INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise patients and their caregiver(s) that there may be drainage from the ear the first few days following ear tube surgery, but if the ear becomes painful, or continuous ear discharge is noted, or the patient develops fever, advise patients and their caregiver(s) to consult their physician.For acute otitis externa, advise patients and/or their caregivers that if the ear continues to be painful, swollen or itchy after week, they should consult their physician.Distributed by:ALK-Abello, Inc.Port Washington, NY 11050 www.otiprio.comOTIPRIO(R) is registered trademark of ALK-Abello, Inc.U.S. Patent Nos: 8,318,817, 9,205,048, 9,220,796, 9,233,068, 9,486,405, and 9,603,796413083-A.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE OTIPRIO is indicated for The treatment of pediatric patients (6 months of age and older) with bilateral otitis media with effusion undergoing tympanostomy tube placement. The treatment of acute otitis externa in patients months of age and older due to Pseudomonas aeruginosa and Staphylococcus aureus.. OTIPRIO is fluoroquinolone antibacterial indicated for the following conditions:The treatment of pediatric patients (age months and older) with bilateral otitis media with effusion undergoing tympanostomy tube placement. (1) The treatment of acute otitis externa in patients months of age and older due to Pseudomonas aeruginosa and Staphylococcus aureus. (1). The treatment of pediatric patients (age months and older) with bilateral otitis media with effusion undergoing tympanostomy tube placement. (1) The treatment of acute otitis externa in patients months of age and older due to Pseudomonas aeruginosa and Staphylococcus aureus. (1).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS Otitis Media with Effusion: The most frequently occurring adverse reactions (with an incidence rate greater than 3%) were nasopharyngitis and irritability. (6.1)Acute Otitis Externa: The most frequently occurring adverse reactions (with an incidence rate of at least 2%) were: ear pruritus, headache, otitis media and ear discomfort. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact ALK-Abello, Inc. at 1-855-216-6497 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.Otitis Media with EffusionIn two randomized, sham-controlled Phase clinical trials, 530 pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement were treated with OTIPRIO or sham administered intratympanically as single dose (0.1 mL to each ear). The median age of the pediatric patients enrolled in the clinical trials was 1.5 years; 62% of patients were months through years of age and 38% of patients were greater than years of age.Adverse reactions that occurred in at least 3% of OTIPRIO patients and at an incidence greater than sham are presented in Table 1.Table 1: Adverse Reactions in Phase Otitis Media with Effusion TrialsAdverse ReactionsOTIPRIO(N=357)Sham(N=173)Nasopharyngitis5%4%Irritability5%3%Rhinorrhea3%2%Acute Otitis ExternaIn single randomized, sham controlled Phase clinical trial, 259 pediatric and adult patients with acute otitis externa were treated with OTIPRIO or sham administered by healthcare professional to the external ear canal as single dose (0.2 mL to each affected ear). The median age of the patients enrolled in the clinical trial was 34 years; 26% were pediatric patients (age to 17 years), 65% were adults (age 18 to 64 years), and 8% were elderly patients (age 65 years and older).Adverse reactions that occurred in at least 2% of OTIPRIO patients and at an incidence greater than sham are presented in Table 2.Table 2: Adverse Reactions in Phase Acute Otitis Externa TrialAdverse ReactionsOTIPRIO(N=127)Sham(N=132)Ear Pruritus2%2%Headache2%1%Otitis Media2%1%Ear Discomfort2%0%.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: Salmonella/Microsome Test (Negative) Escherichia coli DNA Repair Assay (Negative) Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mutation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNA Repair Assay (Positive)Thus, of the in vitro tests were positive, but results of the following in vivo test systems gave negative results: Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice)Long-term carcinogenicity studies in mice and rats have been completed for ciprofloxacin. After daily oral doses of 750 mg/kg in mice and 250 mg/kg in rats (for mice and rats respectively, approximately 300 and 200 times the maximum recommended clinical dose of ototopical ciprofloxacin based upon body surface area, assuming total absorption of ciprofloxacin from the ear of patient treated with OTIPRIO) were administered for up to years, there was no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects in these species.Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg/ day revealed no evidence of impairment. This would be approximately 80 times the maximum recommended clinical dose of ototopical ciprofloxacin based upon body surface area, assuming total absorption of ciprofloxacin from the ear of patient treated with OTIPRIO.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. Ciprofloxacin is fluoroquinolone antibacterial [see Microbiology (12.4 )].. 12.3 Pharmacokinetics. The plasma concentration of ciprofloxacin following otic administration of OTIPRIO was not measured.. 12.4 Microbiology. Mechanism of ActionThe bactericidal action of ciprofloxacin results from interference with the enzyme DNA gyrase, which is needed for the synthesis of bacterial DNA.ResistanceBacterial resistance to fluoroquinolones can develop through chromosomally- or plasmid-mediated mechanisms. In vitro studies demonstrated cross-resistance between ciprofloxacin and some fluoroquinolones. There is generally no cross- resistance between ciprofloxacin and other classes of antibacterial agents, such as beta-lactams or aminoglycosides.Antimicrobial ActivityCiprofloxacin has been shown to be active against most isolates of the following bacteria: Gram-positive Bacteria Staphylococcus aureus Streptococcus pneumoniae Gram-negative Bacteria Haemophilus influenzae Moraxella catarrhalis Pseudomonas aeruginosa.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Bilateral Otitis Media with Effusion. Two randomized, multicenter, sham-controlled clinical trials in 532 pediatric patients with bilateral otitis media with effusion undergoing myringotomy with tympanostomy tube placement evaluated the safety and efficacy of OTIPRIO when administered intratympanically as single dose (NCT 01949155 and NCT 01949142). The median age of patients enrolled in the clinical trials was 1.5 years; 62% of patients were months through years of age and 38% of patients were greater than years of age. The efficacy endpoint for both trials was the cumulative proportion of study treatment failures through Day 15, defined as the occurrence of any of the following events: otorrhea as determined by blinded assessor on or after days post-surgery, otic or systemic antibacterial drug use for any reason any time post-surgery, as well as patients who missed visits or were lost-to-follow-up. Table presents the results from each Phase trial.Table 3: Cumulative Proportion of Treatment Failures Through Day 15 in Phase Trials (Otitis Media with Effusion)Trial (N=266)Trial (N=266)OTIPRIOShamDifference (Sham OTIPRIO) (95% CI)OTIPRIOShamDifference (Sham OTIPRIO) (95% CI)Treatment Failure25% (44/179)45% (39/87)20%(8%, 32%)2 21% (38/178)45% (40/88)24%(12%, 36%)2 Reason for Failure1 Otorrhea7%11%7%27%Otic antibacterial drugs6%17%5%8%Systemic antibacterial drugs2%5%3%3%Lost-to-follow-up and missed visit10%11%6%7%the earliest occurring treatment failure event, and patients were classified as treatment failure due only to that component for the remainder of the study P-value <0.001 for Cochran-Mantel-Haenszel test (adjusted for age-group)Administration of OTIPRIO did not lead to impairment in hearing function, middle ear function or tube patency by Day 29.. the earliest occurring treatment failure event, and patients were classified as treatment failure due only to that component for the remainder of the study P-value <0.001 for Cochran-Mantel-Haenszel test (adjusted for age-group). 14.2 Acute Otitis Externa. One randomized multicenter, sham-controlled clinical trial in 262 pediatric and adult patients with unilateral or bilateral acute otitis externa was designed to evaluate the safety and efficacy of OTIPRIO when administered by healthcare professional as single dose to the external ear canal to patients aged months and older (NCT 02801370). The median age of patients enrolled in the clinical trials was 34 years; 26% of patients were to 17 years of age, 65% of patients were 18 to 64 years of age, and 8% of patients were greater than 65 years of age. No patients less than years of age were enrolled.The primary efficacy endpoint was the proportion of patients with clinical response at Day 8. Clinical response was defined as the complete absence of signs and symptoms of acute otitis externa (i.e., tenderness, erythema, edema, and otorrhea as determined by the blinded assessor), and no concomitant systemic or topical antibacterial drug (given in the study ear) was taken for any reason at or prior to the study visit. Table contains the proportions of patients with clinical response at Day in both the intent to treat (ITT) population which contains all subjects who were randomized and did not have group streptococci cultured on Day and the microbiological ITT population which contains all ITT subjects who had positive culture for S. aureus or P. aeruginosa on Day 1.Table 4: Proportion of Patients with Clinical Response at Study Day (Acute Otitis Externa)Study PopulationOTIPRIOSham% Difference (OTIPRIO Sham) (95% CI)Intention to Treat (ITT) N=26069%90/13046%60/13023.11 (10.66, 34.62)Microbiological ITT (Mic-ITT) N=10860%31/5234%19/5625.72 (6.57, 43.32)1 p<0.001 from Fishers exact test. p=0.012 from Fishers exact test.ITT population all patients who were randomized and did not have group streptococci cultured on Day 1.Mic-ITT population all ITT patients who had positive culture for S. aureus orP. aeruginosa on Day 1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.Otitis Media with EffusionIn two randomized, sham-controlled Phase clinical trials, 530 pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement were treated with OTIPRIO or sham administered intratympanically as single dose (0.1 mL to each ear). The median age of the pediatric patients enrolled in the clinical trials was 1.5 years; 62% of patients were months through years of age and 38% of patients were greater than years of age.Adverse reactions that occurred in at least 3% of OTIPRIO patients and at an incidence greater than sham are presented in Table 1.Table 1: Adverse Reactions in Phase Otitis Media with Effusion TrialsAdverse ReactionsOTIPRIO(N=357)Sham(N=173)Nasopharyngitis5%4%Irritability5%3%Rhinorrhea3%2%Acute Otitis ExternaIn single randomized, sham controlled Phase clinical trial, 259 pediatric and adult patients with acute otitis externa were treated with OTIPRIO or sham administered by healthcare professional to the external ear canal as single dose (0.2 mL to each affected ear). The median age of the patients enrolled in the clinical trial was 34 years; 26% were pediatric patients (age to 17 years), 65% were adults (age 18 to 64 years), and 8% were elderly patients (age 65 years and older).Adverse reactions that occurred in at least 2% of OTIPRIO patients and at an incidence greater than sham are presented in Table 2.Table 2: Adverse Reactions in Phase Acute Otitis Externa TrialAdverse ReactionsOTIPRIO(N=127)Sham(N=132)Ear Pruritus2%2%Headache2%1%Otitis Media2%1%Ear Discomfort2%0%.

DESCRIPTION SECTION.

11 DESCRIPTION OTIPRIO (ciprofloxacin otic suspension) 6% contains the synthetic fluoroquinolone antibacterial, ciprofloxacin. OTIPRIO is for intratympanic administration for otitis media with effusion and otic administration to the external ear canal for acute otitis externa. OTIPRIO is supplied as white, preservative-free, sterile otic suspension of 6% (w/v) ciprofloxacin in neutral pH, buffered, isotonic solution in single-patient use glass vial containing mL. The glass vial is fitted with stopper not made with natural rubber latex. The inactive ingredients are poloxamer 407, sodium chloride, tromethamine, hydrochloric acid and water for injection (WFI).The thermosensitive suspension exists as liquid at room temperature or below and gels when warmed [see How Supplied/Storage and Handling 16 )].Ciprofloxacin has the following nomenclature:1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.3.Its chemical structure is as follows:Figure 2: Structure of Ciprofloxacin. Figure 2.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION OTIPRIO is for intratympanic or otic administration by healthcare professional only. (2.1) OTIPRIO is intended for single-patient use with up to two doses available in each vial. (2.1) For bilateral otitis media with effusion, administer OTIPRIO as single intratympanic administration of one 0.1 mL (6 mg) dose into each affected ear, following suctioning of the middle ear effusion. (2.1) For acute otitis externa, administer OTIPRIO as single 0.2 mL (12 mg) administration to the affected ear(s). (2.1) See Full Prescribing Information for directions for OTIPRIO dose preparation. (2.2). OTIPRIO is for intratympanic or otic administration by healthcare professional only. (2.1) OTIPRIO is intended for single-patient use with up to two doses available in each vial. (2.1) For bilateral otitis media with effusion, administer OTIPRIO as single intratympanic administration of one 0.1 mL (6 mg) dose into each affected ear, following suctioning of the middle ear effusion. (2.1) For acute otitis externa, administer OTIPRIO as single 0.2 mL (12 mg) administration to the affected ear(s). (2.1) See Full Prescribing Information for directions for OTIPRIO dose preparation. (2.2). Figure 1. 2.1 Dosage and Important Administration Instructions. OTIPRIO is for intratympanic or otic administration by healthcare professional only. OTIPRIO is intended for single-patient use, discard unused portion. For bilateral otitis media with effusion, administer OTIPRIO as single intratympanic administration of one 0.1 mL (6 mg) dose into each affected ear of pediatric patients (6 months of age and older), following suctioning of middle ear effusion. For acute otitis externa, administer OTIPRIO as single 0.2 mL (12 mg) administration to the external ear canal of each affected ear of patients aged months and older.. 2.2 Preparation of OTIPRIO. Directions for OTIPRIO dose preparation and handling are presented in Figure 1. The directions differ for each indication. Follow the correct directions.

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionThe bactericidal action of ciprofloxacin results from interference with the enzyme DNA gyrase, which is needed for the synthesis of bacterial DNA.ResistanceBacterial resistance to fluoroquinolones can develop through chromosomally- or plasmid-mediated mechanisms. In vitro studies demonstrated cross-resistance between ciprofloxacin and some fluoroquinolones. There is generally no cross- resistance between ciprofloxacin and other classes of antibacterial agents, such as beta-lactams or aminoglycosides.Antimicrobial ActivityCiprofloxacin has been shown to be active against most isolates of the following bacteria: Gram-positive Bacteria Staphylococcus aureus Streptococcus pneumoniae Gram-negative Bacteria Haemophilus influenzae Moraxella catarrhalis Pseudomonas aeruginosa.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: Salmonella/Microsome Test (Negative) Escherichia coli DNA Repair Assay (Negative) Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mutation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNA Repair Assay (Positive)Thus, of the in vitro tests were positive, but results of the following in vivo test systems gave negative results: Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice)Long-term carcinogenicity studies in mice and rats have been completed for ciprofloxacin. After daily oral doses of 750 mg/kg in mice and 250 mg/kg in rats (for mice and rats respectively, approximately 300 and 200 times the maximum recommended clinical dose of ototopical ciprofloxacin based upon body surface area, assuming total absorption of ciprofloxacin from the ear of patient treated with OTIPRIO) were administered for up to years, there was no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects in these species.Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg/ day revealed no evidence of impairment. This would be approximately 80 times the maximum recommended clinical dose of ototopical ciprofloxacin based upon body surface area, assuming total absorption of ciprofloxacin from the ear of patient treated with OTIPRIO.. 13.2 Animal Toxicology and/or Pharmacology. Guinea pigs dosed in the middle ear with OTIPRIO exhibited no drug-related structural or functional changes of the cochlear hair cells.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of OTIPRIO for the treatment of pediatric patients (6 months of age and older) with bilateral otitis media with effusion undergoing tympanostomy tube placement was established in 530 patients who participated in the Phase trials. The median age of patients enrolled in the clinical trials was 1.5 years; 62% of patients were months through years of age and 38% of patients were greater than years of age [see Adverse Reactions 6.1 and Clinical Studies 14 )]. The safety and effectiveness of OTIPRIO for the treatment of acute otitis externa was established in 67 pediatric patients (3 through 17 years of age) who participated in the Phase trial; 57% of patients were through 11 years of age and 43% of patients were 12 through 17 years of age. The safety and efficacy observed in the pediatric patients was no different from the older population. OTIPRIO is indicated for the treatment of acute otitis externa in pediatric patients months of age and older. [see Indications and Usage 1 ), Dosage and Administration 2 ), Adverse Reactions 6.1 and Clinical Studies 14 )].The safety and effectiveness of OTIPRIO in infants below months of age have not been established for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement and acute otitis externa.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy. Risk SummaryAnimal reproduction studies have not been conducted with OTIPRIO. No adequate and well-controlled studies have been performed in pregnant women. Because of the negligible systemic exposure associated with clinical administration of OTIPRIO, this product is expected to be of minimal risk for maternal and fetal toxicity when administered to pregnant women.. 8.2 Lactation. Risk SummaryCiprofloxacin is excreted in human milk with systemic administration. However, because of the negligible systemic exposure after otic application, nursing infants of mothers receiving OTIPRIO should not be affected.. 8.4 Pediatric Use. The safety and effectiveness of OTIPRIO for the treatment of pediatric patients (6 months of age and older) with bilateral otitis media with effusion undergoing tympanostomy tube placement was established in 530 patients who participated in the Phase trials. The median age of patients enrolled in the clinical trials was 1.5 years; 62% of patients were months through years of age and 38% of patients were greater than years of age [see Adverse Reactions 6.1 and Clinical Studies 14 )]. The safety and effectiveness of OTIPRIO for the treatment of acute otitis externa was established in 67 pediatric patients (3 through 17 years of age) who participated in the Phase trial; 57% of patients were through 11 years of age and 43% of patients were 12 through 17 years of age. The safety and efficacy observed in the pediatric patients was no different from the older population. OTIPRIO is indicated for the treatment of acute otitis externa in pediatric patients months of age and older. [see Indications and Usage 1 ), Dosage and Administration 2 ), Adverse Reactions 6.1 and Clinical Studies 14 )].The safety and effectiveness of OTIPRIO in infants below months of age have not been established for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement and acute otitis externa.. 8.5 Geriatric Use. Clinical studies of OTIPRIO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients [see Adverse Reactions 6.1 and Clinical Studies 14 )].