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Zithromax Preparations (Azithromycin Dihydrate)
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Pharmacology
Azithromycin, a macrolide antibiotic of the azalide subclass, exerts its antibacterial action by binding to the 50s ribosomal subunits of susceptible bacteria and suppressing protein synthesis.
Following oral administration, azithromycin is rapidly absorbed (T max=2to 3hours) and distributed widely throughout the body. Rapid movement of azithromycin from blood into tissue results in significantly higher azithromycin concentrations in tissue than in plasma (up to 50 times the maximum observed concentration in plasma). The absolute bioavailability is approximately 37%.
When azithromycin capsules were administered with food to 11adult healthy male subjects, the rate of absorption (C max) of azithromycin from the capsule formulation was reduced by 52% and the extent of absorption (AUC) by 43%. However, when azithromycin suspension was administered with food to 28adult healthy male subjects, the rate of absorption (C max) was increased by 56% while the extent of absorption (AUC) was unchanged. Therefore, azithromycin capsules and powder for oral suspension should be given 1hour before or 2hours after a meal.
Food does not affect the absorption of azithromycin in the tablet and the Single Dose 1g Packet dosage forms. Unlike the capsule and powder for oral suspension, azithromycin tablets and the Single Dose 1g Packet can be taken without regard to meals. Azithromycin tablets are bioequivalent to the capsule formulation; the oral suspension as a Single Dose 1g Packet is bioequivalent to four 250mg capsules or tablets.
Pharmacokinetics: Adults: Plasma concentrations of azithromycin decline in a polyphasic pattern, resulting in an average terminal half-life of 68hours. The prolonged half-life is likely due to extensive uptake and subsequent release of drug from tissues. Over the dose range of 250to 1000mg orally, the serum concentrations are related to dose. The long tissue half-life and large volume of distribution result from intracytoplasmic uptake and storage in lysosomal phospholipid complexes.
When studied in healthy elderly subjects from age 65to 85years, the pharmacokinetic parameters of azithromycin capsules in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30to 50%) were observed, no significant accumulation occurred. There are no pharmacokinetic data available from studies in hepatically or renally-impaired individuals.
Biliary excretion of azithromycin, predominantly as unchanged drug, is a main route of elimination.
I.V. Administration: In patients hospitalized with community-acquired pneumonia (CAP) receiving single daily 1-hour i.v. infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the median maximum concentration (C max) achieved was 3.00 µg/mL (range: 1.70 to 6.00 µg/mL) while the 24-hour trough level was 0.18 µg/mL (range: 0.07 to 0.60 µg/mL) and the AUC 24 was 8.50 µg.h/mL (range: 5.10 to 19.60 µg.h/mL). The median C max, 24-hour trough and AUC 24 values were 1.20 µg/mL (range: 0.89 to 1.36µg/mL), 0.18 µg/mL (range: 0.15 to 0.21 µg/mL) and 7.98 µg.h/mL (range: 6.45 to 9.80 µg.h/mL), respectively, in normal volunteers receiving a 3-hour i.v. infusion of 500 mg azithromycin at a concentration of 1mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with CAP that received the same 3-hour dosage regimen for 2 to 5 days.
The average Cl t and Vd values were 10.18 mL/min/kg and 33.3L/kg, respectively, in 18 normal volunteers receiving 1000 to 4000mg doses given as 1 mg/mL over 2 hours.
Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500mg i.v. azithromycin shows only an 8% increase in C max but a 61% increase in AUC 24 reflecting the 3-fold rise in C 24 trough levels.
In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) 1-hour i.v. dosage regimen for 5 days, the amount of administered azithromycin dose excreted in the urine in 24hours was about 11% after the first dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral azithromycin administration.
There are no pharmacokinetic data on azithromycin suspension when administered at a dose of 12mg/kg/day in the presence or absence of food.
Azithromycin, a macrolide antibiotic of the azalide subclass, exerts its antibacterial action by binding to the 50s ribosomal subunits of susceptible bacteria and suppressing protein synthesis.
Following oral administration, azithromycin is rapidly absorbed (T max=2to 3hours) and distributed widely throughout the body. Rapid movement of azithromycin from blood into tissue results in significantly higher azithromycin concentrations in tissue than in plasma (up to 50 times the maximum observed concentration in plasma). The absolute bioavailability is approximately 37%.
When azithromycin capsules were administered with food to 11adult healthy male subjects, the rate of absorption (C max) of azithromycin from the capsule formulation was reduced by 52% and the extent of absorption (AUC) by 43%. However, when azithromycin suspension was administered with food to 28adult healthy male subjects, the rate of absorption (C max) was increased by 56% while the extent of absorption (AUC) was unchanged. Therefore, azithromycin capsules and powder for oral suspension should be given 1hour before or 2hours after a meal.
Food does not affect the absorption of azithromycin in the tablet and the Single Dose 1g Packet dosage forms. Unlike the capsule and powder for oral suspension, azithromycin tablets and the Single Dose 1g Packet can be taken without regard to meals. Azithromycin tablets are bioequivalent to the capsule formulation; the oral suspension as a Single Dose 1g Packet is bioequivalent to four 250mg capsules or tablets.
Pharmacokinetics: Adults: Plasma concentrations of azithromycin decline in a polyphasic pattern, resulting in an average terminal half-life of 68hours. The prolonged half-life is likely due to extensive uptake and subsequent release of drug from tissues. Over the dose range of 250to 1000mg orally, the serum concentrations are related to dose. The long tissue half-life and large volume of distribution result from intracytoplasmic uptake and storage in lysosomal phospholipid complexes.
When studied in healthy elderly subjects from age 65to 85years, the pharmacokinetic parameters of azithromycin capsules in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30to 50%) were observed, no significant accumulation occurred. There are no pharmacokinetic data available from studies in hepatically or renally-impaired individuals.
Biliary excretion of azithromycin, predominantly as unchanged drug, is a main route of elimination.
I.V. Administration: In patients hospitalized with community-acquired pneumonia (CAP) receiving single daily 1-hour i.v. infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the median maximum concentration (C max) achieved was 3.00 µg/mL (range: 1.70 to 6.00 µg/mL) while the 24-hour trough level was 0.18 µg/mL (range: 0.07 to 0.60 µg/mL) and the AUC 24 was 8.50 µg.h/mL (range: 5.10 to 19.60 µg.h/mL). The median C max, 24-hour trough and AUC 24 values were 1.20 µg/mL (range: 0.89 to 1.36µg/mL), 0.18 µg/mL (range: 0.15 to 0.21 µg/mL) and 7.98 µg.h/mL (range: 6.45 to 9.80 µg.h/mL), respectively, in normal volunteers receiving a 3-hour i.v. infusion of 500 mg azithromycin at a concentration of 1mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with CAP that received the same 3-hour dosage regimen for 2 to 5 days.
The average Cl t and Vd values were 10.18 mL/min/kg and 33.3L/kg, respectively, in 18 normal volunteers receiving 1000 to 4000mg doses given as 1 mg/mL over 2 hours.
Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500mg i.v. azithromycin shows only an 8% increase in C max but a 61% increase in AUC 24 reflecting the 3-fold rise in C 24 trough levels.
In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) 1-hour i.v. dosage regimen for 5 days, the amount of administered azithromycin dose excreted in the urine in 24hours was about 11% after the first dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral azithromycin administration.
There are no pharmacokinetic data on azithromycin suspension when administered at a dose of 12mg/kg/day in the presence or absence of food.
Indications
Azithromycin, A Macrolide Antibiotic Of The Azalide Subclass, Exerts Its Antibacterial Action By Binding To The 50s Ribosomal Subunits Of Susceptible Bacteria And Suppressing Protein Synthesis.
Following Oral Administration, Azithromycin Is Rapidly Absorbed (T Max=2to 3hours) And Distributed Widely Throughout The Body. Rapid Movement Of Azithromycin From Blood Into Tissue Results In Significantly Higher Azithromycin Concentrations In Tissue Than In Plasma (up To 50 Times The Maximum Observed Concentration In Plasma). The Absolute Bioavailability Is Approximately 37%.
When Azithromycin Capsules Were Administered With Food To 11adult Healthy Male Subjects, The Rate Of Absorption (C Max) Of Azithromycin From The Capsule Formulation Was Reduced By 52% And The Extent Of Absorption (AUC) By 43%. However, When Azithromycin Suspension Was Administered With Food To 28adult Healthy Male Subjects, The Rate Of Absorption (C Max) Was Increased By 56% While The Extent Of Absorption (AUC) Was Unchanged. Therefore, Azithromycin Capsules And Powder For Oral Suspension Should Be Given 1hour Before Or 2hours After A Meal.
Food Does Not Affect The Absorption Of Azithromycin In The Tablet And The Single Dose 1g Packet Dosage Forms. Unlike The Capsule And Powder For Oral Suspension, Azithromycin Tablets And The Single Dose 1g Packet Can Be Taken Without Regard To Meals. Azithromycin Tablets Are Bioequivalent To The Capsule Formulation; The Oral Suspension As A Single Dose 1g Packet Is Bioequivalent To Four 250mg Capsules Or Tablets.
Pharmacokinetics: Adults: Plasma Concentrations Of Azithromycin Decline In A Polyphasic Pattern, Resulting In An Average Terminal Half-life Of 68hours. The Prolonged Half-life Is Likely Due To Extensive Uptake And Subsequent Release Of Drug From Tissues. Over The Dose Range Of 250to 1000mg Orally, The Serum Concentrations Are Related To Dose. The Long Tissue Half-life And Large Volume Of Distribution Result From Intracytoplasmic Uptake And Storage In Lysosomal Phospholipid Complexes.
When Studied In Healthy Elderly Subjects From Age 65to 85years, The Pharmacokinetic Parameters Of Azithromycin Capsules In Elderly Men Were Similar To Those In Young Adults; However, In Elderly Women, Although Higher Peak Concentrations (increased By 30to 50%) Were Observed, No Significant Accumulation Occurred. There Are No Pharmacokinetic Data Available From Studies In Hepatically Or Renally-impaired Individuals.
Biliary Excretion Of Azithromycin, Predominantly As Unchanged Drug, Is A Main Route Of Elimination.
I.V. Administration: In Patients Hospitalized With Community-acquired Pneumonia (CAP) Receiving Single Daily 1-hour I.v. Infusions For 2 To 5 Days Of 500 Mg Azithromycin At A Concentration Of 2 Mg/mL, The Median Maximum Concentration (C Max) Achieved Was 3.00 µg/mL (range: 1.70 To 6.00 µg/mL) While The 24-hour Trough Level Was 0.18 µg/mL (range: 0.07 To 0.60 µg/mL) And The AUC 24 Was 8.50 µg.h/mL (range: 5.10 To 19.60 µg.h/mL). The Median C Max, 24-hour Trough And AUC 24 Values Were 1.20 µg/mL (range: 0.89 To 1.36µg/mL), 0.18 µg/mL (range: 0.15 To 0.21 µg/mL) And 7.98 µg.h/mL (range: 6.45 To 9.80 µg.h/mL), Respectively, In Normal Volunteers Receiving A 3-hour I.v. Infusion Of 500 Mg Azithromycin At A Concentration Of 1mg/mL. Similar Pharmacokinetic Values Were Obtained In Patients Hospitalized With CAP That Received The Same 3-hour Dosage Regimen For 2 To 5 Days.
The Average Cl T And Vd Values Were 10.18 ML/min/kg And 33.3L/kg, Respectively, In 18 Normal Volunteers Receiving 1000 To 4000mg Doses Given As 1 Mg/mL Over 2 Hours.
Comparison Of The Plasma Pharmacokinetic Parameters Following The 1st And 5th Daily Doses Of 500mg I.v. Azithromycin Shows Only An 8% Increase In C Max But A 61% Increase In AUC 24 Reflecting The 3-fold Rise In C 24 Trough Levels.
In A Multiple-dose Study In 12 Normal Volunteers Utilizing A 500 Mg (1 Mg/mL) 1-hour I.v. Dosage Regimen For 5 Days, The Amount Of Administered Azithromycin Dose Excreted In The Urine In 24hours Was About 11% After The First Dose And 14% After The 5th Dose. These Values Are Greater Than The Reported 6% Excreted Unchanged In Urine After Oral Azithromycin Administration.
There Are No Pharmacokinetic Data On Azithromycin Suspension When Administered At A Dose Of 12mg/kg/day In The Presence Or Absence Of Food.
Azithromycin, A Macrolide Antibiotic Of The Azalide Subclass, Exerts Its Antibacterial Action By Binding To The 50s Ribosomal Subunits Of Susceptible Bacteria And Suppressing Protein Synthesis.
Following Oral Administration, Azithromycin Is Rapidly Absorbed (T Max=2to 3hours) And Distributed Widely Throughout The Body. Rapid Movement Of Azithromycin From Blood Into Tissue Results In Significantly Higher Azithromycin Concentrations In Tissue Than In Plasma (up To 50 Times The Maximum Observed Concentration In Plasma). The Absolute Bioavailability Is Approximately 37%.
When Azithromycin Capsules Were Administered With Food To 11adult Healthy Male Subjects, The Rate Of Absorption (C Max) Of Azithromycin From The Capsule Formulation Was Reduced By 52% And The Extent Of Absorption (AUC) By 43%. However, When Azithromycin Suspension Was Administered With Food To 28adult Healthy Male Subjects, The Rate Of Absorption (C Max) Was Increased By 56% While The Extent Of Absorption (AUC) Was Unchanged. Therefore, Azithromycin Capsules And Powder For Oral Suspension Should Be Given 1hour Before Or 2hours After A Meal.
Food Does Not Affect The Absorption Of Azithromycin In The Tablet And The Single Dose 1g Packet Dosage Forms. Unlike The Capsule And Powder For Oral Suspension, Azithromycin Tablets And The Single Dose 1g Packet Can Be Taken Without Regard To Meals. Azithromycin Tablets Are Bioequivalent To The Capsule Formulation; The Oral Suspension As A Single Dose 1g Packet Is Bioequivalent To Four 250mg Capsules Or Tablets.
Pharmacokinetics: Adults: Plasma Concentrations Of Azithromycin Decline In A Polyphasic Pattern, Resulting In An Average Terminal Half-life Of 68hours. The Prolonged Half-life Is Likely Due To Extensive Uptake And Subsequent Release Of Drug From Tissues. Over The Dose Range Of 250to 1000mg Orally, The Serum Concentrations Are Related To Dose. The Long Tissue Half-life And Large Volume Of Distribution Result From Intracytoplasmic Uptake And Storage In Lysosomal Phospholipid Complexes.
When Studied In Healthy Elderly Subjects From Age 65to 85years, The Pharmacokinetic Parameters Of Azithromycin Capsules In Elderly Men Were Similar To Those In Young Adults; However, In Elderly Women, Although Higher Peak Concentrations (increased By 30to 50%) Were Observed, No Significant Accumulation Occurred. There Are No Pharmacokinetic Data Available From Studies In Hepatically Or Renally-impaired Individuals.
Biliary Excretion Of Azithromycin, Predominantly As Unchanged Drug, Is A Main Route Of Elimination.
I.V. Administration: In Patients Hospitalized With Community-acquired Pneumonia (CAP) Receiving Single Daily 1-hour I.v. Infusions For 2 To 5 Days Of 500 Mg Azithromycin At A Concentration Of 2 Mg/mL, The Median Maximum Concentration (C Max) Achieved Was 3.00 µg/mL (range: 1.70 To 6.00 µg/mL) While The 24-hour Trough Level Was 0.18 µg/mL (range: 0.07 To 0.60 µg/mL) And The AUC 24 Was 8.50 µg.h/mL (range: 5.10 To 19.60 µg.h/mL). The Median C Max, 24-hour Trough And AUC 24 Values Were 1.20 µg/mL (range: 0.89 To 1.36µg/mL), 0.18 µg/mL (range: 0.15 To 0.21 µg/mL) And 7.98 µg.h/mL (range: 6.45 To 9.80 µg.h/mL), Respectively, In Normal Volunteers Receiving A 3-hour I.v. Infusion Of 500 Mg Azithromycin At A Concentration Of 1mg/mL. Similar Pharmacokinetic Values Were Obtained In Patients Hospitalized With CAP That Received The Same 3-hour Dosage Regimen For 2 To 5 Days.
The Average Cl T And Vd Values Were 10.18 ML/min/kg And 33.3L/kg, Respectively, In 18 Normal Volunteers Receiving 1000 To 4000mg Doses Given As 1 Mg/mL Over 2 Hours.
Comparison Of The Plasma Pharmacokinetic Parameters Following The 1st And 5th Daily Doses Of 500mg I.v. Azithromycin Shows Only An 8% Increase In C Max But A 61% Increase In AUC 24 Reflecting The 3-fold Rise In C 24 Trough Levels.
In A Multiple-dose Study In 12 Normal Volunteers Utilizing A 500 Mg (1 Mg/mL) 1-hour I.v. Dosage Regimen For 5 Days, The Amount Of Administered Azithromycin Dose Excreted In The Urine In 24hours Was About 11% After The First Dose And 14% After The 5th Dose. These Values Are Greater Than The Reported 6% Excreted Unchanged In Urine After Oral Azithromycin Administration.
There Are No Pharmacokinetic Data On Azithromycin Suspension When Administered At A Dose Of 12mg/kg/day In The Presence Or Absence Of Food.
Contraindications
In patients with known hypersensitivity to azithromycin, erythromycin, or other macrolide antibacterial agents.
In patients with known hypersensitivity to azithromycin, erythromycin, or other macrolide antibacterial agents.
Safety Information / Warning
Rare serious allergic reactions, including angioedema and anaphylaxis (with rare reports of fatalities) have been reported in patients on azithromycin therapy (see Contraindications). Allergic reactions may occur during and soon after treatment with azithromycin. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Pseudomembranous colitis has been reported with nearly all antibacterial agents including azithromycin and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C.difficile is a primary cause of “antibiotic-associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C.difficile .
In the absence of data on the metabolism and pharmacokinetics in patients with lysosomal lipid storage diseases (e.g., Tay-Sachs disease, Niemann-Pick disease) the use of azithromycin in these patients is not recommended.
Rare cases of acute hepatic necrosis requiring liver transplant have been reported in patients following treatment with oral azithromycin.
I.M. use of azithromycin is not recommended; extravasation of drug into the tissues may cause tissue injury.
Rare serious allergic reactions, including angioedema and anaphylaxis (with rare reports of fatalities) have been reported in patients on azithromycin therapy (see Contraindications). Allergic reactions may occur during and soon after treatment with azithromycin. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Pseudomembranous colitis has been reported with nearly all antibacterial agents including azithromycin and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C.difficile is a primary cause of “antibiotic-associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C.difficile .
In the absence of data on the metabolism and pharmacokinetics in patients with lysosomal lipid storage diseases (e.g., Tay-Sachs disease, Niemann-Pick disease) the use of azithromycin in these patients is not recommended.
Rare cases of acute hepatic necrosis requiring liver transplant have been reported in patients following treatment with oral azithromycin.
I.M. use of azithromycin is not recommended; extravasation of drug into the tissues may cause tissue injury.
Precautions
General: Since the liver is the major route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with impaired hepatic function.
No dose adjustment is needed in patients with mild renal impairment (creatinine clearance >40mL/min), but there are no data regarding azithromycin usage in patients with more severe renal impairment (creatinine clearance <40mL/min). Thus caution should be exercised before prescribing azithromycin in these patients.
Azithromycin for injection should be reconstituted and diluted as directed and administered as an i.v. infusion over at least 60 minutes (see Dosage).
Local injection site reactions have been reported with the i.v. administration of azithromycin. The incidence and severity of these reactions were the same when 500mg azithromycin was given over 1 hour (2mg/mL as 250mL infusion). All volunteers who received infusate concentrations above 2.0mg/mL experienced local i.v. site reactions; therefore, higher concentrations should be avoided.
The following adverse events have been reported with macrolide products: ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, in individuals with prolonged QT intervals. Although these adverse events have not been reported in clinical trials with azithromycin, one AIDS patient dosed at 750mg to 1g daily experienced prolonged QT interval and torsades de pointes.
Pregnancy: Animal studies have demonstrated that azithromycin crosses the placenta. Safety of azithromycin for use in human pregnancy has not been established.
Lactation: There are no data on secretion in breast milk. Safety of azithromycin for use in human lactation has not been established.
Children: Acute Otitis Media or Community-acquired Pneumonia: Safety and efficacy of azithromycin in the treatment of children with acute otitis media or community-acquired pneumonia (dosage regimen: 10mg/kg on day 1 followed by 5mg/kg ondays 2to5) under 6months of age have not been established.
Pharyngitis and Tonsillitis: Safety and efficacy of azithromycin in the treatment of children with pharyngitis and tonsillitis (dosage regimen: 12mg/kg on days 1to5) under 2years of age have not been established.
Studies evaluating the use of repeated courses of therapy have not been conducted. Safety data with the use of azithromycin at doses higher than proposed and for durations longer than recommended are limited to a small number of immunocompromised children who underwent chronic treatment.
In animal studies, treatment with azithromycin is associated with accumulation in various tissues, including the extracranial neural ganglia (i.e., retina and sympathetic nervous system). Tissue accumulation is both dose and time dependent, and is associated microscopically with the development of phospholipidosis (intra-lysosomal drug phospholipid complexes). The only evidence in animals that azithromycin is associated with alterations of intracellular phospholipid metabolism has been the documentation of small increases in phospholipid content after prolonged treatment (6months) or exaggerated doses. Phospholipidosis has been observed at total cumulative doses only 2 multiples of the clinical dose. One month after withdrawal of treatment the concentration of azithromycin and the presence of phospholipidosis in tissue, including the retina, is at or near predose levels.
No data exist in humans in regard to the extent of accumulation, duration of exposure, metabolism or excretory mechanisms of azithromycin in neural tissue such as the retina and the cochlea. Rare cases of hearing loss have been reported.
No data are available on the metabolism and pharmacokinetics of azithromycin in children with lysosomal lipid storage diseases.
The safety and effectiveness of azithromycin for injection in children or adolescents under 16years have not been established.
Prevention of Disseminated M.Avium Complex (MAC) Disease: Safety and efficacy of azithromycin for the prevention of MAC in children have not been established.
Limited safety data are available for 24children 5months to 14years of age (mean 4.6years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 186.7days (range 13to 710days) at doses of <5to 20mg/kg/day. Adverse events were similar to those observed in the adult population, most of which involved the gastrointestinal tract. While none of these children prematurely discontinued treatment due to a side effect, 1 child discontinued due to a laboratory abnormality (eosinophilia). Based on available pediatric pharmacokinetic data, a dose of 20mg/kg in children would provide drug exposure similar to the 1200mg adult dose but with a higher C max.
Geriatrics: The pharmacokinetics in elderly volunteers (age 65 to 85) were similar to those in younger volunteers (age 18 to 40) for the 5-day oral therapeutic regimen. Dosage adjustment does not appear to be necessary for elderly patients with normal renal and hepatic function receiving treatment with this dosage regimen. Pharmacokinetic studies with i.v. azithromycin have not been performed in the elderly. Based on clinical trials, there appear to be no significant differences in safety or tolerance of i.v. azithromycin between elderly (age ³65) and younger subjects (ages 16 to £64).
Drug Interactions : Antacids: Aluminum and magnesium containing antacids (Maalox) reduce the peak serum levels but not the extent of azithromycin absorption. These drugs should not be taken simultaneously.
Cimetidine: Administration of cimetidine (800mg) 2hours prior to azithromycin had no effect on azithromycin absorption.
Fluconazole: A single dose of 1200mg azithromycin did not alter the pharmacokinetics of a single 800mg oral dose of fluconazole.
Total exposure and half-life of 1200mg azithromycin were unchanged and C max had a clinically insignificant decrease (18%) by coadministration with 800mg fluconazole.
Trimethoprim/Sulfamethoxazole: Following administration of trimethoprim/sulfamethoxazole DS (160mg/800mg) for 7 days to healthy subjects, coadministration of 1200mg azithromycin on Day 7 had no significant effects on peak concentrations or total exposure or urinary excretion of either trimethoprim or sulfamethoxazole.
Serum concentrations of azithromycin following administration of a single 1200mg dose after administration of trimethoprim/sulfamethoxazole DS for 7 days were similar to those produced following a 1200mg dose of azithromycin in other studies.
Theophylline: Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. Azithromycin did not affect the pharmacokinetics of theophylline administered either as a single i.v. infusion or multiple oral doses at a recommended dose of 300mg every 12hours. There is 1postmarketing report of supraventricular tachycardia associated with an elevated theophylline serum level that developed soon after initiation of treatment with azithromycin. Until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving azithromycin and theophylline concomitantly.
Coumarin-type Oral Anticoagulants: In clinical trials, azithromycin did not affect the prothrombin time response to a single dose of warfarin.
During the postmarketing period, there have been reports of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin-type oral anticoagulants.
Although a causal relationship has not been established, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.
Zidovudine: Single 1g doses and multiple 1200mg or 600mg doses of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine in peripheral blood mononuclear cells.
Nelfinavir: Coadministration of a single dose of 1200mg azithromycin with steady-state nelfinavir (750mg t.i.d.) produced an approximately 16% decrease in mean AUC 0-8 of nelfinavir and its M8 metabolite. C max was not affected.
Coadministration of nelfinavir (750mg t.i.d.) at steady-state with a single dose of 1200mg azithromycin increased the mean AUC 0Ã¥ of azithromycin by 113% and mean C max by 136%.
Dose adjustment of azithromycin is not recommended. However, close monitoring for known side effects of azithromycin, when administered in conjunction with nelfinavir, is warranted.
Indinavir: A single dose of 1200mg azithromycin had no significant effect on the pharmacokinetics of indinavir (800mg indinavir t.i.d. for 5 days).
Efavirenz: Efavirenz, when administered at a dose of 400mg for 7days produced a 22% increase in the C max of azithromycin administered as a 600mg single dose. AUC was not affected.
Administration of a single 600mg dose of azithromycin had no effect on the pharmacokinetics of efavirenz given at 400mg doses for 7days.
Didanosine: Daily doses of 1200mg azithromycin had no effect on the pharmacokinetics of didanosine.
Rifabutin: Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug.
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.
Sildenafil: In normal healthy male volunteers, there was no evidence of a statistically significant effect of azithromycin (500mg daily for 3 days) on the AUC, C max, T max, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite.
Concomitant Therapy: 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 postmarketing experience. Until further data are developed regarding drug interactions, when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised both during and for a short period following therapy:
Digoxin: Elevation of digoxin levels.
Disopyramide: Increase in pharmacological effects.
Ergotamine or Dihydroergotamine: Acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Triazolam: Decreases in the clearance of triazolam and increases in the pharmacologic effect of triazolam.
Drugs Metabolized by the Cytochrome P450 System: Elevations of serum cyclosporine, hexobarbital, cisapride, and phenytoin levels.
Antihistamines: Prolongation of QT intervals, palpitations or cardiac arrhythmias with concomitant administration of astemizole or terfenadine.
No data are available on the concomitant clinical use of azithromycin and gentamicin or other amphophilic drugs which have been reported to alter intracellular lipid metabolism.
General: Since the liver is the major route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with impaired hepatic function.
No dose adjustment is needed in patients with mild renal impairment (creatinine clearance >40mL/min), but there are no data regarding azithromycin usage in patients with more severe renal impairment (creatinine clearance <40mL/min). Thus caution should be exercised before prescribing azithromycin in these patients.
Azithromycin for injection should be reconstituted and diluted as directed and administered as an i.v. infusion over at least 60 minutes (see Dosage).
Local injection site reactions have been reported with the i.v. administration of azithromycin. The incidence and severity of these reactions were the same when 500mg azithromycin was given over 1 hour (2mg/mL as 250mL infusion). All volunteers who received infusate concentrations above 2.0mg/mL experienced local i.v. site reactions; therefore, higher concentrations should be avoided.
The following adverse events have been reported with macrolide products: ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, in individuals with prolonged QT intervals. Although these adverse events have not been reported in clinical trials with azithromycin, one AIDS patient dosed at 750mg to 1g daily experienced prolonged QT interval and torsades de pointes.
Pregnancy: Animal studies have demonstrated that azithromycin crosses the placenta. Safety of azithromycin for use in human pregnancy has not been established.
Lactation: There are no data on secretion in breast milk. Safety of azithromycin for use in human lactation has not been established.
Children: Acute Otitis Media or Community-acquired Pneumonia: Safety and efficacy of azithromycin in the treatment of children with acute otitis media or community-acquired pneumonia (dosage regimen: 10mg/kg on day 1 followed by 5mg/kg ondays 2to5) under 6months of age have not been established.
Pharyngitis and Tonsillitis: Safety and efficacy of azithromycin in the treatment of children with pharyngitis and tonsillitis (dosage regimen: 12mg/kg on days 1to5) under 2years of age have not been established.
Studies evaluating the use of repeated courses of therapy have not been conducted. Safety data with the use of azithromycin at doses higher than proposed and for durations longer than recommended are limited to a small number of immunocompromised children who underwent chronic treatment.
In animal studies, treatment with azithromycin is associated with accumulation in various tissues, including the extracranial neural ganglia (i.e., retina and sympathetic nervous system). Tissue accumulation is both dose and time dependent, and is associated microscopically with the development of phospholipidosis (intra-lysosomal drug phospholipid complexes). The only evidence in animals that azithromycin is associated with alterations of intracellular phospholipid metabolism has been the documentation of small increases in phospholipid content after prolonged treatment (6months) or exaggerated doses. Phospholipidosis has been observed at total cumulative doses only 2 multiples of the clinical dose. One month after withdrawal of treatment the concentration of azithromycin and the presence of phospholipidosis in tissue, including the retina, is at or near predose levels.
No data exist in humans in regard to the extent of accumulation, duration of exposure, metabolism or excretory mechanisms of azithromycin in neural tissue such as the retina and the cochlea. Rare cases of hearing loss have been reported.
No data are available on the metabolism and pharmacokinetics of azithromycin in children with lysosomal lipid storage diseases.
The safety and effectiveness of azithromycin for injection in children or adolescents under 16years have not been established.
Prevention of Disseminated M.Avium Complex (MAC) Disease: Safety and efficacy of azithromycin for the prevention of MAC in children have not been established.
Limited safety data are available for 24children 5months to 14years of age (mean 4.6years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 186.7days (range 13to 710days) at doses of <5to 20mg/kg/day. Adverse events were similar to those observed in the adult population, most of which involved the gastrointestinal tract. While none of these children prematurely discontinued treatment due to a side effect, 1 child discontinued due to a laboratory abnormality (eosinophilia). Based on available pediatric pharmacokinetic data, a dose of 20mg/kg in children would provide drug exposure similar to the 1200mg adult dose but with a higher C max.
Geriatrics: The pharmacokinetics in elderly volunteers (age 65 to 85) were similar to those in younger volunteers (age 18 to 40) for the 5-day oral therapeutic regimen. Dosage adjustment does not appear to be necessary for elderly patients with normal renal and hepatic function receiving treatment with this dosage regimen. Pharmacokinetic studies with i.v. azithromycin have not been performed in the elderly. Based on clinical trials, there appear to be no significant differences in safety or tolerance of i.v. azithromycin between elderly (age ³65) and younger subjects (ages 16 to £64).
Drug Interactions : Antacids: Aluminum and magnesium containing antacids (Maalox) reduce the peak serum levels but not the extent of azithromycin absorption. These drugs should not be taken simultaneously.
Cimetidine: Administration of cimetidine (800mg) 2hours prior to azithromycin had no effect on azithromycin absorption.
Fluconazole: A single dose of 1200mg azithromycin did not alter the pharmacokinetics of a single 800mg oral dose of fluconazole.
Total exposure and half-life of 1200mg azithromycin were unchanged and C max had a clinically insignificant decrease (18%) by coadministration with 800mg fluconazole.
Trimethoprim/Sulfamethoxazole: Following administration of trimethoprim/sulfamethoxazole DS (160mg/800mg) for 7 days to healthy subjects, coadministration of 1200mg azithromycin on Day 7 had no significant effects on peak concentrations or total exposure or urinary excretion of either trimethoprim or sulfamethoxazole.
Serum concentrations of azithromycin following administration of a single 1200mg dose after administration of trimethoprim/sulfamethoxazole DS for 7 days were similar to those produced following a 1200mg dose of azithromycin in other studies.
Theophylline: Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. Azithromycin did not affect the pharmacokinetics of theophylline administered either as a single i.v. infusion or multiple oral doses at a recommended dose of 300mg every 12hours. There is 1postmarketing report of supraventricular tachycardia associated with an elevated theophylline serum level that developed soon after initiation of treatment with azithromycin. Until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving azithromycin and theophylline concomitantly.
Coumarin-type Oral Anticoagulants: In clinical trials, azithromycin did not affect the prothrombin time response to a single dose of warfarin.
During the postmarketing period, there have been reports of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin-type oral anticoagulants.
Although a causal relationship has not been established, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.
Zidovudine: Single 1g doses and multiple 1200mg or 600mg doses of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine in peripheral blood mononuclear cells.
Nelfinavir: Coadministration of a single dose of 1200mg azithromycin with steady-state nelfinavir (750mg t.i.d.) produced an approximately 16% decrease in mean AUC 0-8 of nelfinavir and its M8 metabolite. C max was not affected.
Coadministration of nelfinavir (750mg t.i.d.) at steady-state with a single dose of 1200mg azithromycin increased the mean AUC 0Ã¥ of azithromycin by 113% and mean C max by 136%.
Dose adjustment of azithromycin is not recommended. However, close monitoring for known side effects of azithromycin, when administered in conjunction with nelfinavir, is warranted.
Indinavir: A single dose of 1200mg azithromycin had no significant effect on the pharmacokinetics of indinavir (800mg indinavir t.i.d. for 5 days).
Efavirenz: Efavirenz, when administered at a dose of 400mg for 7days produced a 22% increase in the C max of azithromycin administered as a 600mg single dose. AUC was not affected.
Administration of a single 600mg dose of azithromycin had no effect on the pharmacokinetics of efavirenz given at 400mg doses for 7days.
Didanosine: Daily doses of 1200mg azithromycin had no effect on the pharmacokinetics of didanosine.
Rifabutin: Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug.
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.
Sildenafil: In normal healthy male volunteers, there was no evidence of a statistically significant effect of azithromycin (500mg daily for 3 days) on the AUC, C max, T max, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite.
Concomitant Therapy: 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 postmarketing experience. Until further data are developed regarding drug interactions, when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised both during and for a short period following therapy:
Digoxin: Elevation of digoxin levels.
Disopyramide: Increase in pharmacological effects.
Ergotamine or Dihydroergotamine: Acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Triazolam: Decreases in the clearance of triazolam and increases in the pharmacologic effect of triazolam.
Drugs Metabolized by the Cytochrome P450 System: Elevations of serum cyclosporine, hexobarbital, cisapride, and phenytoin levels.
Antihistamines: Prolongation of QT intervals, palpitations or cardiac arrhythmias with concomitant administration of astemizole or terfenadine.
No data are available on the concomitant clinical use of azithromycin and gentamicin or other amphophilic drugs which have been reported to alter intracellular lipid metabolism.
Side Effects / Adverse Effects
General: The majority of side effects observed in controlled clinical trials involving patients (adults and children) treated with azithromycin were of a mild and transient nature. Approximately 0.7% of both adult patients (n=3812) and children (n=2878) who had multiple doses of azithromycin discontinued therapy because of drug-related side effects. Among adults receiving azithromycin i.v., 1.2% of CAP, and 2% of PID patients discontinued treatment. Discontinuation rates were slightly higher for PID patients receiving concomitant metronidazole therapy (4%). Most of the side effects leading to discontinuation in patients on oral or i.v. therapy were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, along with abdominal pain, rashes and increases in aminotransferases and/or alkaline phosphatase levels in adult patients receiving i.v. azithromycin. Potentially serious side effects including angioedema and cholestatic jaundice occurred in less than 1% of patients.
Oral Regimen: Multiple-dose Regimen (Adults and Children): In adult patients, the most common side effects in patients receiving the multiple-dose regimen of azithromycin were related to the gastrointestinal system with diarrhea (4.3%), abdominal pain (2.6%), vomiting (1.3%) and nausea (3.5%). In children (n=1944) enrolled in North American controlled clinical trials in acute otitis media and S.pyogenes pharyngitis, the type of side effects was comparable to that seen in adults, with diarrhea/loose stools (5.3%), vomiting (3.6%), abdominal pain (2.6%), nausea (1%), rash (1%) and headache (1%) the most frequently reported.
Different side effect incidence rates for the twodosage regimens recommended in children were observed:
Acute Otitis Media: For the recommended dosage regimen of 10mg/kg on day 1 followed by 5mg/kg on days 2to5, the most frequent side effects were diarrhea/loose stools (2%), abdominal pain (2%), vomiting (1%) and nausea (1%).
In the North American controlled clinical trial in community-acquired pneumonia in children (n=310) the following were the most frequent side effects for the recommended dosage regimen of 10mg/kg on day 1followed by 5mg/kg on days 2to 5: diarrhea/loose stools (6%), abdominal pain (2%), and vomiting (2%).
Pharyngitis/Tonsillitis: For the recommended dosage regimen of 12mg/kg ondays 1to5, the most frequent side effects were diarrhea/loose stools (6%), vomiting (5%), abdominal pain (3%), nausea (2%), and headache (1%).
Side effects that occurred with a frequency of 1% or less in patients included the following:
Cardiovascular: palpitations, chest pain.
Gastrointestinal: dyspepsia, flatulence, vomiting, melena, cholestatic jaundice, constipation, anorexia, and gastritis.
Genitourinary: monilia, vaginitis, and nephritis.
Nervous System: dizziness, headache, vertigo, somnolence, agitation, nervousness, insomnia, and hyperkinesia.
General: fatigue, fever, and malaise.
Allergic: rash, photosensitivity, angioedema, erythema multiforme, pruritus, and urticaria.
Single 1g Dose Regimen (Adults): In adult patients (n=904), side effects that occurred on the single 1g dosing regimen of azithromycin with a frequency greater than 1% included diarrhea (6.1%), nausea (4.9%), abdominal pain (4.9%), vomiting (1.7%), vaginitis (1.3%), loose stools (1.2%), and dyspepsia (1.1%).
Single 2g Dose Regimen (Adults): Overall, the most common side effects in patients receiving a single 2g dose of azithromycin were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of a 1% or greater included nausea (18.2%), diarrhea/loose stools (13.8%), vomiting (6.7%), abdominal pain (6.7%), vaginitis (2.2%), dyspepsia (1.1%), and dizziness (1.3%). The majority of these complaints were mild in nature.
Postmarketing Experience: The following adverse experiences have been reported in patients under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain or in patients treated with significantly higher than the recommended doses for prolonged periods:
Allergic: arthralgia, edema, anaphylaxis (with rare reports of fatalities), serum sickness, urticaria, vasculitis.
Cardiovascular: cardiac arrythmias (including ventricular tachycardia), palpitations.
Gastrointestinal: anorexia, constipation, dehydration, dyspepsia, flatulence, pancreatitis, pseudomembranous colitis, rare reports of tongue discoloration.
General: asthenia, paresthesia, muscle pain.
Genitourinary: interstitial nephritis, monilliasis, acute renal failure, nephrotic syndrome.
Hematopoietic: thrombocytopenia.
Liver/Biliary: abnormal liver function including drug-induced hepatitis and cholestatic jaundice have been reported. There have also been rare cases of hepatic necrosis and hepatic failure, which have rarely resulted in death.
Nervous System: aggressive reaction, anxiety, dizziness, headache, hyperactivity, seizure, somnolence.
Skin/Appendages: serious skin reactions including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus, vertigo, reports of taste perversion.
Prevention of M.Avium Complex (MAC) Disease: Chronic therapy with azithromycin 1200mgweekly regimen: The nature of side effects seen with the 1200mgweekly dosing regimen for the prevention of M.avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens.
Side effects related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In one of the studies, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients.
I.V./Oral Regimen (Adults): The most common side effects (greater than 1%) in adult patients who received sequential i.v./oral azithromycin in studies of community-acquired pneumonia were related to the gastrointestinal system: diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%). Approximately 12% of patients experienced a side effect related to the i.v. infusion; most common were pain at the site and/or during the infusion (6.5%) and local inflammation (3.1%).
In adult women who received sequential i.v./oral azithromycin in studies of pelvic inflammatory disease , the most common side effects (greater than 1%) were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most frequently reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was coadministered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), and application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%).
Side effects that occurred with a frequency of 1% or less included: Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis.
Nervous System: headache, somnolence.
Allergic: bronchospasm.
Special Senses: taste perversion.
Laboratory Abnormalities: Oral Therapy: Treatment: Adults: Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials in patients were reported as follows: with an incidence of 1to 2%, elevated serum creatine phosphokinase, potassium, ALT, GGT and AST. With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH and phosphate.
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose clinical trials involving more than 3000patients, 3patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1because of a renal function abnormality.
Prevention of M.Avium Complex (MAC) Disease: In these immunocompromised patients with advanced HIV infection, it was sometimes necessary to assess laboratory abnormalities developing on study with additional criteria if baseline values were outside the normal range.
In a phaseI drug interaction study performed in normal volunteers, 1of 6subjects given the combination of azithromycin and rifabutin, 1of 7given rifabutin alone and 0of 6given azithromycin alone developed a clinically significant neutropenia (<500cells/mm 3).
Treatment: Children: Significant abnormalities (irrespective of drug relationship) occurring during clinical trials were all reported at a frequency of less than 1%, but were similar in type to the adult pattern.
In multiple-dose clinical trials involving almost 3000pediatric patients, no patients discontinued therapy because of treatment-related abnormalities.
I.V. Therapy: With an incidence of 4 to 6%, elevated ALT, AST, and creatinine.
With an incidence of 1 to 3%, elevated LDH and bilirubin.
With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase.
In multiple dose clinical trials involving more than 750 patients treated with sequential i.v./oral azithromycin, less than 2% of patients discontinued therapy because of treatment-related liver enzyme abnormalities.
When follow-up was provided, changes in laboratory tests appeared to be reversible for both oral and i.v. dosing.
General: The majority of side effects observed in controlled clinical trials involving patients (adults and children) treated with azithromycin were of a mild and transient nature. Approximately 0.7% of both adult patients (n=3812) and children (n=2878) who had multiple doses of azithromycin discontinued therapy because of drug-related side effects. Among adults receiving azithromycin i.v., 1.2% of CAP, and 2% of PID patients discontinued treatment. Discontinuation rates were slightly higher for PID patients receiving concomitant metronidazole therapy (4%). Most of the side effects leading to discontinuation in patients on oral or i.v. therapy were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, along with abdominal pain, rashes and increases in aminotransferases and/or alkaline phosphatase levels in adult patients receiving i.v. azithromycin. Potentially serious side effects including angioedema and cholestatic jaundice occurred in less than 1% of patients.
Oral Regimen: Multiple-dose Regimen (Adults and Children): In adult patients, the most common side effects in patients receiving the multiple-dose regimen of azithromycin were related to the gastrointestinal system with diarrhea (4.3%), abdominal pain (2.6%), vomiting (1.3%) and nausea (3.5%). In children (n=1944) enrolled in North American controlled clinical trials in acute otitis media and S.pyogenes pharyngitis, the type of side effects was comparable to that seen in adults, with diarrhea/loose stools (5.3%), vomiting (3.6%), abdominal pain (2.6%), nausea (1%), rash (1%) and headache (1%) the most frequently reported.
Different side effect incidence rates for the twodosage regimens recommended in children were observed:
Acute Otitis Media: For the recommended dosage regimen of 10mg/kg on day 1 followed by 5mg/kg on days 2to5, the most frequent side effects were diarrhea/loose stools (2%), abdominal pain (2%), vomiting (1%) and nausea (1%).
In the North American controlled clinical trial in community-acquired pneumonia in children (n=310) the following were the most frequent side effects for the recommended dosage regimen of 10mg/kg on day 1followed by 5mg/kg on days 2to 5: diarrhea/loose stools (6%), abdominal pain (2%), and vomiting (2%).
Pharyngitis/Tonsillitis: For the recommended dosage regimen of 12mg/kg ondays 1to5, the most frequent side effects were diarrhea/loose stools (6%), vomiting (5%), abdominal pain (3%), nausea (2%), and headache (1%).
Side effects that occurred with a frequency of 1% or less in patients included the following:
Cardiovascular: palpitations, chest pain.
Gastrointestinal: dyspepsia, flatulence, vomiting, melena, cholestatic jaundice, constipation, anorexia, and gastritis.
Genitourinary: monilia, vaginitis, and nephritis.
Nervous System: dizziness, headache, vertigo, somnolence, agitation, nervousness, insomnia, and hyperkinesia.
General: fatigue, fever, and malaise.
Allergic: rash, photosensitivity, angioedema, erythema multiforme, pruritus, and urticaria.
Single 1g Dose Regimen (Adults): In adult patients (n=904), side effects that occurred on the single 1g dosing regimen of azithromycin with a frequency greater than 1% included diarrhea (6.1%), nausea (4.9%), abdominal pain (4.9%), vomiting (1.7%), vaginitis (1.3%), loose stools (1.2%), and dyspepsia (1.1%).
Single 2g Dose Regimen (Adults): Overall, the most common side effects in patients receiving a single 2g dose of azithromycin were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of a 1% or greater included nausea (18.2%), diarrhea/loose stools (13.8%), vomiting (6.7%), abdominal pain (6.7%), vaginitis (2.2%), dyspepsia (1.1%), and dizziness (1.3%). The majority of these complaints were mild in nature.
Postmarketing Experience: The following adverse experiences have been reported in patients under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain or in patients treated with significantly higher than the recommended doses for prolonged periods:
Allergic: arthralgia, edema, anaphylaxis (with rare reports of fatalities), serum sickness, urticaria, vasculitis.
Cardiovascular: cardiac arrythmias (including ventricular tachycardia), palpitations.
Gastrointestinal: anorexia, constipation, dehydration, dyspepsia, flatulence, pancreatitis, pseudomembranous colitis, rare reports of tongue discoloration.
General: asthenia, paresthesia, muscle pain.
Genitourinary: interstitial nephritis, monilliasis, acute renal failure, nephrotic syndrome.
Hematopoietic: thrombocytopenia.
Liver/Biliary: abnormal liver function including drug-induced hepatitis and cholestatic jaundice have been reported. There have also been rare cases of hepatic necrosis and hepatic failure, which have rarely resulted in death.
Nervous System: aggressive reaction, anxiety, dizziness, headache, hyperactivity, seizure, somnolence.
Skin/Appendages: serious skin reactions including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus, vertigo, reports of taste perversion.
Prevention of M.Avium Complex (MAC) Disease: Chronic therapy with azithromycin 1200mgweekly regimen: The nature of side effects seen with the 1200mgweekly dosing regimen for the prevention of M.avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens.
Side effects related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In one of the studies, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients.
I.V./Oral Regimen (Adults): The most common side effects (greater than 1%) in adult patients who received sequential i.v./oral azithromycin in studies of community-acquired pneumonia were related to the gastrointestinal system: diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%). Approximately 12% of patients experienced a side effect related to the i.v. infusion; most common were pain at the site and/or during the infusion (6.5%) and local inflammation (3.1%).
In adult women who received sequential i.v./oral azithromycin in studies of pelvic inflammatory disease , the most common side effects (greater than 1%) were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most frequently reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was coadministered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), and application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%).
Side effects that occurred with a frequency of 1% or less included: Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis.
Nervous System: headache, somnolence.
Allergic: bronchospasm.
Special Senses: taste perversion.
Laboratory Abnormalities: Oral Therapy: Treatment: Adults: Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials in patients were reported as follows: with an incidence of 1to 2%, elevated serum creatine phosphokinase, potassium, ALT, GGT and AST. With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH and phosphate.
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose clinical trials involving more than 3000patients, 3patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1because of a renal function abnormality.
Prevention of M.Avium Complex (MAC) Disease: In these immunocompromised patients with advanced HIV infection, it was sometimes necessary to assess laboratory abnormalities developing on study with additional criteria if baseline values were outside the normal range.
In a phaseI drug interaction study performed in normal volunteers, 1of 6subjects given the combination of azithromycin and rifabutin, 1of 7given rifabutin alone and 0of 6given azithromycin alone developed a clinically significant neutropenia (<500cells/mm 3).
Treatment: Children: Significant abnormalities (irrespective of drug relationship) occurring during clinical trials were all reported at a frequency of less than 1%, but were similar in type to the adult pattern.
In multiple-dose clinical trials involving almost 3000pediatric patients, no patients discontinued therapy because of treatment-related abnormalities.
I.V. Therapy: With an incidence of 4 to 6%, elevated ALT, AST, and creatinine.
With an incidence of 1 to 3%, elevated LDH and bilirubin.
With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase.
In multiple dose clinical trials involving more than 750 patients treated with sequential i.v./oral azithromycin, less than 2% of patients discontinued therapy because of treatment-related liver enzyme abnormalities.
When follow-up was provided, changes in laboratory tests appeared to be reversible for both oral and i.v. dosing.
Overdose
Symptoms and Treatment: Up to 15g cumulative dose of azithromycin over 10days has been administered in clinical trials without apparent adverse effect.
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
Symptoms and Treatment: Up to 15g cumulative dose of azithromycin over 10days has been administered in clinical trials without apparent adverse effect.
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
Recommended Dosage
Oral Therapy: Adults: Tablets: The tablets can be taken with or without food.
Skin and Skin Structure Infections, Upper and Lower Respiratory Tract Infections: The recommended dose for the treatment of individuals 16years of age and older is 500mg as a single dose on the first day followed by 250mg once daily on days 2through 5for a total dose of 1.5g.
Genitourinary: The recommended dose for the treatment of genital ulcer disease due to H.ducreyi (chancroid) and non-gonococcal urethritis and cervicitis due to C.trachomatis is: a single 1g (1000mg) oral dose. This dose can be administered as four 250mgtablets.
The recommended dose for the treatment of urethritis and cervicitis due to N.gonorrhoeae is: a single 2g (2000mg) dose. This dose can be administered as eight 250mgtablets.
Prevention of Disseminated M.Avium Complex (MAC) Disease: Tablets: The tablets may be taken without regard to food. The recommended dose is 1200mg (two 600mg tablets) taken once weekly. This dose may be continued with the approved dosage regimen of rifabutin.
Children: Powder for Oral Suspension: Should be given as a single daily dose at least 1hour before or 2hours after a meal.
Mixing Directions: Powder for Oral Suspension: Tap bottle to loosen powder. Add the directed volume of water. Shake well before each use. Oversized bottle provides shake space. Keep tightly closed. TableVIII indicates the volume of water to be used for reconstitution.
Acute Otitis Media or Community-acquired Pneumonia: The recommended dose of oral suspension for the treatment of children with acute otitis media or community-acquired pneumonia is 10mg/kg as a single-dose on the first day (not to exceed 500mg/day) followed by 5mg/kg ondays 2 through 5 (not to exceed 250mg/day), for a total dose of 30mg/kg.
I.V. Injection: Adults: Azithromycin for injection must be reconstituted and diluted as directed, and administered as an i.v. infusion over at least 60 minutes. Azithromycin for i.v. infusion should not be given as a bolus or an i.m. injection. I.V. therapy should be followed by oral azithromycin. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.
The infusate concentration and rate of infusion for azithromycin should be either 1 mg/mL over 3hours, or 2 mg/mL over 1 hour.
Community-acquired Pneumonia in Patients Who Require Initial I.V. Therapy: The recommended dose is 500 mg i.v. as a single daily infusion for at least 2 days followed by oral therapy at 500 mg daily to complete a 7- to 10-day course of therapy.
Pelvic Inflammatory Disease: The recommended dose is 500 mg i.v. as a single daily infusion for at least 1 day followed by oral therapy at 250 mg daily to complete a 7-day course of therapy. Note: If anaerobic organisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with azithromycin.
Reconstitution: Prepare the initial solution of azithromycin for injection by adding 4.8 mL of Sterile Water for Injection to the 500mg vial. Shake the vial until all of the drug is dissolved. Since the vial is evacuated, it is recommended that a standard 5mL (nonautomated) syringe be used to ensure that the exact volume of 4.8mL is dispensed. Each mL of reconstituted solution contains azithromycin dihydrate equivalent to 100 mg azithromycin. Reconstituted solution is stable for 24hours when stored below 30°C. The reconstituted solution must be further diluted prior to administration.
Diluted solutions prepared in this manner are stable for 24 hours at or below room temperature (30°C), or for 72 hours if stored under refrigeration (5°C). As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should be discarded.
Only limited data are available on the compatibility of Zithromax for Injection with other i.v. substances, therefore additives or other medications should not be added to Zithromax for Injection or infused simultaneously through the same i.v. line. If the same i.v. line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of Zithromax for Injection with an infusion solution compatible with Zithromax for Injection and with any other drug(s) administered via the common line. If Zithromax for Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each drug.
Note: Hepatic Impairment: In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients urinary recovery of azithromycin appears to increase. Hence no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Nonetheless, since the liver is the principal route of elimination for azithromycin, the use of this drug should be undertaken with caution in patients with significant hepatic disease.
Oral Therapy: Adults: Tablets: The tablets can be taken with or without food.
Skin and Skin Structure Infections, Upper and Lower Respiratory Tract Infections: The recommended dose for the treatment of individuals 16years of age and older is 500mg as a single dose on the first day followed by 250mg once daily on days 2through 5for a total dose of 1.5g.
Genitourinary: The recommended dose for the treatment of genital ulcer disease due to H.ducreyi (chancroid) and non-gonococcal urethritis and cervicitis due to C.trachomatis is: a single 1g (1000mg) oral dose. This dose can be administered as four 250mgtablets.
The recommended dose for the treatment of urethritis and cervicitis due to N.gonorrhoeae is: a single 2g (2000mg) dose. This dose can be administered as eight 250mgtablets.
Prevention of Disseminated M.Avium Complex (MAC) Disease: Tablets: The tablets may be taken without regard to food. The recommended dose is 1200mg (two 600mg tablets) taken once weekly. This dose may be continued with the approved dosage regimen of rifabutin.
Children: Powder for Oral Suspension: Should be given as a single daily dose at least 1hour before or 2hours after a meal.
Mixing Directions: Powder for Oral Suspension: Tap bottle to loosen powder. Add the directed volume of water. Shake well before each use. Oversized bottle provides shake space. Keep tightly closed. TableVIII indicates the volume of water to be used for reconstitution.
Acute Otitis Media or Community-acquired Pneumonia: The recommended dose of oral suspension for the treatment of children with acute otitis media or community-acquired pneumonia is 10mg/kg as a single-dose on the first day (not to exceed 500mg/day) followed by 5mg/kg ondays 2 through 5 (not to exceed 250mg/day), for a total dose of 30mg/kg.
I.V. Injection: Adults: Azithromycin for injection must be reconstituted and diluted as directed, and administered as an i.v. infusion over at least 60 minutes. Azithromycin for i.v. infusion should not be given as a bolus or an i.m. injection. I.V. therapy should be followed by oral azithromycin. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.
The infusate concentration and rate of infusion for azithromycin should be either 1 mg/mL over 3hours, or 2 mg/mL over 1 hour.
Community-acquired Pneumonia in Patients Who Require Initial I.V. Therapy: The recommended dose is 500 mg i.v. as a single daily infusion for at least 2 days followed by oral therapy at 500 mg daily to complete a 7- to 10-day course of therapy.
Pelvic Inflammatory Disease: The recommended dose is 500 mg i.v. as a single daily infusion for at least 1 day followed by oral therapy at 250 mg daily to complete a 7-day course of therapy. Note: If anaerobic organisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with azithromycin.
Reconstitution: Prepare the initial solution of azithromycin for injection by adding 4.8 mL of Sterile Water for Injection to the 500mg vial. Shake the vial until all of the drug is dissolved. Since the vial is evacuated, it is recommended that a standard 5mL (nonautomated) syringe be used to ensure that the exact volume of 4.8mL is dispensed. Each mL of reconstituted solution contains azithromycin dihydrate equivalent to 100 mg azithromycin. Reconstituted solution is stable for 24hours when stored below 30°C. The reconstituted solution must be further diluted prior to administration.
Diluted solutions prepared in this manner are stable for 24 hours at or below room temperature (30°C), or for 72 hours if stored under refrigeration (5°C). As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should be discarded.
Only limited data are available on the compatibility of Zithromax for Injection with other i.v. substances, therefore additives or other medications should not be added to Zithromax for Injection or infused simultaneously through the same i.v. line. If the same i.v. line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of Zithromax for Injection with an infusion solution compatible with Zithromax for Injection and with any other drug(s) administered via the common line. If Zithromax for Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each drug.
Note: Hepatic Impairment: In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients urinary recovery of azithromycin appears to increase. Hence no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Nonetheless, since the liver is the principal route of elimination for azithromycin, the use of this drug should be undertaken with caution in patients with significant hepatic disease.
Supplied / Packaging
Injection: Each single dose vial contains: azithromycin dihydrate in a lyophilized form equivalent to azithromycin 500 mg. Nonmedicinal ingredients: anhydrous citric acid and sodium hydroxide for pH adjustment. Cartons of 10. After reconstitution, each mL contains azithromycin dihydrate equivalent to 100 mg azithromycin (see Dosage, Mixing Directions). Dry powder: Store at controlled room temperature (15 to 30°C). Diluted solution: Stable for 24 hours at or below 30°C, or for 3 days if stored under refrigeration (5°C). For single use only. Discard any unused portion after use.
Tablets: 250mg: Each pink, film-coated, modified capsular-shaped tablet, engraved “Pfizer” on the upper face, “306” or scored on the lower face, contains: azithromycin dihydrate equivalent to azithromycin 250mg. Nonmedicinal ingredients: anhydrous calcium phosphate dibasic, D&C Red #30 aluminum lake, hydroxypropyl methylcellulose, lactose, magnesium stearate, pregelatinized starch, sodium croscarmellose, sodium lauryl sulfate, titanium dioxide and triacetin. White plastic (high density polyethylene) bottles of 30. Single treatment package (Z-PAK) of 6blister-packaged tablets per box. Store at controlled room temperature between 15and 30°C.
600mg: Each white, film-coated, modified capsular-shaped tablet, engraved on front with “Pfizer”, “308” or scored on the lower face, contains: azithromycin dihydrate equivalent to azithromycin 600mg. Nonmedicinal ingredients: anhydrous calcium phosphate dibasic, hydroxypropylmethylcellulose, lactose, magnesium stearate, pregelatinized starch, sodium croscarmellose, sodium lauryl sulfate, titanium dioxide and triacetin. White plastic (high density polyethylene) bottles of 30. Store at controlled room temperature between 15and 30°C.
Powder for Oral Suspension: After reconstitution, each bottle of cherry-flavored suspension contains: azithromycin dihydrate equivalent to: 300mg/15mL (100mg/5mL); 600mg/15mL (200mg/5mL); or 900mg/22.5mL (200mg/5mL). Nonmedicinal ingredients: artificial flavors, FD&C Red #40, sodium phosphate, sucrose, tribasic hydroxypropyl cellulose and xanthan gum. A graduated syringe is included in the package. Dry powder: Store at controlled room temperature (15 to 30°C). Reconstituted suspension: Store between 5 and 30°C. Discard unused portion after 10days.
Injection: Each single dose vial contains: azithromycin dihydrate in a lyophilized form equivalent to azithromycin 500 mg. Nonmedicinal ingredients: anhydrous citric acid and sodium hydroxide for pH adjustment. Cartons of 10. After reconstitution, each mL contains azithromycin dihydrate equivalent to 100 mg azithromycin (see Dosage, Mixing Directions). Dry powder: Store at controlled room temperature (15 to 30°C). Diluted solution: Stable for 24 hours at or below 30°C, or for 3 days if stored under refrigeration (5°C). For single use only. Discard any unused portion after use.
Tablets: 250mg: Each pink, film-coated, modified capsular-shaped tablet, engraved “Pfizer” on the upper face, “306” or scored on the lower face, contains: azithromycin dihydrate equivalent to azithromycin 250mg. Nonmedicinal ingredients: anhydrous calcium phosphate dibasic, D&C Red #30 aluminum lake, hydroxypropyl methylcellulose, lactose, magnesium stearate, pregelatinized starch, sodium croscarmellose, sodium lauryl sulfate, titanium dioxide and triacetin. White plastic (high density polyethylene) bottles of 30. Single treatment package (Z-PAK) of 6blister-packaged tablets per box. Store at controlled room temperature between 15and 30°C.
600mg: Each white, film-coated, modified capsular-shaped tablet, engraved on front with “Pfizer”, “308” or scored on the lower face, contains: azithromycin dihydrate equivalent to azithromycin 600mg. Nonmedicinal ingredients: anhydrous calcium phosphate dibasic, hydroxypropylmethylcellulose, lactose, magnesium stearate, pregelatinized starch, sodium croscarmellose, sodium lauryl sulfate, titanium dioxide and triacetin. White plastic (high density polyethylene) bottles of 30. Store at controlled room temperature between 15and 30°C.
Powder for Oral Suspension: After reconstitution, each bottle of cherry-flavored suspension contains: azithromycin dihydrate equivalent to: 300mg/15mL (100mg/5mL); 600mg/15mL (200mg/5mL); or 900mg/22.5mL (200mg/5mL). Nonmedicinal ingredients: artificial flavors, FD&C Red #40, sodium phosphate, sucrose, tribasic hydroxypropyl cellulose and xanthan gum. A graduated syringe is included in the package. Dry powder: Store at controlled room temperature (15 to 30°C). Reconstituted suspension: Store between 5 and 30°C. Discard unused portion after 10days.
Search for a drug
Brand Name
Zithromax Preparations
Zithromax Preparations
Generic Name
Azithromycin Dihydrate
Azithromycin Dihydrate
General Indications
Antibiotic
Antibiotic
