions. Nonetheless, they have been observed with macrolide products, and there have been rare spontaneously reported cases with azithromycin and some of these drugs, in post marketing experience. Until further data are developed regarding drug interactions, when ZITHROMAX and these drugs are used concomitantly, careful monitoring of patients is advised both during and for a short period following therapy:
Prolongation of QT intervals, palpitations or cardiac arrhythmias have been reported with concomitant administration of azithromycin and astemizole or terfenadine.
Increased serum levels of hexobarbital, cisapride or phenytoin have been reported.
Concomitant administration of some macrolide antibiotics with P-glycoprotein substrates, including 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 digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycn and after its discontinuation are necessary.
Disopyramide: Azithromycin may increase the pharmacologic effect of disopyramide.
Azithromycin and ergot derivatives should not be co-administered due to the possibility that ergot toxicity may be precipitated by some macrolide antibiotics. Acute ergot toxicity is characterized by severe peripheral vasospasm including ischemia of the extremities, along with dysesthesia and possible central nervous system effects.
No data are available on the concomitant clinical use of azithromycin and gentamicin or other amphiphilic drugs which have been reported to alter intracellular lipid metabolism.
Azithromycin may decrease the clearance of triazolam and increase the pharmacologic effect of triazolam.
Azithromycin tablets and powder for oral suspension can be taken with or without food.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
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