PRODUCT MONOGRAPH

Pr XTORO*

Finafloxacin Otic Suspension, 0.3% w/v

Antibacterial (Otic)

ALCON Canada Inc. Date of Preparation: 2665 Meadowpine Blvd. March 11, 2016 Mississauga ON L5N 8C7 www.alcon.ca

Submission Control No: 172450

* A trademark of Novartis © 2016 Novartis

XTORO* (finafloxacin otic suspension, 0.3%) Page 1 of 19

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ...... 3 SUMMARY PRODUCT INFORMATION ...... 3 INDICATIONS AND CLINICAL USE ...... 3 CONTRAINDICATIONS ...... 3 WARNINGS AND PRECAUTIONS ...... 4 ADVERSE REACTIONS ...... 5 DRUG INTERACTIONS ...... 6 DOSAGE AND ADMINISTRATION ...... 6 OVERDOSAGE ...... 7 ACTION AND CLINICAL PHARMACOLOGY ...... 7 STORAGE AND STABILITY ...... 9 SPECIAL HANDLING INSTRUCTIONS ...... 9 DOSAGE FORMS, COMPOSITION AND PACKAGING ...... 9

PART II: SCIENTIFIC INFORMATION ...... 10 PHARMACEUTICAL INFORMATION ...... 10 CLINICAL TRIALS ...... 10 DETAILED PHARMACOLOGY ...... 13 MICROBIOLOGY ...... 14 TOXICOLOGY ...... 15 REFERENCES ...... 16

PART III: CONSUMER INFORMATION...... 17

XTORO* (finafloxacin otic suspension, 0.3%) Page 2 of 19

Pr XTORO* Finafloxacin Otic Suspension, 0.3% w/v

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Dosage Form / Clinically Relevant Nonmedicinal Administration Strength Ingredients Otic (topical) Suspension, 0.3% w/v Magnesium Chloride

For a complete listing see Dosage Forms, Composition and Packaging section.

INDICATIONS AND CLINICAL USE

XTORO* (finafloxacin otic suspension), 0.3% is indicated for the treatment of acute otitis externa (AOE) caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus, with or without an otowick, in patients age 1 year and older.

Geriatrics (≥ 65 years of age): No overall differences in safety and effectiveness have been observed between elderly and younger patients.

Pediatrics (1 year of age): The safety and efficacy of XTORO* in infants below one year of age have not been established. The safety and efficacy of XTORO* has been studied in pediatric patients 1 year and older (314 patients) in controlled clinical trials.

CONTRAINDICATIONS

The use of XTORO* is contraindicated in patients with a history of hypersensitivity to finafloxacin, to other quinolones, or to any of the components in this medication.

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WARNINGS AND PRECAUTIONS

General This product is for otic use only and not approved for ophthalmic use.

This product is not approved for injection. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, were reported in patients receiving treatment based on systemically administered quinolones. Serious acute hypersensitivity reactions may require immediate emergency treatment.

If otorrhea persists after a full course of therapy, or if two or more episodes of otorrhea occur within six months, further evaluation is recommended to exclude an underlying condition such as cholesteatoma, foreign body, or a tumor.

Drug resistant organisms: As with other antibacterial preparations, prolonged use may lead to overgrowth of resistant organisms, including yeast and fungi. If the infection has not improved after one week of treatment, this treatment should be discontinued and cultures should be obtained to guide further treatment.

Carcinogenesis and Mutagenesis Carcinogenic potential of finafloxacin has not been studied. Finafloxacin was shown to be genotoxic and clastogenic in reverse mutation assay, mouse lymphoma cell forward mutation assay, and micronucleus assay in vitro.

Special Populations

Pregnant Women: Teratogenic Effects: Finafloxacin was shown to be teratogenic following intravenous administration in rabbits. In the rabbit, the maternal NOEL was 3 mg/kg and fetal toxicity was observed at the lowest dose, 1 mg/kg. Fetal toxicity at 1 mg/kg was characterized by paw hyperflexure, exencephaly, decreased brain tissue, enlarged fontanel, and skeletal effects. Finafloxacin administered to male and female rats at oral doses of 100 mg/kg/day, approximately 60,000 times higher than the clinical dose (based on a 30 μL drop size, 4 drop per dose, BID, and a 50 kg person), resulted in no changes in the fertility index and implantation rate. Effects on male reproductive parameters, markedly low sperm counts and decreased motility, were observed at doses of 500mg/kg/day. Since there are no adequate and well- controlled studies in pregnant women, this drug should not be used in pregnant women unless the potential benefit to the mother justifies the potential risk to the embryo or fetus.

Nursing Women: Finafloxacin has been identified in the milk of nursing rats following oral administration. It is not known whether topical otic administration could result in sufficient systemic absorption to produce detectable quantities in the human breast milk. Nevertheless, caution should be exercised when finafloxacin is administered to a nursing mother.

Pediatrics (> 1 year and older): The safety and efficacy of XTORO* in infants below one year of age have not been established.

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Geriatrics (≥ 65 years of age): No overall differences in safety and effectiveness have been observed between elderly and younger patients.

ADVERSE REACTIONS

Adverse Drug Reaction Overview A total of 618 patients were treated with XTORO* in two Phase 3 clinical trials. No serious adverse reactions were reported. The most frequently reported adverse reactions of those exposed to XTORO*occurring at an incidence of 0.5% included ear pruritus and dizziness.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug- related adverse events and for approximating rates.

Table 1 - Overall Frequency and Incidence of Common Treatment-Emergent Adverse Events Occurring at ≥ 1.0% - C-10-018 and C-10-019 Finafloxacin Vehicle n= 618 n= 616 Coded Adverse Event (%) (%) Ear and labyrinth disorders Ear pruritus 8 (1.3) 6 (1.0) Ear Pain 3 (0.5) 9 (1.5) Ear discomfort 2 (0.3) 9 (1.5) Gastrointestinal disorders Nausea 7 (1.1) 1 (0.2) Infections and infestations Otitis media 8 (1.3) 14 (2.3) Otitis externa 11 (1.8) 9 (1.5) Nervous system disorders Headache 11 (1.8) 18 (2.9) Coded adverse event = MedDRA Preferred Term (version 15.0) presented by System Organ Class.

A total of 91 patients (14.7%) reported treatment-emergent adverse events in the finafloxacin otic suspension, 0.3% group, and 99 patients (16.1%) reported treatment-emergent adverse events in the Vehicle group. Table 1 presents common treatment-emergent adverse events reported at rates ≥ 1.0% during the Phase 3 efficacy and safety studies (C-10-018 and C-10- 019).

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Less Common Clinical Trial Adverse Drug Reactions (<1%) The following adverse drug reactions (events assessed to be related in clinical trials to the use of XTORO*) were reported at a rate of < 1.0%: Ear and labyrinth disorders: ear pruritus, cerumen impaction, hypoacusis Gastrointestinal disorders: nausea Infections and infestations: ear infection fungal, otitis externa candida Nervous system disorders: dizziness, headache

Abnormal Hematologic and Clinical Chemistry Findings XTORO* had no clinically relevant treatment-related effect upon laboratory parameters.

DRUG INTERACTIONS Overview Specific drug interaction studies have not been conducted with XTORO*. Given the low systemic concentration of finafloxacin following topical otic administration of the product, drug interactions are unlikely to occur.

Drug-Drug Interactions Specific drug interaction studies have not been conducted with XTORO* (finafloxacin otic suspension, 0.3%). Given the low systemic concentration of finafloxacin following topical otic administration of the product, drug interactions are unlikely to occur.

Drug-Food Interactions Interactions with food have not been established.

Drug-Herb Interactions Interactions with herbal products have not been established.

Drug-Laboratory Interactions Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment Instill four drops into the affected ear twice daily for seven days. For patients requiring use of an otowick, the initial dose can be doubled (to 8 drops), followed by 4 drops instilled into the affected ear twice daily for seven days.

Missed Dose If a dose is missed, it should be given as soon as possible. If it is almost time for the next dose, skip the next dose and go back to the regular dosing schedule.

Administration The suspension should be warmed by holding the bottle in the hand for one or two minutes prior to dosing in order to avoid dizziness which may result from the instillation of a cold

XTORO* (finafloxacin otic suspension, 0.3%) Page 6 of 19 suspension. The suspension should be shaken well immediately before using. The patient should lie with the affected ear upward and then the drops should be instilled. The position should be maintained for 60 seconds to facilitate penetration of the drops into the ear canal. Repeat if necessary for the opposite ear. Discard unused portion after therapy is complete.

This product is sterile when packaged. Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the suspension.

Patients should be advised that if rash or allergic reaction occurs, they should discontinue the use of the product immediately and contact their physician.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Due to the characteristics of this preparation, no toxic effects are expected with an otic overdose of this product, nor in the event of accidental ingestion of the contents of one bottle.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action Finafloxacin is a fluoroquinolone antibiotic targeting bacterial DNA gyrase and topoisomerase IV enzymes. DNA gyrase is important in DNA replication by relaxing the supercoiled DNA. Topoisomerase IV is implicated in separation of linked replicated daughter chromosomes. Inhibition of either or both of these enzymes will result in death of the replicating cell. Evidence that finafloxacin targets DNA gyrase and/or topoisomerase IV was shown by investigations of the activity of finafloxacin against bacteria with mutations in the genes encoding either DNA gyrase or topoisomerase IV enzymes.

Pharmacodynamics Finafloxacin is an antibiotic that demonstrates improved antibacterial activity under acidic conditions (pH 5.8). Finafloxacin belongs to fluoroquinolone class of antibacterials which involves the inhibition of bacterial type II topoisomerase, DNA gyrase and topoisomerase IV. These enzymes are required for bacterial DNA replication, transcription, repair and recombination. Finafloxacin has been shown to be active against most isolates of Pseudomonas aeruginosa and Staphylococcus aureus, in both in vitro and clinical studies.

Pharmacokinetics Systemic pharmacokinetics of finafloxacin after ototopical administration of XTORO* (finafloxacin otic suspension, 0.3%) has been studied in healthy subjects and in patients with acute otitis externa. Systemic exposure to finafloxacin was extremely low; and as a result there was insufficient data to determine pharmacokinetic parameters.

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In a clinical study, healthy subjects received 4 drops in each ear twice daily for 7.5 days. Quantifiable finafloxacin concentrations (> 0.05 ng/mL) were observed in plasma samples from only 2 of the 14 subjects at 3 time points and the concentrations in these 3 samples were slightly above the quantitation limit. On Day 1, at 1 and 4 hours post dose, samples from 1subject showed plasma levels of 0.0534 ng/mL and 0.0603 ng/mL, respectively. On Day 8, at 12 hours post dose, the sample from the second subject showed a plasma level of 0.0812 ng/mL. At all other sampling time points, plasma levels in these 2 subjects were below the quantitation limit.

In another clinical study, AOE patients were randomized to the following 2 treatment groups: 4 drops of finafloxacin with otowick and 4 drops of finafloxacin without otowick. An additional nonrandomized treatment group of 8 drops of finafloxacin with otowick was included. Each treatment group consisted of 12 patients. Quantifiable finafloxacin concentrations (> 0.05 ng/mL) were observed in plasma samples from 2 of the 36 patients. Plasma concentrations of finafloxacin were not quantifiable (< 0.05 ng/mL) in all other samples collected. In the first of the 2 patients (male, 4 drops without otowick), quantifiable levels of 0.12 ng/mL, 0.100 ng/mL and 0.0735 ng/mL were observed at 0.5, 1.0 and 2 hours, respectively. In the second subject (female, 8 drops with otowick), quantifiable levels of 0.141 ng/mL and 0.234 ng/mL were observed at 1 and 2 hours, respectively.

Absorption: Finafloxacin plasma concentrations are very low following repeated ototopical doses of XTORO* (finafloxacin otic suspension), 0.3%. In healthy subjects administered 4 drops in each ear daily for seven days quantifiable finafloxacin concentrations were observed in only 2 of 14 subjects at a total of 3 time points; and these concentrations were just above the quantitation limit (0.05 ng/mL).

Distribution: The protein binding of finafloxacin was determined in rat, dog and human plasma using the equilibrium dialysis method. Over a concentration range of 10 to 1000 ng/mL, the percent of bound drug was independent of concentration. At 10 ng/mL, a level relevant to levels following ototopical administration, the percents of bound drug in rat, dog and human plasma were 44.1%, 17.1% and 21.0%, respectively.

The distribution of 14C-AL-60731 as total radioactivity into blood cells was determined with blood and plasma from rats following a 2 mg (free base)/kg oral dose. At Cmax, the blood to plasma ratio was 0.91, which corresponds to a blood cell-to-plasma ratio of 0.79 at an assumed hematocrit of 0.45.

Metabolism: The systemic exposure to finafloxacin is extremely low following ototopical doses. Using a very sensitive mass spectrometry assay with a lower quantitation limit of 0.05 ng/mL, unchanged parent drug was detected in only a few samples.

Excretion: Data in rats showed the primary route of excretion of drug-derived radioactivity was via urine with a mean of 57.5 ± 3.45% of the dose recovered in urine through 120 hours post-dose. Excretion in feces accounted for 38.7 ± 5.66% of the dose. Only a trace of quantifiable radioactivity was recovered in traps designed for collection of expired CO2 and organic volatile components. An additional 5.50 ± 2.88% was recovered in cage rinses. At study termination (120 hours), a total of 102 ± 3.44% of the dose was recovered.

XTORO* (finafloxacin otic suspension, 0.3%) Page 8 of 19 The excretion of radioactive drug equivalents was rapid with 92% of the dose recovered in the first 24 hours. The excretion of radioactivity in the bile following the intravenous dose indicates radioactive drug equivalents are excreted in the bile.

Special Populations and Conditions

Pediatrics: The safety and efficacy of XTORO* has been established in pediatric patients 1 year and older (314 patients) in adequate and well controlled clinical trials.

Geriatrics: No overall differences in safety and effectiveness have been observed between elderly and younger patients.

Gender and Race: The extent of exposure was slightly higher in females compared to males. The elimination half-life was similar between females and males.

A review of adverse events in the Phase 3 efficacy and safety studies (C-10-018 and C-10-019) by age category, gender, and race revealed no clinically relevant differences between the subgroups.

Renal Insufficiency & Hepatic Insufficiency: There are no specific studies in patients with renal insufficiency or with hepatic insufficiency.

Genetic Polymorphism: No data available.

STORAGE AND STABILITY Store at 2°C – 25°C. Do not freeze. Protect from light. Shake well before use.

SPECIAL HANDLING INSTRUCTIONS None.

DOSAGE FORMS, COMPOSITION AND PACKAGING XTORO* (finafloxacin otic suspension) 0.3% w/v is a sterile, preserved, aqueous, ototopical suspension supplied in an opaque plastic bottle with a controlled drop tip and a white cap.

Net contents are 0.5 mL in a 4ml bottle (sample), 5 ml supplied in an 8 mL bottle and 7.5 mL supplied in an 10 mL bottle.

XTORO* (finafloxacin otic suspension), 0.3% w/v. Active ingredient: finafloxacin, 0.3% w/v. Preservative: benzalkonium chloride (0.005 % w/v). Inactive ingredients include: sodium chloride, hydroxyethylcellulose, tyloxapol, magnesium chloride, and purified water. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.

During drug product manufacturing, finafloxacin forms a complex with magnesium.

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: finafloxacin

Chemical name: (-)-8-cyano-1-cyclopropyl-6-fluoro-7-[(4aS,7aS)- hexahydropyrrolo[3,4-b]-1,4-oxazin-6(2H)-y]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid

Molecular formula and molecular mass: C20H19FN4O4; 398.4

Structural formula:

Physicochemical properties: Finafloxacin is a white to yellow powder or crystals that is slightly soluble in water (0.125 mg/mL). Polymorphic form A

pH and pKa: The dissociation constants reported for finafloxacin are pKa1 5.6 (carboxylate function and pKa2 7.8 (N in C7 substituent). During drug product manufacturing, finafloxacin forms a complex with magnesium in situ.

CLINICAL TRIALS

Study demographics and trial design

Two pivotal clinical studies were conducted (C-10-018 and C-10-019). Both studies were multicenter, double-masked, parallel-group, vehicle-controlled, randomized studies and were conducted in patients 6 months of age and older. The objective of these studies was to demonstrate the superiority of XTORO* (finafloxacin otic suspension, 0.3%) relative to Finafloxacin Vehicle (Vehicle) based upon clinical cures at test-of-cure (TOC) for the treatment of AOE.

The patient population chosen for inclusion in these clinical studies are directly representative of patients that are expected to be treated with XTORO* in the general population.

XTORO* (finafloxacin otic suspension, 0.3%) Page 10 of 19 Table 2 - Summary of patient demographics for pivotal clinical trials for the treatment of acute otitis externa (AOE) Study # Trial design Dosage, route of Study subjects Mean age Gender administration and (n=number) (Range) duration C-10-018 Multicenter, double- 4 drops, twice daily n = 686 31.6 Male: 301 masked, for 7 days (0.8 – 85.0) Female: 385 parallel-group, Ototpoical vehicle-controlled, administration randomized C-10-019 Multicenter, double- 4 drops, twice daily n = 548 18.9 Male:230 masked, for 7 days (0.9 – 82.0) Female: 318 parallel-group, Ototpoical vehicle-controlled, administration randomized

Study results In two randomized multicenter, vehicle-controlled clinical trials, XTORO* dosed 2 times per day for 7 days was superior to its Vehicle for both clinical and microbiological outcomes as well as in time to cessation of pain in patients with acute otitis externa (AOE). Among 560 patients (161 with an otowick) that were pathogen positive (baseline microbiological specimen that contained Staphylococcus aureus and/or Pseudomonas aeruginosa), clinical cure on Day 11 was 72% and 69% in XTORO* versus 33% and 40% in Vehicle.

Table 3 – Clinical Cure Rate at Day 11 (TOC) for Pathogen Positive Subsets of ITT Population STUDY C-10-018 Fina Veh (N=145) (N=138) n (%) n (%) Difference 95% CIa p-valueb 104 (71.7) 46 (33.3) 38.4 (27.6, 49.1) <0.0001 STUDY C-10-019 Fina Veh (N=147) (N=130) n (%) n (%) Difference 95% CIa p-valueb 101 (68.7) 52 (40.0) 28.7 (17.4, 40.0) <0.0001 POOLED Fina Veh (N=292) (N=268) n (%) n (%) Difference 95% CIa p-valueb 205 (70.2) 98 (36.6) 33.6 (25.8, 41.4) <0.0001 Fina = Finafloxacin Otic Suspension, 0.3% Veh = Finafloxacin Vehicle Clinical cure at Day 11 (TOC) was attained if the sum of tenderness, erythema, and edema was zero (i.e. none) at the Day 11 (TOC) visit. CI = Confidence interval a 95% confidence interval based on non-stratified analysis. b Test = stratified CMH

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In these same patients microbiological success (eradication of all baseline organisms) was achieved on Day 11 in 67% and 66% in XTORO* versus 13% and 12% in the Vehicle treated patients.

Table 4 – Microbiological Success Rate at Day 11 (TOC) for Pathogen Positive Subsets of ITT Population STUDY C-10-018 Fina Veh (N=145) (N=138) n (%) n (%) Difference 95% CIa p-valueb 97 (66.9) 18 (13.0) 53.9 (44.4, 63.4) <0.0001 STUDY C-10-019 Fina Veh (N=147) (N=130) n (%) n (%) Difference 95% CIa p-valueb 97 (66.0) 15 (11.5) 54.4 (45.0, 63.9) <0.0001 POOLED Fina Veh (N=292) (N=268) n (%) n (%) Difference 95% CIa p-valueb 194 (66.4) 33 (12.3) 54.1 (47.4, 60.8) <0.0001 Fina = Finafloxacin Otic Suspension, 0.3% Veh = Finafloxacin Vehicle Microbial success was attained if all pretherapy bacteria were absent from the exit specimen. CI = Confidence interval a 95% confidence interval based on non-stratified analysis. b Test = stratified CMH

XTORO* (finafloxacin otic suspension, 0.3%) Page 12 of 19 The median time to cessation of ear pain in patients treated with XTORO* was 4.0 and 3.0 days compared to 7.0 and 6.5 days in vehicle.

Table 5 – Time to Cessation of Pain for Pathogen Positive Subsets of ITT Population STUDY C-10-018 STUDY C-10-019 POOLED Fina Veh Fina Veh Fina Veh (N=138) (N=128) (N=138) (N=125) (N=276) (N=253) Event 123 (89.1%) 88 (68.8%) 122 (88.4%) 86 (68.8%) 245 (88.8%) 174 (68.8%)

Median 4.0 7.0 3.0 6.5 3.5 7.0 (95% CIa) (3.5, 4.5) (5.0, 8.5) (2.5, 3.5) (5.0, 8.0) (3.0, 3.5) (5.5, 8.0) Difference in -3.0 -3.6 -3.3 Medians (-5.0, -0.8) (-5.0, -2.0) (-4.5, -2.0) (95% CIb) Hazard Ratio 1.8 2.3 2.0 (95% CI) (1.4, 2.4) (1.7, 3.0) (1.6, 2.4) p-valuec <0.0001 <0.0001 <0.0001 Fina = Finafloxacin Otic Suspension, 0.3% Veh = Finafloxacin Vehicle CI = Confidence interval Cessation of ear pain was defined as occurring at the first time point that ear pain was absent (morning or evening) and did not return for any/all subsequent diary entries. a Medians are product-limit estimates; 95% confidence intervals estimated using Brookmeyer-Crowley method with log-log transformation. b Difference and 95% confidence interval estimated using bootstrap procedure with 10,000 bootstrap samples, non-stratified analysis. c Test = Cox proportional hazard model, adjusted for pain medication use, for treatment comparisons.

In clinically cured patients XTORO* demonstrated eradication rates 90% and 89% in Staphylococcus aureus and 88% and 90% for Pseudomonas aeruginosa. Vehicle eradication rates were 33% and 31% for Staphylococcus aureus and 15% and 24% for Pseudomonas aeruginosa.

DETAILED PHARMACOLOGY Human Pharmacodynamics Since absorption is very low after ototopical administration of XTORO* (finafloxacin otic suspension, 0.3%), no human pharmacodynamics studies were conducted.

Animal Pharmacodynamics Initial evaluations centered on the in vitro characterization of Gram-positive and Gram-negative clinical isolates of multiple species of bacteria associated with otic infections. The antibacterial activities of finafloxacin were increased at lower pH environment with the optimal pH range between pH 5.8–6.2. Finafloxacin demonstrated potent activity against otic pathogens P. aeruginosa and S. aureus when tested at pH 5.8 and neutral pH in vitro studies.

The finafloxacin clinical formulation was evaluated in the guinea pig AOE model using P. aeruginosa clinical isolates, from human subjects with AOE, as the challenge organism. The finafloxacin clinical formulation reduced the number of P. aeruginosa by approximately

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5-log CFU/mL.

Human Pharmacokinetics The systemic pharmacokinetics of finafloxacin after ototopical administration of XTORO* in healthy subjects and in patients with acute otitis externa were studied. In the ototopical pharmacokinetic studies, systemic exposure to finafloxacin was extremely low; and as a result there was insufficient data to determine pharmacokinetic parameters.

Because of the very low levels of systemic exposure following ototopical doses of XTORO*, drug-drug interactions are not likely. In addition, in vitro and in vivo studies have shown the following that support the lack of a potential for drug-drug interactions. Protein binding is relatively low (21%). Finafloxacin is not an inhibitor of the major cytochrome P-450 isozymes. No detectable conversion of finafloxacin was observed in incubations with human (as well as rat, rabbit and monkey) hepatic microsomes. Little or no oxidative Phase I metabolism has been observed in rats and dogs with the only discernible metabolite being a glucuronide metabolite.

Animal Pharmacokinetics The systemic absorption, distribution and excretion pharmacokinetics of finafloxacin were determined in rats and dogs which are the primary species used in safety assessment studies.

Very low amounts of 14C- finafloxacin radioactive drug equivalents distribute into the inner ear past the tympanic membrane and external ear canal of guinea pigs even after multiple ototopical doses (BID for 7 days).

Protein binding in rat, dog and human plasma is relatively low (range 17.1% to 44.1%) and is not a concern for drug-drug interactions relating to protein binding.

Radioactive drug equivalents are secreted in the milk of lactating rats. However, both milk and maternal plasma drug equivalent levels decline in parallel and are <0.1% of those at Cmax after 12 hours post-dose.

Finafloxacin is not an inhibitor of the major cytochrome P450 isozymes (1A2, 2D6, 2C9, 2C19 and 3A4) indicating a low potential for cytochrome P450 mediated drug-drug interactions. Following repeated doses in rats with finafloxacin, no meaningful changes were found in hepatic enzyme activities (total microsomal protein, total cytochrome P-450 content and cytochrome P450 and uridine-diphosphoglucuronosyl transferase activities.

MICROBIOLOGY Microbiology Finafloxacin belongs to fluoroquinolone class of antibacterials involved in the inhibition of bacterial type II topoisomerase, DNA gyrase and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair and recombination. Finafloxacin has been shown in vitro and clinical studies to be active against the bacterial pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, associated with acute otitis externa.

XTORO* (finafloxacin otic suspension, 0.3%) Page 14 of 19 Resistance: Cross-resistance has been observed between finafloxacin and other fluoroquinolones. There is generally no cross-resistance between quinolones and other classes of antibacterial agents.

TOXICOLOGY Carcinogenesis and Mutagenesis Finafloxacin was not assessed for carcinogenic potential in mice or rats as the proposed finafloxacin drug product will only be used for infrequent short courses (7 day) of low dose topical clinical administration and the systemic exposure following topical otic administration is low.

Finafloxacin was shown to be genotoxic and clastogenic in reverse mutation assay, mouse lymphoma cell forward mutation assay, and micronucleus assay in vitro, although V79/HRPT test with or without UV irradiation and micronucleus test in vivo were negative.

Reproductive Toxicity and Teratogenicity Finafloxacin administered to male and female rats at oral doses of 100 mg/kg/day, approximately 60,000 times higher than the clinical dose (based on a 30 μL drop size, 4 drop per dose, BID, and a 50 kg person), resulted in no changes in the fertility index and implantation rate. Effects on male reproductive parameters, markedly low sperm counts and decreased motility, were observed at doses of 500mg/kg/day, approximately 300,000 times higher than the clinical dose.

Two studies were performed investigating the effects on embryo-fetal development in rats (oral) and rabbits (IV). Finafloxacin was shown to be teratogenic following intravenous administration in rabbits, but not in the rat following oral administration. In the rabbit, the maternal NOEL was 3 mg/kg and fetal toxicity was observed at the lowest dose, 1 mg/kg. Fetal toxicity at 1 mg/kg was characterized by paw hyperflexure, exencephaly, decreased brain tissue, enlarged fontanel, and skeletal effects. Finafloxacin has been identified in the milk of nursing rats following oral administration.

Animal Toxicology and/or Pharmacology In multiple studies performed in rodents and non-rodents, subchronic and chronic toxicity tests of finafloxacin showed systemic effects such as joint/cartilage defects in dogs and centrilobular hepatocellular hypertrophy in female dogs. Most, if not all of these effects were reversible after drug withdrawal. The NOAELs were 30 and 100 mg/kg/day in the dog and rat, respectively, which are 55,000x greater than given or absorbed by the otic route.

Two 14-day repeated-dose administration studies have been conducted utilizing administration to the external auditory canal of rabbits. Based upon the results of histological evaluations, there were no adverse effects of repeated administration of the finafloxacin suspension.

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REFERENCES

1. Human Pharmacokinetics and Safety Profile of Finafloxacin, a New Fluoroquinolone Antibiotic, in Healthy Volunteers. Heena Patel, Arne Andresen, Andreas Vente, Hans-Dietrich Heilmann, Will Stubbings, Michael Seiberling, Luis Lopez-Lazaro, Rolf Pokorny, Harald Labischinski: Antimicrob Agents Chemother. 2011 September; 55(9): 4386–4393.

2. In Vitro Spectrum of Activity of Finafloxacin, a Novel, pH-Activated Fluoroquinolone, under Standard and Acidic Conditions. Will Stubbings, Pamela Leow, Goh Chee Yong, Falicia Goh, Barbara Körber-Irrgang, Michael Kresken, Rainer Endermann, Harald Labischinski: Antimicrob Agents Chemother. 2011 September; 55(9): 4394–4397.

3. Activity of the Investigational Fluoroquinolone Finafloxacin against Ciprofloxacin- Sensitive and -Resistant Acinetobacter baumannii Isolates. Paul G. Higgins, Will Stubbings, Hilmar Wisplinghoff, Harald Seifert: Antimicrob Agents Chemother. 2010 April; 54(4): 1613–1615.

4. Comparative In Vitro Activities of the Novel Antibacterial Finafloxacin against Selected Gram-Positive and Gram-Negative Bacteria Tested in Mueller-Hinton Broth and Synthetic Urine. Axel Dalhoff, Will Stubbings, Sabine Schubert: Antimicrob Agents Chemother. 2011 April; 55(4): 1814–1818.

XTORO* (finafloxacin otic suspension, 0.3%) Page 16 of 19 IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION  you are taking any other medications (see Interactions with this medication). Pr XTORO* Finafloxacin Otic Suspension, 0.3% w/v XTORO* otic suspension is for use in the ear only. Do not drop it in your eyes or mouth. This leaflet is part III of a three-part "Product Monograph" published when XTORO* was approved for sale in Canada Do not give this product to children less than 1 year old. and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about XTORO*. Use XTORO* otic suspension exactly as your healthcare provider Contact your doctor or pharmacist if you have any questions tells you. Do not stop taking XTORO* otic suspension without about the drug. talking to your healthcare provider.

The bottle, and any remaining product, should be discarded after ABOUT THIS MEDICATION the prescribed therapy or after the expiration date on the medicine label or box.

What the medication is used for: It is important that the infected ear(s) remain clean and dry. When  the treatment of acute otitis externa (AOE), with or without bathing avoid getting the infected ear(s) wet. Avoid swimming, otowick, in pediatric (age 1 year and older), adult and unless your healthcare provider has instructed otherwise. elderly patients. An otowick is a medicated sponge inserted into the ear to keep the ear canal open and help deliver Do not use XTORO* otic suspension for a condition for which it medication deeper into the ear. was not prescribed. Do not give XTORO* otic suspension to other people, even if they have the same conditions as you. It may harm What it does: * them. XTORO interferes with bacterial DNA to stop growth and division, thereby leading to bacterial death and reducing the infection. INTERACTIONS WITH THIS MEDICATION

When it should not be used: No specific drug interaction studies have been done with * Do not use XTORO (finafloxacin otic suspension, 0.3% w/v) if XTORO* otic suspension. you are allergic to finafloxacin or any other fluoroquinolones or * any ingredients contained in XTORO otic suspension (see What Tell your health care provider about all the medicines you are the nonmedicinal ingredients are). taking (or recently took), including prescription and nonprescription medicines, over the counter, vitamins, and herbal What the medicinal ingredient is: products. XTORO* otic suspension and other medicines may Finafloxacin affect each other, causing side effects.

What the important nonmedicinal ingredients are: Preservative: benzalkonium chloride (0.005% w/v) Inactive ingredients: hydroxyethylcellulose, tyloxapol, magnesium PROPER USE OF THIS MEDICATION chloride, purified water and sodium chloride. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. During drug Usual dose: Adults and children over 1 year old: product manufacturing, finafloxacin forms a complex with Apply four (4) drops into the affected ear(s) twice daily for seven magnesium. days. For patients requiring use of an otowick, the initial dose can be doubled (to 8 drops), followed by 4 drops in affected ear(s) What dosage forms it comes in: twice daily for seven days. XTORO* (finafloxacin otic suspension, 0.3% w/v) is a sterile, preserved, aqueous, ototopical suspension supplied in an opaque How to use: plastic bottle with a controlled drop tip and a white cap. For use in the ear only. It is best if another person can put the drops in for you. WARNINGS AND PRECAUTIONS Children should never be allowed to put the drops in themselves.

* BEFORE you use XTORO Otic Suspension talk to your 1. Wash hands doctor or pharmacist if: The person giving XTORO* otic suspension should wash his/her  pregnant or planning to become pregnant. It is not known hands with soap and water before using XTORO*. * if XTORO otic suspension will harm your unborn baby.  breast-feeding a baby or planning to breastfeed during 2. Warm & shake the bottle treatment with this product. It is not known if finafloxacin The person giving XTORO* otic suspension should hold the passes into breast milk. bottle in their hand(s) for one or two minutes to warm the suspension (picture 1) to avoid the dizziness that may result from

XTORO* (finafloxacin otic suspension, 0.3%) Page 17 of 19 IMPORTANT: PLEASE READ the instillation of a cold suspension into the ear canal, then shake 5. Stay on side the bottle well before use. The patient should remain on his/her side for at least 60 seconds. Repeat Steps 2-4 for the other ear if both ears are infected.

Overdose:

In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

Missed Dose: 1 If a dose is missed, it should be given as soon as possible. If it is 3. Add drops almost time for the next dose, skip the missed dose and go back to * The person receiving XTORO otic suspension should lie on the regular dosing schedule. Do not double the dose. his/her side with the infected ear up (picture 2).

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Common side effects (1-10%) include itchiness in the ear canal and headache.

Other side effects include earwax buildup, reduced sensitivity to sounds, nausea, dizziness and ear infection.

Tell your doctor or pharmacist if you have any side effects that bother you or do not go away. 2

* If a severe allergic reaction occurs, with symptoms such as Patient should have 4 drops of XTORO otic suspension put into swelling of the lips, mouth and throat, difficulty breathing, rash, the infected ear (picture 3). If otowick is in place, patient should or hives, stop using XTORO* and contact your doctor or have 4 drops of XTORO* put into the infected ear at the surface of pharmacist immediately. the otowick. Do not touch the ear, fingers or any other surfaces with the tip of the bottle as it could contaminate the drops. This is not a complete list of side effects. For any unexpected effects while taking XTORO* otic suspension, contact your doctor or pharmacist.

HOW TO STORE IT

Store at 2°C – 25°C. Do not freeze. Protect from light. Shake well before use. Keep out of the reach and sight of children.

3

4. While the patient lies on his/her side, the person giving XTORO* otic suspension should gently pull the outer ear lobe upward and backward (picture 4). This will allow the ear drops to flow down into the ear canal.

4

XTORO* (finafloxacin otic suspension, 0.3%) Page 18 of 19 IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: ------ Report online at www.healthcanada.gc.ca/medeffect  Call toll-free at 1-866-234-2345  Complete a Canada Vigilance Reporting Form and: - Fax toll-free to 1-866-678-6789, or - Mail to: Canada Vigilance Program Health Canada Postal Locator 0701D Ottawa, Ontario K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.alcon.ca or by contacting the sponsor, Alcon Canada Inc., at: 1-800-613-2245

This leaflet was prepared by Alcon Canada Inc.

Last revised: March 11, 2016

* A trademark of Novartis © 2016 Novartis

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