Pharmacology
Pharmacodynamics
Azithromycin is a macrolide antibiotic belonging to the azalide group. The mechanism of action of azithromycin is based on the suppression of bacterial protein synthesis, meaning it binds to the ribosomal 50s sub-unit and inhibits the translocation of peptides. Azithromycin acts as a bacteriostatic. Nucleic acid synthesis is not affected.
Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30 after 1 hour of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Azithromycin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections:
Aerobic Gram-positive Bacteria
Methicillin-susceptible Staphylococcus aureus,Streptococcus agalactiae, Penicillin-susceptible Streptococcus pneumonia,Streptococcus pyogenes (Group A),Aerobic Gram-negative Bacteria Haemophilus influenza, Moraxella catarrhalis, Neisseria gonorrhoeae, Haemophilus parainfluenzae, Pasteurella multocida
Other Bacteria
Chlamydophila pneumonia, Chlamydia trachomatis, Mycoplasma pneumonia, Legionella pneumophila, Mycobacterium avium, Mycobacterium intracellulare
Pharmacokinetics
Absorption
Bioavailability after oral administration is approximately 37%. Peak concentrations in the plasma are attained 2–3 hours after taking the medicinal product.
In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high-fat meal, food was shown to increase the Cmax by 23% but had no effect on the AUC.
When azithromycin suspension was administered with food to 28 adult healthy male subjects, the Cmax increased by 56% and the AUC was unchanged.
Distribution
Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues. The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity.
Metabolism
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.
Ten metabolites were also detected, which were formed through N- and O-demethylation, hydroxylation of desosamine- and aglycone rings and degradation of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.
Elimination
Plasma concentrations of azithromycin following single 500 mg oral and intravenous doses declined in a polyphasic pattern, with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Contraindications
Azithromycin is contraindicated in patients with a known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic or any of its excipients.
Azithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
Information for Patients
Azithromycin tablets can be taken with or without food.
Patients should also be cautioned not to take aluminium- and magnesium-containing antacids and azithromycin simultaneously.
The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.
Diarrhoea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Renal Impairment
No dosage adjustment is recommended for subjects with mild-to-moderate renal impairment (GFR 10–80 ml/min). Caution should be exercised when azithromycin is administered to subjects with severe renal impairment (GFR)10 ml/min). In patients with severe renal impairment (GFR) 10 ml/min) a 33% increase in systemic exposure to azithromycin was observed.
Hepatic Impairment
A dose adjustment is not necessary for patients with mild-to-moderately impaired liver function.
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.
Lactation
Azithromycin has been reported to be excreted in human breast milk in small amounts. Caution should be exercised when azithromycin is administered to a nursing mother.
Paediatric Use
Safety and effectiveness in the treatment of paediatric patients with acute otitis media, acute bacterial sinusitis and community-acquired pneumonia under 6 months of age have not been established. Use of azithromycin for the treatment of acute bacterial sinusitis and community-acquired pneumonia in paediatric patients (6 months of age or greater) is supported by adequate and well controlled trials in adults. Safety and effectiveness in the treatment of paediatric patients with pharyngitis/tonsillitis under 1 year of age have not been established. Safety and efficacy for prevention or treatment of M. avium complex in children have not been established.
Geriatric Use
In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4,949) and 3% of patients (144/4,949) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but the greater sensitivity of some older individuals cannot be ruled out.
Elderly patients may be more susceptible to development of torsades de pointes arrhythmia than younger patients

Overdosage
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.

Storage and Handling Instructions
Before Opening
Store at room temperature. Protect from moisture.