Product Monograph - Azasite (Insite Vision)
SUMMARY PRODUCT INFORMATION
| Route of Administration | Dosage Form/ Strength | Clinically Relevant Nonmedicinal Ingredients |
| Ophthalmic Topical | 5 mL bottle containing 2.5 mL of 1% sterile ophthalmic solution | Contains poloxamer 407, polycarbophil, benzalkonium chloride. For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING Section. |
INDICATIONS AND CLINICAL USE
AzaSite™ (azithromycin ophthalmic solution) 1% w/w is indicated for use in adult and pediatric patients aged 1 year and older for topical treatment of bacterial conjunctivitis caused by the following microorganisms:
Haemophilus influenzae
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis
Streptococcus pneumoniae (penicillin-susceptible isolates only)
Geriatrics (>65 years of age)
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
Pediatrics (<1 years old)
The safety and efficacy of AzaSite™ in patients <1 year of age have not been established.
CONTRAINDICATIONS
Patients who are hypersensitive to azithromycin, erythromycin, any macrolide, or ketolide antibacterial agents or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
WARNINGS AND PRECAUTIONS
General
NOT FOR INJECTION INTO THE EYE. FOR TOPICAL OPHTHALMIC USE ONLY.
AzaSite™ (azithromycin ophthalmic solution) 1% w/w should not be administered systemically, injected subconjunctivally, or introduced directly into the anterior chamber of the eye.
Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis.
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 azithromycin ophthalmic solution, 1% w/w. This effect was reversible upon cessation of azithromycin ophthalmic solution, 1% w/w treatment. Phospholipidosis was not observed in the retina or iris/ciliary bodies of Dutch Belted rabbits administered azithromycin ophthalmic solution, 1% w/w twice daily in the right eye from 14 days to 30 days. The significance of these toxicological findings for animals and for humans is unknown.
If superinfection occurs or if clinical improvement is not noted within 7 days, discontinue use and institute appropriate therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and where appropriate, fluorescein staining.
Carcinogenesis and Mutagenesis
Long term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has not shown mutagenic potential in standard laboratory tests (see PART II, TOXICOLOGY, Carcinogenesis, Mutagenesis).
Immune
Anaphylaxis and Hypersensitivity
In patients receiving systemically administered azithromycin, serious allergic reactions including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy. Although rare, fatalities have been reported.
Allergic reactions including facial swelling, hives, periocular swelling, rash, and urticaria have been reported with the use of AzaSite™ (azithromycin ophthalmic solution) 1% w/w (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). The potential for anaphylaxis or other hypersensitivity reactions should be considered since patients with a known hypersensitivity to azithromycin or erythromycin were excluded from study.
If any allergic reaction occurs, AzaSite™ should be discontinued and appropriate therapy should be administered as clinically indicated.
Special Populations
Pregnant Women: No clinical studies of AzaSite™ (azithromycin ophthalmic solution) 1% w/w have been conducted in pregnant women. AzaSite™ should not be used during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus. No reproductive toxicology studies have been conducted with AzaSite™. However, studies conducted with azithromycin in rats and mice at a dose of 200 mg/kg/d were associated with moderate maternal toxicity. This dose is estimated to be approximately 5000 times the maximum (2 mg) human ocular daily dose of AzaSite™.
Nursing Women: The safety of AzaSite™ (azithromycin ophthalmic solution) 1% w/w in breast-fed infants of mothers who received AzaSite™ has not been established. Following systemic administration of azithromycin, it is unknown whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
Overall the frequency of Investigator determined drug-related adverse events for AzaSite™ (azithromycin ophthalmic solution) 1% w/w in the combined Phase III clinical studies (n=698) was 4.7% (33/698). The most frequent adverse event reported with AzaSite™ was eye irritation (1.4%). The most frequent adverse event reported with vehicle was headache (1.4%).
The incidence of discontinuations of AzaSite™ due to drug-related adverse events was 1.6% (N=11/698). Adverse events that led to discontinuation were: conjunctivitis that spread to the fellow eye in N=3 patients, worsening of symptoms in the fellow eye (severe conjunctival chemosis, bulbar injection and palpebral injection), sinusitis, irritability, otitis media-right ear, throat infection and dehydration, herpes zoster, bilateral iritis, and upper respiratory tract infection.
Clinical Study Adverse Drug Reactions
Because clinical studies are conducted under very specific conditions the adverse reaction rates observed in the clinical studies may not reflect the rates observed in practice and should not be compared to the rates in the clinical studies of another drug. Adverse drug reaction information from clinical studies is useful for identifying drug-related adverse events for approximating rates.
The safety of AzaSite™ (azithromycin ophthalmic solution) 1% w/w was assessed in 2 controlled Phase III clinical studies in N=698 adult and pediatric patients between 1 and 87 years of age, who used at least one dose of AzaSite™ for a 5-day (2 drops twice daily for the first 2 days and then 1 drop once daily for the next 3 days) regimen. The most common drug-related adverse events (≥1%) reported in patients treated with AzaSite™ or vehicle in the Phase III studies are shown in Table 1. The median duration of eye irritation was 5 days.
Table 1 Drug-related Adverse Events Reported by ≥ 1% of Patients Treated with AzaSite™ and Vehicle in Phase III Clinical Studies
| Adverse Event | AzaSite™ (n=698)* | Vehicle (n=350) |
Eye Disorders Eye Irritation Nervous system disorders Headache | 10 (1.4%) 2 (0.3%) | 0 5 (1.4%) |
*In the AzaSite™ group, 32% of the patients were pediatric (age 1-11).
Less Common Clinical Study Adverse Drug Reactions (<1% of Subjects)
Other adverse drug reactions associated with the use of AzaSite™ and vehicle reported in less than 1% of patients included the following:
Eye disorders: instillation site burning and stinging, eye discharge, eye pruritus, corneal erosion, keratoconjunctivitis sicca, instillation site irritation, punctate keratitis, conjunctivitis, conjuctival oedema, and vision blurred.
Nervous system disorders: dysgeusia.
Respiratory, thoracic and mediastinal disorders: nasal congestion, sinusitis, and pharyngolaryngeal pain.
Investigations: sputum abnormal.
Skin and subcutaneous tissue disorders: dermatitis contact and dermatitis allergic.
Post-Market Adverse Drug Reactions
In addition to adverse events reported from clinical studies, the following events have been identified during post approval use of AzaSite™. Eye: blurring, eyelid swelling, itching, pain, and visual acuity reduction. General: allergic reactions including facial swelling, hives, periocular swelling, rash, and urticaria. These events were reported voluntarily from a population of unknown size, and the frequency of occurrence cannot be determined precisely. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to AzaSite™ or a combination of these factors.
DRUG INTERACTIONS
Drug-Drug Interactions
The effect of concurrent administration of AzaSite™ (azithromycin ophthalmic solution) 1% w/w and other topical and systemic products has not been studied.
Drug-Food Interactions
Interactions of AzaSite™ with food have not been established.
Drug-Herb Interactions
Interactions of AzaSite™ with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions of AzaSite™ with laboratory tests have not been established.
DOSAGE AND ADMINISTRATION
Dosing Considerations
AzaSite™ (azithromycin ophthalmic solution) 1% w/w is administered by instillation into the affected eye(s). It is indicated for topical ophthalmic use only, and should not be administered systemically, injected subconjunctivally, or introduced directly into the anterior chamber of the eye. AzaSite™ is NOT FOR INJECTION.
Special Populations and Conditions
Pediatrics: The safety and effectiveness of AzaSite™ in children <1 year of age have not been established; therefore, it should not be used.
Geriatrics: No dosage adjustment is necessary.
Hepatic Insufficiency: No dosage adjustment is necessary. In view of the low systemic exposure to azithromycin following topical ophthalmic instillation, hepatic impairment is not expected to result in systemic exposure of clinical concern (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Renal Insufficiency: No dosage adjustment is necessary. In view of the low systemic exposure to azithromycin following topical ophthalmic instillation, renal impairment is not expected to result in systemic exposure of clinical concern (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Recommended Dose and Dosage Adjustment
The recommended dosage regimen of AzaSite™ (azithromycin ophthalmic solution) 1% w/w for both adult and pediatric patients 1 year of age and older is:
Days 1 and 2: instill 1 drop in the affected eye(s) twice daily, eight to twelve hours apart.
Days 3 to 7: instill 1 drop in the affected eye(s) once daily.
Missed Dose
AzaSite™ (azithromycin ophthalmic solution) 1% w/w should only be taken as prescribed. If a dose is missed an extra dose should not be taken. The usual dose should be taken the following day.
Administration
Thoroughly wash hands prior to using AzaSite™ (azithromycin ophthalmic solution) 1% w/w. Avoid contaminating the applicator tip by allowing it to touch the eyes, fingers or other sources. Holding the bottle upright, remove the tan cap. This will allow any excess pressure in the bottle to be released. Replace the tan cap on the bottle and close securely. Invert closed bottle (upside down) and shake once before each use. Remove cap with bottle still in the inverted position. Tilt head back, and with the bottle inverted, gently squeeze the bottle to instill one drop into the affected eye(s).
OVERDOSAGE
For management of suspected drug overdose contact your regional Poison Control Centre.
Adverse reactions specifically associated with AzaSite™ (azithromycin ophthalmic solution) 1% w/w have not been reported.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Azithromycin is a 15-membered ring macrolide antibiotic and acts by binding to the 50S ribosomal subunit of susceptible microorganisms and interfering with microbial protein synthesis.
Pharmacodynamics
Due to low systemic exposure to azithromycin with AzaSite™ (azithromycin ophthalmic solution) 1% w/w QT prolongation in patients is unlikely (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Azithromycin is a broad-spectrum antibiotic and is active against both Gram-positive and Gram-negative microorganisms (see PART II, MICROBIOLOGY).
Pharmacokinetics
Conjunctival concentrations of azithromycin were determined following a single ocular administration of AzaSite™ (azithromycin ophthalmic solution) 1% w/w in N=24 healthy volunteers in the study eye only. The mean concentration of azithromycin peaked 30 minutes after instillation (131 µg/g) and was still detectable 24 hours after treatment. The mean AUC(0-24 h) estimate was 1190 h*µg/g and the half-life was 24.4 hours.
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.
STORAGE AND STABILITY
Store unopened bottle under refrigeration at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, store at 2°C to 25°C (36°F to 77°F) for up to 14 days. Discard after the 14 days.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Availability of Dosage Form
AzaSite™ (azithromycin ophthalmic solution) 1% w/w is currently available in a 5 mL bottle (filled to 2.5 mL) containing a total of 25 mg of azithromycin.
AzaSite™ is a sterile aqueous topical ophthalmic formulation of 1% azithromycin in a white, round, low-density polyethylene (LDPE) bottle, with a natural LDPE dropper tip, and a tan- colored high-density polyethylene (HDPE) eyedropper cap. A white tamper-evident overcap is provided.
Composition
Active Ingredient: azithromycin. Non-medicinal ingredients include: mannitol, citric acid, sodium citrate, benzalkonium chloride, poloxamer 407 NF, polycarbophil USP, edetate disodium (EDTA), sodium chloride, water for injection, and sodium hydroxide to adjust pH to 6.3.
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: Azithromycin
Chemical name: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C- methyl-3-O-methyl-α-L-ribo-hexopyranosyl)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 monohydrate
Molecular formula C38H72N2O12 H2O
Molecular mass: 767 g/mol
Structural Formula:
O
C
N
H3C
CH3
OH
CH3
H3C
CH3
O
H2C
H3C
H3C
HO
OH
H3C
O
O
HO
N
CH3
CH3
CH3
O
O
OCH3
CH3
HO
CH3 H2O
Description: Azithromycin is a macrolide antibiotic with a 15-membered ring and is a white to off-white crystalline powder.
Physiochemical properties: This monohydrate is an odorless crystalline powder white to off-white in color. It is relatively insoluble in water but soluble in some organics. In solution it has an optical rotation between -45 to -49 (20 mg/mL in dehydrated ethanol) and a pH of 9.0 to 11.0 (2 g/L in 1:1 water:methanol).
CLINICAL STUDIES
AzaSite™ (azithromycin ophthalmic solution) 1% w/w was the subject of 2 pivotal Phase III studies in patients 1 year of age or older with a confirmed clinical diagnosis of acute bacterial conjunctivitis for 3 days or less.
Patients were excluded from the study if they had ocular surgery (including laser surgery) in either eye within the past 6 weeks, history of recurrent corneal erosion syndrome, either idiopathic or secondary to previous corneal trauma or dry eye syndrome, ulcerative keratitis, blepharitis, or suspected iritis.
Study Design and Demographics
Table 2 Summary of Phase III Clinical Study Designs and Demographics in Patients with a Confirmed Clinical Diagnosis of Bacterial Conjunctivitis in Intent-to-Treat* and Per Protocol** Populations
| Study Design | Dosage, Route of Administration and Duration | Study Subjects n | Mean Age in Years (Range) Gender % Female | ||
| ITT* | PP** | ITT* | PP** | ||
C-01-401-003 Randomized, double-blind, multicenter, vehicle-controlled study Countries: U.S., Mexico, Guatemala, and Dominican Republic | Instillation of AzaSite™ ophthalmic solution 1% w/w: Days 1 and 2: one drop twice daily Days 3 to 5: one drop once daily Instillation of Vehicle: Days 1 and 2: one drop twice daily Days 3 to 5: one drop once daily Total Study Duration: 5 days | 675 | 279 | 31.0 (1-96) 62.7% | 28.4 (1-96) 57.3% |
C-01-401-004 Randomized, double-blind, multicenter, active-controlled study Countries: U.S., Costa Rica, Mexico, and Panama | Instillation of AzaSite™ ophthalmic solution 1% w/w: Days 1 and 2: one drop twice daily Days 3 to 5: one drop once daily Instillation of Tobramycin ophthalmic solution 0.3% Days 1 to 5: one drop 4 times daily Total study duration: 5 days | 735 | 316 | 27.1 (1-93) 56.7% | 20.4 (1-83) 54.1% |
*Intent-to-Treat (ITT) population consisted of subjects with clinical symptom (mucopurulent or purulent) conjunctival discharge and clinical signs (redness) due to bulbar and/or palpebral conjunctival injection, and who received at least 1 drop of study medication, and who had at least one clinical assessment after the first dose. **Per-Protocol (PP) population consisted of subjects with clinical symptom (mucopurulent or purulent) conjunctival discharge and clinical signs (redness) due to bulbar and/or palpebral conjunctival injection and who received at least 1 dose of the study medication, who demonstrated evidence of pathogenic bacterial levels, and who had at least one clinical assessment after the first dose.
Study Results
Table 3 presents the clinical resolution and bacterial eradication at Visit 3 (Days 1-2 after cessation of therapy).
Table 3 Clinical Response for Studies 003 and 004 in Per Protocol (PP) Population with Last Observation Carried Forward (LOCF) in Patients with Acute Bacterial Conjuctivitis at End of Therapy at Visit 3 (Days 1-2 After Cessation of Therapy)
| Endpoints | C-01-401-003 (Per Protocol with LOCF) | C-01-401-004 (Per Protocol with LOCF) | ||||
| AzaSite™ (n=130) | Vehicle (n=149) | P-value[c] Difference 95%CI | AzaSite™ (n=159) | Comparator (n=157) | P-value[c] Difference 95%CI | |
Primary Endpoint: Clinical Resolution Visit 3[a] Success | 63.1% (82) | 49.7% (74) | 0.030 13.4% (1.9, 25%) | 79.9% (127) | 78.3% (123) | 0.783 1.5% (-7.4, 10.5) |
Secondary Endpoint: Bacterial Eradication Visit 3[b] Success | 88.5% (115) | 66.4% (99) | <0.001 22.0% (12.7, 31.4%) | 88.1% (140) | 94.3% (148) | 0.073 -6.2% (-12.4, 0.0%) |
[a]The Primary Efficacy Endpoint was Clinical Resolution at Visit 3 (Days 1-2 after cessation of therapy). Clinical Resolution is defined as a clinical severity rating of 0 for the following: clinical symptom of ocular (conjunctival) discharge and clinical signs of bulbar and/or palpebral conjunctival injection.
[b]The Secondary Endpoint was the eradication of causative pathogens (bacterial eradication) at Visit 3. Bacterial Eradication is defined as the absence of growth (0 CFU/mL) of the original infecting organism(s).. [c]P-value is from Fisher’s Exact Test.
Table 4 presents the results for clinical response in the Per Protocol (PP) Population against the most common conjunctival pathogens at End of Therapy (Visit 3) after cessation of therapy.
Table 4 Clinical Response by Baseline Pathogen in Per Protocol Population
| Species | Clinical Resolution at Visit 3 (Days 6-7) | ||||
| Haemophilus influenzae | 80/96 (83.3%) | ||||
| Staphylococcus aureus | 31/40 (77.5%) | ||||
| (methicillin-susceptible isolates only) | |||||
| Staphylococcus epidermidis | 7/9 (77.8%) | ||||
| Streptococcus pneumoniae | 71/91 (78.0%) | ||||
| (penicillin-susceptible isolates only) | |||||
Microbiologic eradication does not always correlate with clinical outcomes in anti-infective studies.
Pediatrics: In the combined Phase III clinical studies, 52.2% of patients treated with AzaSite™ were pediatric (1-11 years old) and 47.8% were non-pediatric (12 years of age and older). Clinical resolution was 76.8% in the pediatric population (1-11 years of age) compared to 67.4% in the patient population of 12 years and older; p-value 0.042.
DETAILED PHARMACOLOGY
Animal Pharmacology
Pharmacodynamics: In a series of general pharmacological test systems designed to study neuropharmacological, cardiovascular/respiratory toxicities and renal effects after systemic exposure of azithromycin, no neuropharmacological effects and minimal potential for cardiovascular/respiratory toxicities were reported at a dose of 1.5 g of azithromycin over 5 days. This dose is approximately 250 times higher than the proposed maximum human ocular daily dose of AzaSite™, which is 2 mg.
Pharmacokinetics: Single topical ocular instillation (25 mg) of a drop of azithromycin ophthalmic solution, 0.5% w/w in both eyes of New Zealand (albino) rabbits demonstrated pharmacokinetic parameters as shown in Table 5.
Table 5 Pharmacokinetic Parameters for 0.5% Azithromycin Ophthalmic Solution: Single Instillation in New Zealand (Albino) Rabbits
| Tissues | Cmax (μg/g) | Tmax (h) | Terminal t1/2 (h) | AUC [(μg/g) x h] |
| Tears | 180.2 | 0.5 | 8.4 | 277.9 |
| Conjunctiva | 20.0 | 2.0 | 46 | 213.4 |
| Cornea | 17.4 | 0.5 | 72 | 222.5 |
| Eyelid | 50.7 | 1.0 | 110 | 345.9 |
After instillation of a single drop (25 mg) of azithromycin ophthalmic solutions, 1% w/w or 0.5% w/w, in both eyes of New Zealand (albino) rabbits, azithromycin ophthalmic solution, 1% w/w achieved a much higher concentration in tears and conjunctiva. The peak azithromycin concentrations in tears and conjunctiva in rabbits instilled with a drop of azithromycin ophthalmic solution, 1.0% w/w were 288.4 µg/g and 82.7 µg/g, respectively. The amount of azithromycin that reached the retina was negligible.
Systemic Exposure: Instillation of one drop (25 mg) of azithromycin ophthalmic solution, 0.5% w/w into both eyes of a New Zealand white rabbit once daily for 5 days demonstrated very low peak blood azithromycin levels on Day 1 and Day 5, i.e., 2 ng/mL and 3 ng/mL, respectively. A subsequent study showed that instillation of one drop (25 mg) of azithromycin ophthalmic solution, 1% w/w, into both eyes of New Zealand white rabbits, also resulted in a peak azithromycin blood level of about 4 ng/mL.
PK/PD Parameters
Parameter of free drug AUC0-24hrs/MIC >25 correlates with efficacy of azithromycin.
Human Pharmacology
Protein Binding: The serum protein binding of azithromycin is variable in the concentration range approximating human exposure. Protein binding decreased at higher human exposure, e.g., 7% at 2 µg/mL.
MICROBIOLOGY
Mechanism of Action
Azithromycin is a macrolide antibiotic, and acts by binding to the 50S ribosomal subunit of susceptible microorganisms and interfering with microbial protein synthesis.
Development of Resistance
The two most common mechanisms of resistance are the presence of efflux pump and methylation of macrolide ribosomal binding sites. Methylation of macrolide ribosomal binding sites is through post-transcriptional modification of the 23S rRNA by an adenine-N6 methyltransferase encoded by the erm (erythromycin ribosome methylation) gene. Erm mutations usually confer a much higher level of bacterial resistance.
Cross-Resistance
Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.
Spectrum of Activity
Azithromycin has been shown to be active against most isolates of the following microorganisms, in clinical bacterial conjunctival infections:
| Species | N | Range µg/mL | MIC50 µg/mL | MIC90 µg/mL |
| Haemophilus influenzae | 215 | 0.03 - 8.0 | 2.0 | 2.0 |
Staphylococcus aureus (methicillin-susceptible isolates only) | 83 | 1.0 - >1024 | 2.0 | >1024 |
| Staphylococcus epidermidis | 30 | 0.5 - >1024 | 64.0 | >1024 |
Streptococcus pneumoniae (penicillin-susceptible isolates only) | 143 | 0.12 - 32.0 | 0.12 | 0.25 |
The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of AzaSite™ (azithromycin ophthalmic solution) 1% w/w in treating ophthalmological infections due to these microorganisms have not been established. This list of microorganisms is provided as an aid only in assessing the potential treatment of conjunctival infections.
| Species | N | MIC Range µg/mL | MIC50 µg/mL | MIC90 µg/mL |
| Chlamydia pneumoniae | 10 | 0.062 - 0.125 | 0.062 | 0.125 |
| Chlamydia trachomatis | 10 | 0.062 - 0.125 | 0.125 | 0.125 |
| Mycoplasma hominis | 43 | 16 - 32 | 32 | 32 |
| Mycoplasma pneumoniae | 45 | 0.008 - 0.12 | 0.015 | 0.03 |
| Streptococcus (Groups C, F, G) | 104 | ≤0.008 - >16 | 0.12 | 8 |
| Streptococcus pyogenes | 101 | 0.06 - >16 | 0.12 | 0.12 |
| Streptococcus agalactiae | 54 | N/A | 0.05 | 0.10 |
| Ureaplasma urealyticum | 33 | 0.25 - 0.5 | 0.5 | 0.5 |
| Streptococcus viridans group | 104 | 0.015 - >16 | 0.25 | 16 |
N/A = not available
Susceptibility Tests
There are currently no CLSI approved standards for assessing in vitro susceptibility of conjunctival isolates to topical antibiotics, including azithromycin. Standardized systemic susceptibility tests may not be appropriate to predict clinical effectiveness in treating conjunctivitis.
TOXICOLOGY
Carcinogenesis, Mutagenesis
Long term studies in animals have not been conducted because of low (less than 10 ng/mL) systemic exposure upon topical ocular application of a (2 mg) dose of AzaSite™ (azithromycin ophthalmic solution) 1% w/w.
Genotoxicity studies using azithromycin demonstrated negative results in Ames Salmonella typhimurium tester strains TA1535, TA1537, TA98 and TA100, thymidine kinase locus of L5178Y/TK cells and in vivo conditions in mice. Azithromycin did not cause gene mutations in microbial or mammalian cells, or chromosomal aberrations in cultured human lymphocytes or in vivo in mouse bone marrow.
Juvenile Toxicity
Studies with azithromycin ophthalmic solution, 1% w/w in juvenile animals have not been conducted. Based upon available animal data with low systemic exposure upon topical administration of azithromycin ophthalmic solution, 1% w/w, children administered AzaSite™ are not expected to exhibit phospholipidosis in internal organs.
Phototoxicity
Azithromycin has a very low phototoxic potential based upon absorption spectrum in the UVC range. Based upon low systemic exposure in animals after topical administration of azithromycin ophthalmic solution, 1% w/w, AzaSite™ has a low phototoxic potential.
Phospholipidosis
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 azithromycin ophthalmic solution, 1% w/w. This effect was reversible upon cessation of azithromycin ophthalmic solution, 1% w/w treatment. Phospholipidosis was not observed in the retina or iris/ciliary bodies of Dutch Belted rabbits administered azithromycin ophthalmic solution, 1% w/w twice daily in the right eye from 14 days to 30 days. The significance of these toxicological findings for animals and for humans is unknown.
Binding to Melanin
30-day ocular toxicity studies in Dutch Belted pigmented rabbits did not detect any toxicity in ocular pigmented tissues such as iris/ciliary bodies and retina due to administration of azithromycin ophthalmic solution, 1% w/w twice daily in the right eye of the rabbits.
Benzalkonium chloride (BAC)
AzaSite™ (azithromycin ophthalmic solution) 1% w/w contains 0.003% BAC as a preservative. 0.003% of BAC has shown corneal cell toxicity in in vitro conditions. Upon instillation to the eyes, instant 20 fold dilution occurs because of tearing and blinking. The diluted BAC in AzaSite™ should have little or no effect on the corneal epithelium.
Poloxamer 407
AzaSite™ (azithromycin ophthalmic solution) 1% w/w contains poloxamer 407 as a surfactant. When the vitreous was replaced by 20% poloxamer 407, electroretinographic amplitude decreased dramatically to a flat tracing by 24 hours after the replacement. Histopathologic examinations revealed marked destruction of the retina by 2 weeks after the procedure. These data suggest that poloxamer 407 may be safe for extraocular but not intraocular use.
Studies performed in rabbits revealed very few systemic side effects and no significant toxicological effects when azithromycin ophthalmic solution, 1% w/w was administered topically to the eye.
The following table provides a summary of the toxicology studies used to assess the safety of azithromycin when administered systemically and ophthalmically.
| Type of Study | Species/ Strain/Sex/No. Per Group | Route Of Administration/ Duration of Dosing | Doses | Principal Effects Observed |
| Repeat Dose Toxicity | New Zealand white rabbits 3/sex/group | Ocular Topical 14 days azithromycin ophthalmic solutions, 0.2% to 1.0% w/w or vehicle were instilled in one eye. The other eye served as untreated control. | one drop azithromycin ophthalmic solution, 0.2% w/w four times daily; one drop azithromycin ophthalmic solution, 0.5% w/w four times daily; one drop azithromycin ophthalmic solution, 1.0% w/w four times daily; one drop vehicle four times daily. | None except microvacuolation in corneal epithelium and stroma. |
| Repeat Dose Toxicity | Dutch Belted rabbits 7/sex/group | Ocular Topical 1-month dosing with a 1- and 2-month recovery azithromycin ophthalmic solution, 1.0% w/w or vehicle were instilled in one eye. The other eye served as untreated control. | one drop azithromycin ophthalmic solution, 1.0% w/w twice daily; one drop vehicle twice daily. | No adverse effects and no ocular findings were observed. Minimal to mild, reversible multifocal cytoplasmic microvacuolation in the ocular corneal epithelium was noted. |
| Repeat Dose Toxicity | Dutch Belted rabbits 12 males/group | Ocular Topical 1-month dosing with a 2-month recovery azithromycin ophthalmic solution, 1.0% w/w; degraded azithromycin ophthalmic solution, 1.0% w/w; or vehicle was instilled in one eye. The other eye served as untreated control. | one drop azithromycin ophthalmic solution, 1.0% w/w twice daily; one drop degraded azithromycin ophthalmic solution, 1.0% w/w formulation twice daily; one drop vehicle, twice daily. | No adverse effects and no ocular findings were observed. Minimal to mild, reversible multifocal cytoplasmic microvacuolation in the ocular corneal epithelium was noted. |
| Type of Study | Species/ Strain/Sex/No. Per Group | Route Of Administration/ Duration of Dosing | Doses | Principal Effects Observed |
| Repeat Dose Toxicity | New Zealand white rabbits 10/sex/group | Ocular Topical 52 weeks 0.6% DuraSite (Carbopol 976, or Noveon AA-1, or polycarbophil) formulation; 1.3% DuraSite formulation; or one drop of Optisoft, a vehicle control, were instilled in one eye. The other eye served as untreated control. | one drop of 0.6% DuraSite (Carbopol 976, or Noveon AA-1, or polycarbophil) formulation three times daily; one drop of 1.3% DuraSite formulation three times daily; One drop of Optisoft, a vehicle control, three times daily. | Ocular administration of DuraSite with concentrations ranging from 0.6% to 1.3% three times daily for at least 52 weeks elicited no evidence of ocular or systemic toxicity. |
| Reproductive Toxicity | Long Evans rats: 15 males and 30 females/group for the active 30 males and 60 females for the vehicle | Oral According to standard protocol | azithromycin 10, 20, 30 mg/kg/day | Minimum reduction in pregnancy rates were observed at 20 and 30 mg/kg doses, but still within historical control range. |
Sprague Dawley rats: 15 males and 30 females/group for the active 20 inseminated females/group for the vehicle | Oral According to standard protocol | azithromycin 10, 20, 40, 50, 100 and 200 mg/kg/day | No embryotoxicity and teratogenicity were observed up to 200 mg/kg. A slight delay in ossification was noted at the 200 mg/kg dose which was attributed to maternal toxicity. | |
albino mice: 15 males and 30 females/group for the active 20 females/group for the vehicle | Oral According to standard protocol | azithromycin 10, 20, 40, 50, 100 and 200 mg/kg/day | No embryotoxicity and teratogenicity were observed up to 200 mg/kg. | |
| Ototoxicity | Duncan-Hartley guinea pigs 5/group | Oral Two doses azithromycin | 45 mg/kg azithromycin | Azithromycin produced a reversible reduction in transiently evoked otoacoustic emissions. |
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