DESCRIPTION
AzaSite (azithromycin ophthalmic solution) is a 1% sterile aqueous topical ophthalmic solution of azithromycin formulated in DuraSite® (polycarbophil, edetate disodium, sodium chloride). AzaSite is an off-white, viscous liquid with an osmolality of approximately 290 mOsm/kg.
Preservative: 0.003% benzalkonium chloride. Inactives: mannitol, citric acid, sodium citrate, poloxamer 407, polycarbophil, edetate disodium (EDTA), sodium chloride, water for injection, and sodium hydroxide to adjust pH to 6.3.
Azithromycin is a macrolide antibiotic with a 15-membered ring. Its chemical name is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]1-oxa-6-aza-cyclopentadecan-15-one, and the structural formula is:
Azithromycin has a molecular weight of 749, and its empirical formula is C38H72N2O12.
|
CLINICAL PHARMACOLOGY
Mechanism of Action
Azithromycin is a macrolide antibiotic [see Clinical Pharmacology ].
Pharmacokinetics
The plasma concentration of azithromycin following ocular administration of AzaSite (azithromycin ophthalmic solution) in humans is unknown. Based on the proposed dose of one drop to each eye (total dose of 100 mcL or 1 mg) and exposure information from systemic administration, the systemic concentration of azithromycin following ocular administration is estimated to be below quantifiable limits (≤10 ng/mL) at steady-state in humans, assuming 100% systemic availability.
Microbiology
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and interfering with microbial protein synthesis.
Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and clinically in conjunctival infections [see Indications and Usage (1)].
-
CDC coryneform group G*
-
Haemophilus influenzae
-
Staphylococcus aureus
-
Streptococcus mitis group
-
Streptococcus pneumoniae
-
* Efficacy for this organism was studied in fewer than 10 infections.
The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of AzaSite in treating ophthalmological infections due to these microorganisms have not been established.
The following microorganisms are considered susceptible when evaluated using systemic break points. However, a correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. This list of microorganisms is provided as an aid only in assessing the potential treatment of conjunctival infections. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of equal or less (systemic susceptible breakpoint) against most (≥90%) of isolates of the following ocular pathogens:
-
Chlamydia pneumoniae
-
Chlamydia trachomatis
-
Legionella pneumophila
-
Moraxella catarrhalis
-
Mycoplasma hominis
-
Mycoplasma pneumoniae
-
Neisseria gonorrhoeae
-
Peptostreptococcus species
-
Streptococci (Groups C, F, G)
-
Streptococcus pyogenes
-
Streptococcus agalactiae
-
Ureaplasma urealyticum
-
Viridans group streptococci
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to azithromycin was found in mice or rats that received oral doses of up to 200 mg/kg/day.
Animal Toxicology and/or Pharmacology
Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple systemic doses of azithromycin. Cytoplasmic microvacuolation, which is likely a manifestation of phospholipidosis, has been observed in the corneas of rabbits given multiple ocular doses of AzaSite. This effect was reversible upon cessation of AzaSite treatment. The significance of this toxicological finding for animals and for humans is unknown.
|
CLINICAL STUDIES
In a randomized, vehicle-controlled, double-blind, multicenter clinical study in which patients were dosed twice daily for the first two days, then once daily on days 3, 4, and 5, AzaSite solution was superior to vehicle on days 6-7 in patients who had a confirmed clinical diagnosis of bacterial conjunctivitis. Clinical resolution was achieved in 63% (82/130) of patients treated with AzaSite versus 50% (74/149) of patients treated with vehicle. The p-value for the comparison was 0.03 and the 95% confidence interval around the 13% (63%-50%) difference was 2% to 25%. The microbiological success rate for the eradication of the baseline pathogens was approximately 88% compared to 66% of patients treated with vehicle (p<0.001, confidence interval around the 22% difference was 13% to 31%). Microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.
|
