AZASITE

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with the rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice. The data described below reflect exposure to AzaSite in 698 patients. The population was between 1 and 87 years old with clinical signs and symptoms of bacterial conjunctivitis. The most frequently reported ocular adverse reaction reported in patients receiving AzaSite was eye irritation. This reaction occurred in approximately 1-2% of patients. Other adverse reactions associated with the use of AzaSite were reported in less than 1% of patients and included ocular reactions (blurred vision, burning, stinging and irritation upon instillation, contact dermatitis, corneal erosion, dry eye, eye pain, itching, ocular discharge, punctate keratitis, visual acuity reduction) and non-ocular reactions (dysgeusia, facial swelling, hives, nasal congestion, periocular swelling, rash, sinusitis, urticaria). Most common adverse reaction reported in patients was eye irritation (1-2% of patients). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Thea Pharma Inc. at 1-833-838-4028 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS Hypersensitivity to any component of this product. Hypersensitivity ( 4 )

11 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 C 38 H 72 N 2 O 12 . Chemical Structure

2 DOSAGE AND ADMINISTRATION The recommended dosage regimen for the treatment of bacterial conjunctivitis is: Instill 1 drop in the affected eye(s) twice daily, eight to twelve hours apart for the first two days and then instill 1 drop in the affected eye(s) once daily for the next five days. Instill 1 drop in the affected eye(s) twice daily, eight to twelve hours apart for the first two days and then instill 1 drop in the affected eye(s) once daily for the next five days. ( 2 )

1 INDICATIONS AND USAGE AzaSite ® is indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following microorganisms: CDC coryneform group G Efficacy for this organism was studied in fewer than 10 infections. Haemophilus influenzae Staphylococcus aureus Streptococcus mitis group Streptococcus pneumoniae AzaSite is a macrolide antibiotic indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following microorganisms: CDC coryneform group G, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and Streptococcus pneumoniae. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azithromycin is a macrolide antibiotic [see Clinical Pharmacology (12.4) ] . 12.3 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. 12.4 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 Efficacy for this organism was studied in fewer than 10 infections. Haemophilus influenzae Staphylococcus aureus Streptococcus mitis group Streptococcus pneumoniae 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 breakpoints. 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

12.1 Mechanism of Action Azithromycin is a macrolide antibiotic [see Clinical Pharmacology (12.4) ] .

12.3 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.

20230106

3

3 DOSAGE FORMS AND STRENGTHS 2.5 mL of a 1% sterile topical ophthalmic solution. 2.5 mL of 1% sterile topical ophthalmic solution. ( 3 )

AZASITE azithromycin monohydrate BENZALKONIUM CHLORIDE MANNITOL CITRIC ACID MONOHYDRATE SODIUM CITRATE, UNSPECIFIED FORM POLOXAMER 407 POLYCARBOPHIL SODIUM CHLORIDE EDETATE DISODIUM WATER SODIUM HYDROXIDE AZITHROMYCIN MONOHYDRATE AZITHROMYCIN ANHYDROUS

13.2 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.

13.1 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.

13 NONCLINICAL TOXICOLOGY 13.1 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. 13.2 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.

NDA050810

AZASITE

azithromycin monohydrate

82584-307

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

12.4 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 Efficacy for this organism was studied in fewer than 10 infections. Haemophilus influenzae Staphylococcus aureus Streptococcus mitis group Streptococcus pneumoniae 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 breakpoints. 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

PRINCIPAL DISPLAY PANEL - 2.5 mL Bottle Carton NDC 82584-307-03 AzaSITE ® (azithromycin ophthalmic solution) 1% Sterile 2.5 mL Rx Only FOR OPHTHALMIC USE ONLY PRINCIPAL DISPLAY PANEL - 2.5 mL Bottle Carton

Manufactured for: Thea Pharma Inc. Lexington, MA 02420 U.S. Patent No.: 7,758,553 AzaSite is a registered trademark of Sun Pharma © 2022. Thea Pharma Inc. All rights reserved Rev. 05/22 N10270C2USA/0522A

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling ( Patient Information ). Patients should be advised to avoid contaminating the applicator tip by allowing it to touch the eye, fingers or other sources. Patients should be directed to discontinue use and contact a physician if any signs of an allergic reaction occur. Patients should be told that although it is common to feel better early in the course of the therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AzaSite (azithromycin ophthalmic solution) or other antibacterial drugs in the future. Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis. Patients should be advised to thoroughly wash hands prior to using AzaSite. Patients should be advised to invert the closed bottle (upside down) and shake once before each use. Remove cap with bottle still in the inverted position. Tilt head back, and with bottle inverted, gently squeeze bottle to instill one drop into the affected eye(s).

Instructions for Use AzaSite ® (A-zuh-site) (azithromycin ophthalmic solution) 1% Read this Instructions for Use for AzaSite before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment. Important: AzaSite is for use as an eye drop only. The checklist below tells you when to use your medicine for each eye that has bacterial conjunctivitis: □ □ Day 1: 1 drop in the morning and 1 drop in the evening □ □ Day 2: 1 drop in the morning and 1 drop in the evening □ Day 3 1 drop anytime during the day □ Day 4 1 drop anytime during the day □ Day 5 1 drop anytime during the day □ Day 6 1 drop anytime during the day □ Day 7 1 drop anytime during the day This is a total of 9 drops of AzaSite for each infected eye. Avoid letting the applicator tip touch your eye, your fingers, or other objects. If a drop misses your eye, try again. Follow the steps below to use AzaSite correctly. Before using a new bottle of AzaSite: Turn the white cap clockwise until it comes off. Throw away the white cap. See Figure A Hold the bottle straight, turn the tan cap counterclockwise until it comes off. Put the tan cap back on the bottle and close tightly. (This lets out the air.) See Figure B Wash your hands each time you use AzaSite. To use AzaSite: Step 1. Turn the closed bottle upside down. See Figure C Step 2. Shake your hand firmly. This helps move the medicine into the tip of the bottle. See Figure D Step 3. Hold the bottle upside down and take off the tan cap. See Figure E Step 4. Tilt your head back. Hold the bottle over your eye and gently squeeze the bottle to let 1 drop into each eye that has bacterial conjunctivitis. Put the tan cap back on the bottle and close tightly. See Figure F If a drop does not come out of the bottle, repeat steps one to four. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured for: Thea Pharma Inc. Lexington, MA 02420 U.S. Patent No.: 7,758,553 AzaSite is a registered trademark of Sun Pharma. © 2022. Thea Pharma Inc. All rights reserved Rev. 05/22 N10270C2USA/0522B Figure A Figure B Figure C Figure D Figure E Figure F

14 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.

8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.

8.3 Nursing Mothers It is not known 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.

8.4 Pediatric Use The safety and effectiveness of AzaSite solution in pediatric patients below 1 year of age have not been established. The efficacy of AzaSite in treating bacterial conjunctivitis in pediatric patients one year or older has been demonstrated in controlled clinical trials [see Clinical Studies (14) ] .

8.1 Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and mice at doses up to 200 mg/kg/day. The highest dose was associated with moderate maternal toxicity. These doses are estimated to be approximately 5,000 times the maximum human ocular daily dose of 2 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, 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.

Pregnancy Category B. Reproduction studies have been performed in rats and mice at doses up to 200 mg/kg/day. The highest dose was associated with moderate maternal toxicity. These doses are estimated to be approximately 5,000 times the maximum human ocular daily dose of 2 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and mice at doses up to 200 mg/kg/day. The highest dose was associated with moderate maternal toxicity. These doses are estimated to be approximately 5,000 times the maximum human ocular daily dose of 2 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, 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. 8.3 Nursing Mothers It is not known 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. 8.4 Pediatric Use The safety and effectiveness of AzaSite solution in pediatric patients below 1 year of age have not been established. The efficacy of AzaSite in treating bacterial conjunctivitis in pediatric patients one year or older has been demonstrated in controlled clinical trials [see Clinical Studies (14) ] . 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.

16 HOW SUPPLIED/STORAGE AND HANDLING AzaSite is a sterile aqueous topical ophthalmic formulation of 1% azithromycin. NDC 82584-307-03: 2.5 mL in 5 mL bottle containing a total of 25 mg of azithromycin in a white, round, low-density polyethylene (LDPE) bottle, with a clear LDPE dropper tip, and a tan colored high density polyethylene (HDPE) eyedropper cap. A white tamper evident over-cap is provided. NDC 82584-307-04: 2.5 mL in 4 mL bottle containing a total of 25 mg of azithromycin in a white, round, low-density polyethylene (LDPE) bottle, with a clear LDPE dropper tip, and a tan colored high density polyethylene (HDPE) eyedropper cap. A white tamper evident over-cap is provided. Storage and Handling: Store unopened bottle under refrigeration at 2° to 8°C (36° to 46°F). Once the bottle is opened, store at 2° to 25°C (36° to 77°F) for up to 14 days. Discard after the 14 days.

Storage and Handling: Store unopened bottle under refrigeration at 2° to 8°C (36° to 46°F). Once the bottle is opened, store at 2° to 25°C (36° to 77°F) for up to 14 days. Discard after the 14 days.