ZITHROMAX (azithromycin dihydrate) for oral administration is indicated for treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the following diseases and specific conditions. As recommended dosages, durations of therapy and applicable patient populations vary among these infections, see 4 DOSAGE AND ADMINISTRATION for specific dosing recommendations.
Because some strains are resistant to azithromycin, when applicable, appropriate culture and susceptibility tests should be initiated before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with ZITHROMAX may be initiated before results of these tests are known; once the results become available, antibiotic treatment should be adjusted accordingly.
Pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci) occurring in individuals who cannot use first line therapy.
NOTE: Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. ZITHROMAX is often effective in the eradication of susceptible strains of streptococci from the oropharynx. However, data establishing the efficacy of ZITHROMAX in the subsequent prevention of rheumatic fever are not available at present.
Acute bacterial exacerbations of chronic obstructive pulmonary diseases caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
Community-acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Chlamydia pneumoniae in patients for whom oral therapy is appropriate.
Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, patients with nosocomial acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or debilitated patients, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).
Uncomplicated skin and skin structure infections caused by Staphylococcus aureus, Streptococcus pyogenes or Streptococcus agalactiae.
Urethritis and cervicitis due to Neisseria gonorrhoeae or Chlamydia trachomatis. Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.
Patients should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed.
ZITHROMAX, taken at a dose of 1200 mg weekly, alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in persons with advanced HIV infections (see 14 CLINICAL TRIALS).
ZITHROMAX for Injection is indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
ZITHROMAX for Injection should be followed by oral administration of ZITHROMAX as required (see 4 DOSAGE AND ADMINISTRATION).
Community-acquired pneumonia (CAP) due to Chlamydia pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients who require initial intravenous therapy.
Pelvic inflammatory disease (PID) due to Chlamydia trachomatis, Neisseria gonorrhoeae or Mycoplasma hominis in patients who require initial intravenous therapy. If anaerobic organisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with ZITHROMAX.
Patients should have a serologic test for syphilis performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for this disease should be initiated if infection is confirmed.
Because some strains are resistant to azithromycin, appropriate culture and susceptibility tests should be initiated before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with ZITHROMAX may be initiated before results of these tests are known; once the results become available, antibiotic treatment should be adjusted accordingly.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZITHROMAX and other antibacterial drugs, ZITHROMAX should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Acute otitis media caused by Haemophilus influenzae (β-lactamase positive and negative strains), Moraxella catarrhalis or Streptococcus pneumoniae.
Pediatrics (<6 months): Safety and efficacy have not been established.
Pediatrics (< 2 years): Safety and efficacy have not been established.
Community-acquired pneumonia caused by Haemophilus influenzae, Streptococcus pneumoniae, Mycoplasma pneumoniae or Chlamydia pneumoniae in patients for whom oral therapy is appropriate.
Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for outpatient oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, patients with nosocomial acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).
Safety and effectiveness for pneumonia due to Haemophilus influenzae and Streptococcus pneumoniae were not documented bacteriologically in the pediatric clinical trial due to difficulty in obtaining specimens. Use of azithromycin for these two microorganisms is supported, however, by evidence from adequate and well-controlled studies in adults.
Pediatrics (< 6 months): Safety and efficacy have not been established.
See 4.2 Recommended Dose and Dosage Adjustment; 7.1.3 Pediatrics
ZITHROMAX for Injection
Pediatrics (< 16 years): The safety and effectiveness of ZITHROMAX for Injection have not been established.
See 7.1.3 Pediatrics
Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is not associated with differences in safety or effectiveness. However, elderly patients may be more susceptible to development of torsade de pointes arrhythmias. (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular; 7.1.4 Geriatrics; 10 CLINICAL PHARMACOLOGY)
ZITHROMAX (azithromycin dihydrate) is contraindicated:
ZITHROMAX immediate-release oral formulations (tablets or oral suspension) are not bioequivalent and are not interchangeable with azithromycin sustained release due to a different pharmacokinetic profile.
No dose adjustment of oral ZITHROMAX preparations is recommended for patients with mild to moderate hepatic impairment. Azithromycin has not been studied in patients with severe hepatic impairment. Since the liver is the principal route of elimination for azithromycin, the use of oral ZITHROMAX preparations should be undertaken with caution in patients with impaired hepatic function (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY). Due to the lack of data, ZITHROMAX for Injection should be used with caution in patients with hepatic impairment.
No dosage adjustment of oral ZITHROMAX preparations is recommended for subjects with GFR 10-80 mL/min. The mean AUC0-120 increased 35% in subjects with GFR 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).
Due to the lack of data, ZITHROMAX for Injection should be used with caution in patients with renal impairment (including patients on dialysis).
TABLETS: ZITHROMAX Tablets can be taken with or without food.
The recommended dose of ZITHROMAX for individuals 16 years of age or older in the treatment of mild to moderate acute bacterial exacerbations of chronic obstructive pulmonary disease due to the indicated organisms is: either 500 mg per day for 3 days or 500 mg as a single dose on the first day followed by 250 mg once daily on days 2 through 5 for a total dose of 1.5 grams.
The recommended dose of ZITHROMAX for the treatment of community-acquired pneumonia of mild severity, uncomplicated skin and skin structure infections, and for pharyngitis/tonsillitis (as second-line therapy) due to the indicated organisms is: 500 mg as a single dose on the first day followed by 250 mg once daily on days 2 through 5 for a total dose of 1.5 grams.
The recommended dose of ZITHROMAX for the treatment of genital ulcer disease due to Haemophilus ducreyi (chancroid) and non-gonococcal urethritis and cervicitis due to C. trachomatis is: a single 1 gram (1000 mg) oral dose of ZITHROMAX. This dose can be administered as four 250 mg tablets.
The recommended dose of ZITHROMAX for the treatment of urethritis and cervicitis due to Neisseria gonorrhoeae is: a single 2 gram (2000 mg) dose of ZITHROMAX. This dose can be administered as eight 250 mg tablets.
The recommended dose of ZITHROMAX for the prevention of disseminated Mycobacterium avium complex (MAC) disease is 1200 mg (two 600 mg tablets) taken once weekly. This dose of ZITHROMAX may be continued with the approved dosage regimen of rifabutin.
POWDER FOR ORAL SUSPENSION: ZITHROMAX Powder for Oral Suspension can be taken with or without food (see 10 CINICAL PHARMACOLOGY).
The recommended total dose for children is 30 mg/kg for otitis media and community acquired pneumonia. For pharyngitis/tonsillitis, the recommended total dose is 60 mg/kg.
The recommended dose of ZITHROMAX oral suspension for the treatment of children with acute otitis media is 30 mg/kg given as a single dose (not to exceed 1500 mg) or 10 mg/kg once daily for 3 days (not to exceed 500 mg/day) or 10 mg/kg as a single dose on the first day (not to exceed 500 mg/day) followed by 5 mg/kg/day on days 2 through 5 (not to exceed 250 mg/day). (See chart #1, 2 and 3 respectively below).
The safety of re-dosing azithromycin in children who vomit after receiving 30 mg/kg as a single dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, eight patients who vomited within 30 minutes of dosing were re-dosed at the same total dose.
The recommended dose of ZITHROMAX for oral suspension for the treatment of children with community-acquired pneumonia is 10 mg/kg as a single dose on the first day (not to exceed 500 mg/day) followed by 5 mg/kg on days 2 through 5 (not to exceed 250 mg/day). (See chart #3 below).
Effectiveness of the 3-day or 1-day regimen in children with community-acquired pneumonia has not been established.
The recommended dose for children with pharyngitis and tonsillitis is 12 mg/kg once daily for 5 days (not to exceed 500 mg/day). (See chart #4 below).
PEDIATRIC DOSAGE GUIDELINESBASED on BODY Weight
Effectiveness of the 1-day regimen in children with community-acquired pneumonia has not been established.
Effectiveness of the 3-day regimen in children with community-acquired pneumonia has not been established.
ZITHROMAX for Injection must be reconstituted and diluted, as directed, and administered as an intravenous infusion over at least 60 minutes. Do not administer as an intravenous bolus or an intramuscular injection (see 7 WARNINGS AND PRECAUTIONS). Intravenous therapy should be followed by oral ZITHROMAX. 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 ZITHROMAX should be either 1 mg/mL over 3 hours, or 2 mg/mL over 1 hour.
COMMUNITY-ACQUIRED PNEUMONIA: in patients who require initial intravenous 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 7-10 day course of therapy.
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 ZITHROMAX.
Tap bottle to loosen powder. Add the directed volume of water. Shake well before each use. Oversized bottle provides shake space. Keep tightly closed. The table below indicates the volume of water to be used for reconstitution:
Use only the dosing device provided to measure the correct amount of suspension (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING). The dosing device may need to be filled multiple times to provide the complete dose prescribed. Rinse the device with water after the complete daily dose has been administered.
Following constitution, and for use with the oral syringe, the supplied plastic stopper should be inserted into the neck of the bottle then sealed with the original closure.
ZITHROMAX for Injection:
Prepare the initial solution of ZITHROMAX for Injection by adding 4.8 mL of Sterile Water for Injection to the 500 mg vial. Shake the vial until all of the drug is dissolved. Since the vial is evacuated, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact volume of 4.8 mL is dispensed. Each mL of reconstituted solution contains azithromycin dihydrate equivalent to 100 mg azithromycin. Reconstituted solution is stable for 24 hours when stored below 30°C. The reconstituted solution must be further diluted prior to administration.
Dilution of reconstituted solution: To provide azithromycin over a concentration range of 1.0 - 2.0 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of the following diluents:
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 (2-8°C). As with all parenteral drug products, intravenous 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 intravenous substances, therefore additives or other medications should not be added to ZITHROMAX for Injection or infused simultaneously through the same intravenous line. If the same intravenous 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.
In case of missed dose, patients should not double the next dose.
Activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended.
Ototoxicity and gastrointestinal adverse events may occur with an overdose of azithromycin.
Up to 15 grams cumulative dose of ZITHROMAX (azithromycin dihydrate) over 10 days 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.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
TABLETS 250 mg: Each pink, film-coated, unscored, modified capsule shaped ZITHROMAX tablet, engraved “ZTM 250” or “306” on one side and “Pfizer” on the other side, contains azithromycin dihydrate equivalent to 250 mg of azithromycin and the following inactive ingredients: pregelatinized starch (27 mg), anhydrous calcium phosphate dibasic, sodium croscarmellose (9 mg), magnesium stearate, sodium lauryl sulphate, hydroxypropyl methylcellulose, lactose (tablet coating), titanium dioxide, triacetin and D&C Red #30 aluminum lake. The tablets are packaged in white plastic (high density polyethylene) bottles of 30 or in a single treatment package (Z-pak) of 6 blister packaged tablets per box.
TABLETS 600 mg: Each white, film-coated, unscored, modified oval shaped ZITHROMAX tablet, debossed with “PFIZER” on one side and “308” on the other side, contains azithromycin dihydrate equivalent to 600 mg azithromycin and the following non-medicinal ingredients: anhydrous calcium phosphate dibasic, pregelatinized starch (64.8 mg), sodium croscarmellose (21.6 mg), magnesium stearate, sodium lauryl sulphate, hydroxypropyl methylcellulose, lactose (tablet coating), titanium dioxide and triacetin. These are packaged in HDPE bottles of 30 tablets.
POWDER FOR ORAL SUSPENSION: ZITHROMAX Powder for Oral Suspension, contains azithromycin dihydrate equivalent to: 300 mg; 600 mg; and 900 mg of azithromycin per bottle. After reconstitution, each bottle (high density polyethylene) contains a cherry flavoured suspension with azithromycin dihydrate equivalent to: 300 mg per 15 mL (100 mg/5 mL); 600 mg per 15 mL (200 mg/5 mL); 900 mg per 22.5 mL (200 mg/5 mL) azithromycin. The non-medicinal ingredients include: sucrose (3.86 g per 100 mg/5 mL and 3.87 g per 200 mg/5 mL); sodium phosphate (8.76 mg per 100 mg/5 mL and 17.50 mg per 200 mg/5 mL), tribasic hydroxypropyl cellulose; xanthan gum; FD&C Red #40 and artificial flavours (see 4.3 Reconstitution). The 300 mg bottle (100 mg/5 mL) is supplied with a plastic stopper and a calibrated syringe. The 600 mg bottle (200 mg/5 mL) and the 900 mg bottle (200 mg/5 mL) are supplied with a plastic stopper, and a calibrated syringe and dosing cup.
ZITHROMAX for Injection 500 mg: Each vial contains azithromycin dihydrate in a lyophilized form equivalent to 500 mg azithromycin for injection. The non-medicinal ingredients include: 384.6 mg anhydrous citric acid and 198.5 mg sodium hydroxide for pH adjustment. After reconstitution, each mL contains azithromycin dihydrate equivalent to 100 mg azithromycin (500 mg/5 mL) (see 4.3 Reconstitution). ZITHROMAX for Injection is supplied in cartons of 10 single dose vials.
Long term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no genotoxic or mutagenic potential in standard laboratory tests (see 16 NON-CLINICAL TOXICOLOGY).
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including azithromycin (see 8 ADVERSE REACTIONS). Prescribers should consider the risk of QT prolongation which can lead to fatal events when weighing the risks and benefits of azithromycin. Risk factors for torsade de pointes include patients:
There is information that 'QT Related Adverse Events' may occur in some patients receiving azithromycin. There have been spontaneous reports from post‑marketing experience of prolonged QT interval and torsade de pointes (see 8.5 Post-Market Adverse Reactions). These include but are not limited to: one AIDS patient dosed at 750 mg to 1 g daily experienced prolonged QT interval and torsade de pointes; a patient with previous history of arrhythmias who experienced torsade de pointes and subsequent myocardial infarction following a course of azithromycin therapy; and a pediatric case report of prolonged QT interval experienced at a therapeutic dose of azithromycin which reversed to normal upon discontinuation (see 10 CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).
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 ZITHROMAX in these patients is not recommended.
A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Azithromycin was administered to a limited number of subjects with GFR<10 mL/min.
Clostridium difficile-associated disease
Clostridium difficile associated disease (CDAD) has been reported with use of many antibacterial agents including azithromycin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agents. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.
If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see 8 ADVERSE REACTIONS).
Severe neutropenia (WBC < 1000/mm3) may adversely affect the distribution of azithromycin and its transport to the site of infection. Antibacterials with proven efficacy in this population should be used, as outlined by the relevant guidelines for treatment of patients with severe neutropenia. Efficacy and safety of azithromycin have not been studied in patients with severe neutropenia.
Since the liver is the principal route of elimination for azithromycin, the use of oral ZITHROMAX preparations should be undertaken with caution in patients with impaired hepatic function. Azithromycin has not been studied in patients with severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY).
Due to the lack of data, ZITHROMAX for Injection should be used with caution in patients with hepatic impairment.
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Rare cases of acute hepatic necrosis requiring liver transplant or causing death have been reported in patients following treatment with oral azithromycin. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur (see 8 ADVERSE REACTIONS).
Allergic reactions may occur during and soon after treatment with ZITHROMAX. 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.
Monitoring of QT/QTc intervals during treatment with ZITHROMAX may be considered by the physician as appropriate.
Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. The use of azithromycin in patients with a known history of myasthenia gravis is not recommended.
The safety, efficacy and pharmacokinetics of Zithromax in patients with renal impairment have not been established. No dose adjustment is recommended for patients with GFR 10-80 mL/min. Caution should be exercised when Zithromax is administered to patients with GFR <10 mL/min. This precaution is based on a clinical study of azithromycin immediate-release tablets, in which patients with GFR <10 mL/min showed a significant (61%) increase in mean Cmax and a significant (35%) increase in systemic exposure to azithromycin, and experienced a high incidence of gastrointestinal adverse events (8 of 19 clinical study subjects). Patients with GFR 10-80 mL/min showed only slightly increased serum azithromycin levels compared to patients with normal renal function.
Due to limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing oral azithromycin in these patients (see 10 CLINICAL PHARMACOLOGY).
There are no adequate and well-controlled studies in humans. In fertility studies conducted in the rat, reduced pregnancy rates were noted following administration of azithromycin. The predictive value of these data to the response in humans has not been established (see 16 NON-CLINICAL TOXICOLOGY).
Prescribing ZITHROMAX in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Serious allergic reactions, including angioedema, anaphylaxis, and dermatological reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermolysis, toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic symptoms (DRESS) have been reported rarely (with rare reports of fatalities), in patients on ZITHROMAX (azithromycin dihydrate) therapy (see 2 CONTRAINDICATIONS).
Azithromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any potential risk to the fetus.
There is a large amount of data from observational studies performed in several countries on exposure to azithromycin during pregnancy, compared to no antibiotic use or use of another antibiotic during the same period. While most studies do not suggest an association with adverse fetal effects such as major congenital malformations or cardiovascular malformations, there is limited epidemiological evidence of an increased risk of miscarriage following azithromycin exposure in early pregnancy.
In animal reproduction studies in mice and rats, at azithromycin doses up to 200 mg/kg/day (moderately maternally toxic), effects were noted in the rat at 200 mg/kg/day, during the prenatal development period (delayed ossification) and during the postnatal development period (decreased viability, delayed developmental landmarks, differences in performance of learning task). The 200 mg/kg/day dose in mice and rats, is approximately 0.5-fold and 1-fold, respectively, the single adult oral dose of 2 g, based on mg/m2 (body surface area). Pharmacokinetic data from the 200 mg/kg/day dose level in these studies showed that azithromycin crossed the placenta and distributed to fetal tissue at 5 to 9-fold the maternal plasma Cmax of 2 ug/mL (see 16 NON-CLINICAL TOXICOLOGY).
ZITHROMAX should not be used in the treatment of nursing women unless the expected benefit to the mother outweighs any potential risk to the infant. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Because azithromycin may accumulate in breast milk over time with continued ZITHROMAX therapy, if the lactating mother is treated with ZITHROMAX, the breast milk should be expressed and discarded during treatment.
Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breast-fed infants were observed. However, the safety of azithromycin has not been studied in infants less than 6 months of age.
Pediatrics (< 18 years of age):
Acute Otitis Media: Safety and efficacy in the treatment of children with otitis media under 6 months of age have not been established.
Community-acquired pneumonia: Safety and efficacy in the treatment of children with communityacquired pneumonia under 6 months of age have not been established.
Pharyngitis and tonsillitis: Safety and efficacy in the treatment of children with pharyngitis and tonsillitis under 2 years 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 ZITHROMAX at doses higher than proposed and for durations longer than recommended are limited to a small number of immunocompromised children who underwent chronic treatment.
Infantile hypertrophic pyloric stenosis (IHPS)
Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.
The safety and effectiveness of ZITHROMAX for Injection in children or adolescents under 16 years have not been established.
Prevention of Disseminated Mycobacterium Avium Complex (MAC) Disease:Safety and efficacy of ZITHROMAX for the prevention of MAC in children have not been established.
Limited safety data are available for 24 children 5 months to 14 years of age (mean 4.6 years) who received ZITHROMAX for treatment of opportunistic infections. The mean duration of therapy was 186.7 days (range 13-710 days) at doses of <5 to 20 mg/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, one child discontinued due to a laboratory abnormality (eosinophilia). Based on available pediatric pharmacokinetic data, a dose of 20 mg/kg in children would provide drug exposure similar to the 1200 mg adult dose but with a higher Cmax.
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 intravenous azithromycin have not been performed in the elderly. Based on clinical trials, there appear to be no significant differences in safety or tolerance of intravenous azithromycin between elderly (age ≥ 65) and younger subjects (ages 16 to ≤ 64).However, elderly patients may be more susceptible to development of torsade de pointes arrhythmias.
The majority of side effects observed in controlled clinical trials involving patients (adults and children) treated with oral ZITHROMAX (azithromycin dihydrate) were of a mild and transient nature. Approximately 0.7% of both adult patients (n=3812) and children (n=2878) from the 5-day multiple dose clinical trials discontinued ZITHROMAX therapy because of drug related side effects. Among adults receiving ZITHROMAX intravenously, 1.2% of CAP, and 2% of PID patients discontinued treatment. Discontinuation rates were slightly higher for PID patients receiving concomitant metronidazole therapy (4%).
In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects was 0.4%. In clinical trials in children given 30 mg/kg, orally either as a single dose (n= 487) or over 3 days, (n=1729) discontinuation from therapy due to treatment-related side effects was approximately 1%.
Most of the side effects leading to discontinuation in patients on oral or intravenous 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 intravenous ZITHROMAX. Potentially serious treatment-related side effects including angioedema and cholestatic jaundice occurred in less than 1% of patients.
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
In adult patients, the most common treatment-related side effects in patients receiving the 3 or 5 day oral multiple-dose regimens of ZITHROMAX were related to the gastrointestinal system with diarrhea/loose stools (4-5%), nausea (3-4%), abdominal pain (2-3%) and vomiting (1%).
In adult patients (n=904), side effects that occurred on the single one-gram dosing regimen of ZITHROMAX 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%).
Overall, the most common side effects in patients receiving a single 2-gram dose of ZITHROMAX 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.
Chronic therapy with ZITHROMAX 1200 mg weekly regimen: The nature of side effects seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens.
Includes those events considered possibly or probably related to study drug
>2% adverse event rates for any group
Reflects the occurrence of ≥1 event during the entire treatment period
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.
The most common side effects (greater than 1%) in adult patients who received sequential I.V./oral ZITHROMAX 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 intravenous 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 ZITHROMAX 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 co-administered 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%).
In children enrolled in controlled clinical trials in acute otitis media and S. pyogenes pharyngitis, the type of side effects were comparable to those seen in adults (see below). Different side effect incidence rates for the dosage regimens recommended in children were observed.
Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (≥1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. The incidence, based on dosing regimen, is described in the table below:
Community-Acquired Pneumonia: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting/nausea and rash. The incidence is described in the table below:
Pharyngitis/tonsillitis: For the recommended total dosage regimen of 60 mg/kg, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache. The incidence is described in the table below:
Side effects that occurred with a frequency of 1% or less in patients included the following:
Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials in patients were reported as follows:
With an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, monocytes, albumin and blood glucose, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT and AST (SGOT), BUN, creatinine, blood glucose, platelet count, eosinophils and monocytes.
With an incidence of less than 1%: leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, LDH and phosphate.
The majority of subjects with elevated serum creatine also had abnormal values at baseline.
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose clinical trials involving more than 4500 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities, one for treatment-related elevated transaminases and triglycerides and one because of a renal function abnormality.
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.
secondary criteria also applied if baseline abnormal, as follows: Hemoglobin, 10% decrease; Platelet, 20% decrease; WBC count, 25% decrease; Neutrophils, 50% decrease; AST (SGOT), 50% increase; ALT (SGPT), 50% increase.
lower limit of normal
upper limit of normal
In a phase I drug interaction study performed in normal volunteers, 1 of 6 subjects given the combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone and 0 of 6 given azithromycin alone developed a clinically significant neutropenia (<500 cells/mm3).
One-, Three- and Five-Day Regimens Laboratory data collected from 64 subjects receiving azithromycin in comparative clinical trials employing the 1-day regimen (30 mg/kg as a single dose), 1198 and 169 subjects receiving azithromycin respectively employing the two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.
Similar results were obtained in subjects receiving the two 5-day regimens. Overall, 1948 and 421 patients were exposed to 30 mg/kg or 60 mg/kg, respectively in divided doses over 5 days. The data collected in the subset of azithromycin patients assessed for laboratory abnormalities were similar to those in all comparators combined with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.
In a single center clinical trial, a decrease in absolute neutrophils was observed in the range of 21-29% for azithromycin regimens of 30 mg/kg given either as a single dose or over 3 days, as well as the comparator. No patients had significant neutropenia defined as an absolute neutrophil count <500 cells/mm3 (see 14 CLINICAL TRIALS).
In clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.
With an incidence of 4-6%, elevated ALT, AST, and creatinine. With an incidence of 1-3%, 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 ZITHROMAX 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.
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.
In addition, because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency is not always possible.
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.
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.
ZITHROMAX (azithromycin dihydrate), a macrolide antibiotic of the azalide subclass, exerts its antibacterial action by binding to the 23S rRNA of the 50s ribosomal subunits of susceptible bacteria. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.
QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial. A total of 119 healthy subjects were enrolled (mean age of 35.5 years; range 18-55 years), of which 116 subjects (97 males) completed the study and were included in the analysis. Subjects were randomized to one of 5 treatments and received orally once daily for 3 days: placebo, chloroquine 600 mg base only, or chloroquine 600 mg base in combination with azithromycin 500 mg, 1000 mg, and 1500 mg. On Day 3, the azithromycin mean (%CV) plasma Cmax values for the 500, 1000 and 1500 mg azithromycin dose regimens were 0.536 (33), 0.957 (31), and 1.54 (28) µg/mL, respectively. Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the day 3 maximum mean (90% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
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.
Plasma concentrations of azithromycin decline in a polyphasic pattern, resulting in an average terminal half-life of 68 hours. The prolonged half-life is likely due to extensive uptake and subsequent release of drug from tissues. Over the dose range of 250 to 1000 mg orally, the serum concentrations are related to dose.
In adults, the following pharmacokinetic data have been reported:
In patients hospitalized with community-acquired pneumonia (CAP) receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the median maximum concentration (Cmax) achieved was 3.00 µg/mL (range: 1.70-6.00 µg/mL) while the 24-hour trough level was 0.18 µg/mL (range: 0.07-0.60 µg/mL) and the AUC24 was 8.50 µgh/mL (range: 5.10-19.60 µg.h/mL).
The median Cmax, 24-hour trough and AUC24 values were 1.20 µg/mL (range: 0.89-1.36 µg/mL), 0.18 µg/mL (range: 0.15-0.21 µg/mL) and 7.98 µgh/mL (range: 6.45-9.80 µgh/mL), respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with CAP that received the same 3-hour dosage regimen for 2-5 days.
500 mg (2 mg/mL) for 2-5 days in CAP patients
500 mg (1 mg/mL) for 5 days in healthy subjects
The average Clt and Vd values were 10.18 mL/min/kg and 33.3 L/kg, respectively, in 18 normal volunteers receiving 1000 to 4000 mg doses given as 1 mg/mL over 2 hours.
Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin shows only an 8% increase in Cmax but a 61% increase in AUC24 reflecting the three-fold rise in C24 trough levels.
In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenous dosage regimen for 5 days, the amount of administered azithromycin dose excreted in the urine in 24 hours 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.
Following oral administration, azithromycin is rapidly absorbed (Tmax = 2-3 hours) and distributed widely throughout the body.
The absolute bioavailability is approximately 37%.
When azithromycin suspension was administered with food to 28 adult healthy male subjects, the rate of absorption (Cmax) was increased by 56% while the extent of absorption (AUC) was unchanged. Food does not affect the absorption of azithromycin in the tablet dosage form. Azithromycin tablets and powder for oral suspension can be taken with or without food.
The serum protein binding of azithromycin is concentration dependent, decreasing from 51% at 0.02 μg/mL to 7% at 2.0 μg/mL. Following oral administration, azithromycin is widely distributed throughout the body with a steady-state apparent volume of distribution of 31.1 L/kg.
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 long tissue half-life and large volume of distribution result from intracytoplasmic uptake and storage in lysosomal phospholipid complexes.
The majority of systemically available azithromycin is excreted unchanged in the bile. Metabolites of azithromycin were identified in bile but have not been studied further.
Biliary excretion of azithromycin, predominantly as unchanged drug, is a main route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in the urine.
Pharmacokinetics in children receiving a total dose of 30 mg/kg:The table below shows mean pharmacokinetic parameters on day 5 in children 1 to 5 years and 5 to 15 years of age when azithromycin oral suspension was dosed in the absence of food at a total dose of 30 mg/kg delivered as 10 mg/kg on day 1 and 5 mg/kg on days 2-5.
Pharmacokinetics in children receiving a 60 mg/kg total dose:Two clinical studies enrolled 35 and 33 children respectively aged 3-16 years with pharyngitis/tonsillitis to determine the pharmacokinetics and safety of azithromycin for oral suspension in children when given 60 mg/kg in divided doses delivered as 20 mg/kg/day over 3 days or 12mg/kg/day over 5 days with a maximum daily dose of 500 mg.
The following table shows pharmacokinetic data in the subset of children who received a total dose of 60 mg/kg. In both studies azithromycin concentrations were determined over a 24 hour period following the last daily dose.
Similarity of overall exposure (AUC 0-∞) between the 3 and 5 day regimen is unknown.
maximum weight for 3 day regimen was ≤ 25 kg and for 5 day regimen was ≤41.7 kg
When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.
There are no significant differences in the disposition of immediate-release azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.
In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of oral ZITHROMAX 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. Azithromycin has not been studied in patients with severe hepatic impairment.
Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0-120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR 80 mL/min).
Store ZITHROMAX Film-Coated Tablets at controlled room temperature (15-30°C).
Powder for Oral Suspension:Dry powder: Store at controlled room temperature (15-30°C).Reconstituted suspension: Store between 5°C and 30°C. Discard unused portion after 10 days.
ZITHROMAX for Injection: Dry powder: Store at controlled room temperature (15-30°C).Diluted solution: Stable for 24 hours at or below 30°C, or for 72 hoursif stored under refrigeration (2-8°C). For single-use only. Discard any unused portion after use.
There are no special handling instructions for this drug product.
Control #: 270217 April 27, 2023
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