Billing and Coding Guide

Billing and Coding Guide Updated July 1, 2016 UPDATED INFORMATION: Please see coding sections for updated information regarding reimbursement for OTIPRIO. 1

OTIPRIO (ciprofloxacin otic suspension) 6% Disclaimer This guide is intended solely for educational purposes regarding possible codes that may be available for OTIPRIO. The information provided contains general reimbursement information only and represents Otonomy s understanding of current reimbursement policies as of July 1, 2016. This coding and reimbursement information is subject to change and may become outdated. Information should not be construed as legal advice nor is it advice about how to code, complete, bill, or submit any particular claim for payment. It is important to check with the health plan directly to confirm coverage for individual patients. Information provided is not intended to increase or maximize reimbursement by any payer. Otonomy disclaims any responsibility for claims submitted by providers or physicians. The information provided in this Guide is not a guarantee of coverage in any individual case. It is the provider s and physician s responsibility to determine appropriate codes, charges, and modifiers, and to submit bills for services and products consistent with what was rendered as well as the patient s insurer requirements. Third-party payers may have different coverage and reimbursement policies and coding requirements. Such policies can change over time. Providers are encouraged to contact third-party payers for each patient to verify specific information on their coding policies. 2

Billing and Coding Guide Contents OTIPRIO Indications and Important Safety Information...4 Introduction... 5 Reimbursement Overview... 5 Private/Commercial...6 Medicaid...6 Medicare...6 Coding for OTIPRIO... 7 HCPCS Level II Codes for OTIPRIO... 7 About Transitional Pass-Through Payment... 8 National Drug Code (NDC)... 8 Coding for Physician Services...9 Potential CPT Codes...9 Potential ICD-9-CM and ICD-10-PCS Procedure Codes...9 Coding for the Patient s Disease/Condition...10 Potential ICD-10-CM Diagnosis Codes...10 Frequently Asked Questions...11 3

OTIPRIO (ciprofloxacin otic suspension) 6% INDICATIONS AND USAGE OTIPRIO TM (ciprofloxacin otic suspension) 6% is a fluoroquinolone antibacterial indicated for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS OTIPRIO is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to other quinolones, or to any of the components of OTIPRIO. WARNINGS AND PRECAUTIONS Potential for Microbial Overgrowth: OTIPRIO may result in overgrowth of nonsusceptible bacteria and fungi. If such infections occur, institute alternative therapy. ADVERSE REACTIONS Adverse reactions (incidence at least 3%) that occurred in two Phase 3 trials with OTIPRIO vs sham were: nasopharyngitis (5% vs 4%), irritability (5% vs 3%), and rhinorrhea (3% vs 2%). USE IN SPECIFIC POPULATIONS Pediatric Use: The safety and effectiveness of OTIPRIO in infants below six months of age have not been established. Please see accompanying full Prescribing Information. 4

Billing and Coding Guide Introduction Otonomy, Inc. has developed this reference guide to provide general billing and coding information related to OTIPRIO for physician and hospital billing staff when used in the ambulatory surgical center (ASC), hospital outpatient department (HOPD), or hospital inpatient setting. To assist you in preparing claims, this guide contains the following: u Reimbursement Overview u Billing and Coding Information u Frequently Asked Questions (FAQs) Reimbursement Overview Coverage and coding guidelines for OTIPRIO and its administration will differ by insurer and are updated regularly. In addition, payment rates may vary by insurer and are frequently established by the provider s specific contract. It is a best practice to contact your patient s health insurance company directly to ensure that you have the most recent local billing, coding, and coverage policy information, as well as answer any payment inquiries. Codes allow healthcare providers to communicate with insurance companies to facilitate the reimbursement process and explain why the patient needed treatment, what drugs and services were provided, and where services were rendered. Coding guidelines may differ by insurer and are often updated regularly to reflect the addition and deletion of applicable codes. The following table provides an overview of the different codes and their description that may be applicable when billing for items and services related to OTIPRIO. Code Set CPT 1 Codes (Level I HCPCS Codes) HCPCS Level II Codes ICD-9-CM/ICD-10-CM Diagnosis Codes ICD-9-CM/ICD-10-PCS Procedure Codes NDC Revenue Codes Description/Purpose Numeric coding system used to report medical services and procedures provided by healthcare professionals; includes CPT E/M codes, which are numeric codes used to report office visit services provided by physicians Alpha-numeric coding system used to report specific drugs, supplies, and other healthcare equipment Numeric and alpha-numeric codes used to report diagnosis Numeric and alpha-numeric codes used to report procedures, services, devices, and drugs in acute-care hospitals and other facility-based settings Numeric product identifier used to report human drugs Numeric codes used by hospitals to report services and supplies to specific cost centers Legend CPT : Current Procedural Terminology HCPCS: Healthcare Common Procedure Coding System ICD-9-CM: International Classification of Diseases, 9th Revision, Clinical Modification ICD-10-CM: International Classification of Diseases, 10th Revision, Clinical Modification ICD-10-PCS: International Classification of Diseases, 10th Revision, Procedure Coding System NDC: National Drug Code 1 CPT copyright 2014 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association. 5

OTIPRIO (ciprofloxacin otic suspension) 6% In addition, coverage and payment will also vary based on individual patient insurance parameters and provider contracts. An overview of the major insurer types is provided below. Private/Commercial Private insurance coverage policies for OTIPRIO and its administration may vary. Each private insurer determines its own coverage policies for drugs and procedures. In addition, most insurers offer multiple plans; coverage for procedures and/or drugs may vary depending on the details of that exact plan. Medicaid In general, state Medicaid programs will cover drugs for their FDA-approved indications. It will be important to understand your state Medicaid program s specific coverage criteria for OTIPRIO and its administration as each state s Medicaid agency determines its own coverage and payment policies. Medicaid recipients may also have the opportunity to enroll in managed care organizations (MCOs) offered in a particular state. Typically, Managed Medicaid guidelines for coverage are similar to private or commercial insurers and often vary by plan. Medicare Traditional or fee-for-service Medicare consists of beneficiaries who receive their medical benefits through the following: u Medicare Part A: Inpatient services, hospitalizations, hospice care, skilled nursing facility stays, and some home health services u Medicare Part B: Physician and outpatient services, durable medical equipment (DME), and some home health care, laboratory service Currently, there is no Medicare national coverage determination (NCD) for OTIPRIO. As with most Part B covered drugs, local Medicare contractors have the discretion to develop local coverage determinations (LCDs) if necessary. Formal published guidelines may be developed for certain products and procedures when insurers are concerned about appropriate utilization and costs; published policies regarding coverage for OTIPRIO may not be available. Contacting each patient s insurance company to understand the specific guidelines for OTIPRIO is recommended. 6

Billing and Coding Guide Coding for OTIPRIO Regardless of the setting of care in which the drug was administered, most payers require providers to list an HCPCS code and the NDC code on the claim form when billing for a particular drug. HCPCS Level II Codes for OTIPRIO Most payers recognize Healthcare Common Procedure Coding System (HCPCS) Level II national codes to identify and report drugs. Effective July 1, 2016, the Centers for Medicare & Medicaid Services (CMS) granted transitional pass-through status for OTIPRIO. When pass-through status is granted, CMS creates a unique HCPCS code, or C-Code, which billers can use to identify the drug on the claim form. For more information on pass-through payment, please see page 8. HCPCS Code Description C9479* Instillation, ciprofloxacin otic suspension, 6 mg J3490 Unclassified drugs * Note on reporting C9479: Each vial of C9479 contains 60 mg. If one single-use vial is used for both patient s ears with the remainder of the drug in the vial unused, then two units of C9479 should be reported on the claim form as administered to the patient; any discarded amount should be reported with the JW modifier according to the Medicare Claims Processing Manual, Chapter 17, Drugs and Biologicals; Section 40, Discarded Drugs and Biologicals. Note on reporting J3490: If the patient s insurer does not accept C9479, you may need to report OTIPRIO using J3490. Report only one unit of J3490 on the claim form per single-patient use vial. Do not bill wastage. Please consult payer-specific guidelines for the appropriate code to use for OTIPRIO to communicate which drug was provided and how much was administered. 7

OTIPRIO (ciprofloxacin otic suspension) 6% About Transitional Pass-Through Payment Transitional pass-through status is a temporary payment policy granted by the Centers for Medicare & Medicaid Services (CMS), the federal agency that administers the Medicare program. When a drug is granted pass-through status by CMS, ambulatory surgery centers and other outpatient facilities are eligible to receive separate payment for the drug, in addition to the payment received for the patient encounter for Medicare patients. Pass-through status remains in effect for 2 to 3 years. When pass-through status is granted, CMS creates a temporary, unique Healthcare Common Procedure Coding System (HCPCS) code, or C-Code, which billers use to identify the drug on the claim form. Pass-through status is applicable to Medicare patients only. However, some Medicaid and commercial plans may allow providers that treat non-medicare patients to use the C-Code when billing, in lieu of an unlisted J-Code and even more, some may recognize Medicare s pass-through status policy and allow for separate payment for drugs with pass-through status which would otherwise not be allowed separate reimbursement. Ambulatory surgery centers (ASCs) and other hospital outpatient departments (HOPDs) may be eligible to receive separate payment for OTIPRIO, in addition to the payment received for the patient encounter when providers bill for OTIPRIO using HCPCS code C9479. National Drug Code (NDC) The FDA and the manufacturer assign drugs/biologics a unique, 3-segment number, known as the National Drug Code (NDC). Many NDCs (including the one assigned to OTIPRIO) are displayed in a 10-digit format on the FDA-approved product labelling. Proper billing for most payers or electronic data interchange systems requires that the NDC be submitted in the 11-digit numeric 5-4-2 format (ie, 55555-4444-22). Converting a 10-digit NDC to 11-digit format requires a strategically placed zero preceding the section that does not comply with the 5-4-2 format. Do not use hyphens when entering the actual data on your claim. For example: 10-Digit Format OTIPRIO 10-Digit NDC 11-Digit Format OTIPRIO 11-Digit NDC Reporting on claim form 5-3-2 69251-201-01 5-4-2 69251-0201-01 69251020101 8

Billing and Coding Guide Coding for Physician Services Coding procedures may vary depending on the setting of care. In the physician office, HOPD, and ASC, CPT codes are used to describe procedures. In the hospital inpatient department, billers are required to use ICD-10-PCS codes to bill for procedures. Potential CPT Codes Current Procedural Terminology (CPT ) codes are used to identify professional services (ie, drug administration). According to the CPT instructions for use of the CPT codebook, select the name of the procedure or service that accurately identifies the service performed. Do not select a CPT code that merely approximates the service provided. When provided during tube placement surgery, the administration of OTIPRIO is considered inclusive of the primary procedure and therefore not coded separately. Providers should use the appropriate tympanostomy CPT code that best describes the services provided. Also, when performed bilaterally, report with modifier 50. CPT Code Description 69433 Tympanostomy (requiring insertion of ventilating tube), local or topical anesthesia 69436 Tympanostomy (requiring insertion of ventilating tube), general anesthesia Potential ICD-9-CM and ICD-10-PCS Procedure Codes ICD-9-CM and ICD-10-PCS codes are typically used to bill for procedures performed on inpatients. Effective October 1, 2015, all Health Insurance Portability and Accountability Act (HIPAA)-covered entities were required to transition from the ICD-9-CM coding system and bill procedures using ICD-10-PCS. There is no category-specific code for drugs administered via intratympanic administration. Hospitals may therefore choose the code that best describes the procedure. Below is a list of the existing ICD-9-CM code and the ICD-10-PCS Crosswalk that may be applicable for describing the administration of OTIPRIO when administered during tube placement surgery. ICD-9-CM Procedure Code ICD-10-PCS 3E0B7GC Introduction of other therapeutic substance into ear, via natural or artificial opening 20.94 Injection of tympanum 3E0B3GC Introduction of other therapeutic substance into ear, percutaneous approach 3E0BXGC Introduction of other therapeutic substance into ear, external approach 099500Z Drainage of right middle ear with drainage device, open approach 20.01 Myringotomy with insertion of tube 099600Z Drainage of left middle ear with drainage device, open approach 099770Z Drainage of right tympanic membrane with drainage device, via natural or artificial opening 099870Z Drainage of left tympanic membrane with drainage device, via natural or artificial opening 9

OTIPRIO (ciprofloxacin otic suspension) 6% Coding for the Patient s Disease/Condition Potential ICD-10-CM Diagnosis Codes ICD-10-CM diagnosis codes are used to report diseases and conditions and identify why a patient needs treatment. OTIPRIO is indicated for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement. The following ICD-9-CM diagnosis codes and the equivalent ICD-10-CM crosswalk below are examples of some codes that may be appropriate to describe a patient s chief complaint. Diagnosis Code System Code Description ICD-9-CM 381.00 Acute nonsuppurative otitis media, unspecified ICD-9-CM 382.00 Acute suppurative otitis media without spontaneous rupture of ear drum ICD-10-CM H65.191 H65.199 Other acute nonsuppurative otitis media ICD-10-CM H66.001 H66.009 Acute suppurative otitis media without spontaneous rupture of ear drum 10

Billing and Coding Guide Frequently Asked Questions Q1: What HCPCS code do I use to bill for OTIPRIO? Effective July 1, 2016, the Centers for Medicare & Medicaid Services (CMS) granted transitional pass-through status for OTIPRIO. When pass-through status is granted, CMS creates a unique Healthcare Common Procedure Coding System (HCPCS) code, or C-Code, which billers can use to identify the drug on the claim form. Some insurers will not accept C-Codes and require providers to bill using an unclassified HCPCS code or unlisted J-Code when a permanent J-Code is not available. These coding options are available on page 7 of the billing and coding guide. Please consult payer-specific guidelines for the appropriate code to use for OTIPRIO to communicate which drug was provided and how much was administered. Q2: My patient s insurer won t allow me to bill using the OTIPRIO C-Code and says I must bill using the unclassified HCPCS drug code J3490. What else do I need to know about coding OTIPRIO with an unclassified HCPCS drug code? OTIPRIO was approved in 2015. Not all insurers will be familiar with OTIPRIO. Hence, the product may be billed using an unclassified drug code until OTIPRIO is assigned its own product-specific code. 2 The patient s insurer may need more information if they are unfamiliar with OTIPRIO; therefore, the provider s billing staff should be prepared to submit the following information if requested: u Drug name (brand/generic) u Route of administration u Drug strength and dosage u 11-digit National Drug Code (NDC) u Customized letter of medical necessity u Invoice u FDA approval letter u Package insert u Chart notes u Laboratory test results upatient medical history and documentation of medical necessity u Prior therapies usupporting peer-reviewed medical journals and other clinical literature 2 Unclassified codes do not have unit values and are generally reported as 1 Unit on the claim form or its electronic equivalent, regardless of the amount of drug administered. Check payer guidelines for appropriate reporting of units for an unclassified code. 11

OTIPRIO (ciprofloxacin otic suspension) 6% Frequently Asked Questions (cont.) Q3: What CPT code do I use to bill for the administration of OTIPRIO in the ASC or HOPD? When provided during tube placement surgery, the administration of OTIPRIO is considered inclusive of the primary procedure and therefore not coded separately. Providers should use the appropriate tympanostomy CPT code (69433 or 69436) that best describes the services provided. Also, when performed bilaterally, report with modifier 50. It is important to remember that insurers billing and coding guidelines may vary. Please contact the patient s insurer if you have any questions related to coding. Q4: How do I know if OTIPRIO is covered for my patient? Otonomy does not anticipate that many payers will develop a formal policy regarding coverage for OTIPRIO. In general, it is a good rule of thumb to contact each payer to verify coverage parameters prior to the procedure. Q5: What is the reimbursement for OTIPRIO? Reimbursement for OTIPRIO will be based on the contracted arrangement between the provider and the payer. Please contact your patient s insurer for specific information on payment rates and to understand how OTIPRIO is reimbursed. 12

For additional support or questions, please visit www.otiprio.com or contact by e-mail at Reimbursement@Otonomy.com or by phone at 1-800-826-6411. 2016 Otonomy, Inc. All rights reserved. OTIPRIO is a trademark of Otonomy, Inc. 1-OTI16039-v1 13

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OTIPRIO safely and effectively. See full prescribing information for OTIPRIO. OTIPRIO TM (ciprofloxacin otic suspension), for intratympanic use Initial U.S. Approval: 1987 ---------------------------INDICATIONS AND USAGE-------------------------- OTIPRIO is a fluoroquinolone antibacterial indicated for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement. (1) -----------------------DOSAGE AND ADMINISTRATION---------------------- OTIPRIO is for intratympanic administration only. (2.1) OTIPRIO is intended for single-patient use with two 0.1 ml doses available in each vial. (2.1) Administer OTIPRIO as a single intratympanic administration of one 0.1 ml (6 mg) dose into each affected ear, following suctioning of the middle ear effusion. (2.1) See Full Prescribing Information for directions for OTIPRIO dose preparation. (2.2) ----------------------DOSAGE FORMS AND STRENGTHS-------------------- Otic Suspension: Each OTIPRIO vial contains 1 ml of 6% (60 mg/ml) ciprofloxacin otic suspension. (3) ------------------------------CONTRAINDICATIONS--------------------------- OTIPRIO is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to quinolones, or to any component of OTIPRIO. (4) ------------------------WARNINGS AND PRECAUTIONS---------------------- Potential for Microbial Overgrowth: OTIPRIO may result in overgrowth of non-susceptible bacteria and fungi. (5.1) ------------------------------ADVERSE REACTIONS--------------------------- The most frequently occurring adverse reactions (with an incidence rate greater than 3%) were nasopharyngitis and irritability. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Otonomy at 1-800-826-6411 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Potential for Microbial Overgrowth 6 ADVERSE REACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1

FULL PRESCRIBING INFORMATION 3 1 Otic Suspension: Each 1 ml of OTIPRIO contains a white, preservative-free, sterile otic suspension consisting of 6% (60 mg/ml) ciprofloxacin in a single-patient use glass vial. INDICATIONS AND USAGE OTIPRIO is indicated for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement. 4 DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS 2 DOSAGE AND ADMINISTRATION 2.1 Dosage and Important Administration Instructions OTIPRIO is for intratympanic administration only. OTIPRIO is intended for single-patient use, discard unused portion. Administer OTIPRIO as a single intratympanic administration of one 0.1 ml (6 mg) dose into each affected ear, following suctioning of middle ear effusion. 5 WARNINGS AND PRECAUTIONS 5.1 Potential for Microbial Overgrowth 2.2 Preparation of OTIPRIO 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience OTIPRIO is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to other quinolones, or to any of the components of OTIPRIO. OTIPRIO may result in overgrowth of nonsusceptible bacteria and fungi. If such infections occur, institute alternative therapy. Directions for OTIPRIO dose preparation and handling is illustrated in Figure 1 below. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In two randomized, sham-controlled Phase 3 clinical trials, 530 pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement were treated with OTIPRIO or sham administered intra-operatively as a single dose. The median age of the pediatric patients enrolled in the clinical trials was 1.5 years; 62% of patients were 6 months through 2 years of age and 38% of patients were greater than 2 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. Figure 1: Directions for OTIPRIO Dose Preparation STEP 1 Preparation Materials needed: 1 vial of OTIPRIO (enough for 2 doses); Two 1 ml luer lock syringes; Two 18G-21G preparation needles; Two 20-24G, 2-3 inch blunt, flexible administration needles; Alcohol pads; Optional: ice pack and drape to keep OTIPRIO vial cold Keep product cold during preparation. If OTIPRIO thickens during preparation, place the vial back in refrigeration. Table 1: Adverse Reactions STEP 2 OTIPRIO Mixing To keep the vial cold during shaking, hold the OTIPRIO vial by the aluminum seal to prevent gelation. Shake the vial for 5 to 8 seconds to mix well until a visually homogenous suspension is obtained. Always hold the vial by the aluminum seal to prevent gelation. Nasopharyngitis Irritability Rhinorrhea OTIPRIO (N=357) Sham (N=173) 5% 5% 3% 4% 3% 2% 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Animal 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. STEP 3 OTIPRIO Removal Using an 18-21G needle, withdraw 0.3 ml of the suspension into the 1 ml syringe. 8.2 STEP 4 Replace with the Administration Needle Replace the needle with a 20-24G, 2-3 inch blunt, flexible needle to be used for administration. Lactation Risk Summary Ciprofloxacin 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 in infants below six months of age have not been established. The safety and effectiveness of OTIPRIO was established in 530 pediatric patients with bilateral otitis media with middle ear effusion undergoing myringotomy with tympanostomy tube placement. The median age of patients enrolled in the clinical trials was 1.5 years; 62% of patients were 6 months through 2 years of age and 38% of patients were greater than 2 years of age [see Adverse Reactions (6.1) and Clinical Studies (14)]. STEP 5 Priming the Syringe Prime the needle leaving a dose of 0.1 ml (0.1 cc). STEP 6 Preparing Second Dose for Bilateral Administration Only Repeat Steps 3, 4, and 5 using the same vial to prepare a second syringe for the other ear and dispose of the vial. Use a different syringe for each ear. After preparation, syringes can be kept at room temperature or in the refrigerator prior to administration. Keep syringes on their side. Discard syringes if not administered in 3 hours. Adverse Reactions in Phase 3 Trials 11 DESCRIPTION OTIPRIO (ciprofloxacin otic suspension) 6% contains the synthetic fluoroquinolone antibacterial, ciprofloxacin. OTIPRIO is for intratympanic administration. OTIPRIO is supplied as a white, preservative-free, sterile otic suspension of 6% (w/v) ciprofloxacin in a neutral ph, buffered, isotonic solution in a single-patient use glass vial with a rubber stopper containing 1 ml. The inactive ingredients are poloxamer 407, sodium chloride, tromethamine, hydrochloric acid and water for injection (WFI). The thermosensitive suspension exists as a liquid at room temperature or below and gels when warmed [see How Supplied/Storage and Handling (16)]. 2

Ciprofloxacin has the following nomenclature: 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C 17 H 18 FN 3 O 3 and its molecular weight is 331.3. Its chemical structure is as follows: Figure 2: Structure of Ciprofloxacin 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ciprofloxacin is a fluoroquinolone antibacterial [see Microbiology (12.4)]. 12.3 Pharmacokinetics The plasma concentration of ciprofloxacin following bilateral administration of 0.1 ml OTIPRIO was not measured. 12.4 Microbiology Mechanism of Action The bactericidal action of ciprofloxacin results from interference with the enzyme DNA gyrase, which is needed for the synthesis of bacterial DNA. Resistance Bacterial resistance to fluoroquinolones can develop through chromosomallyor plasmid-mediated mechanisms. In vitro studies demonstrated cross-resistance between ciprofloxacin and some fluoroquinolones. There is generally no crossresistance between ciprofloxacin and other classes of antibacterial agents, such as beta-lactams or aminoglycosides. Antimicrobial Activity Ciprofloxacin 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 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, 2 of the 8 in vitro tests were positive, but results of the following 3 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 a patient treated with OTIPRIO) were administered for up to 2 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 a 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. 14 CLINICAL STUDIES Two randomized, multicenter, 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 intra-operatively as a single dose. The median age of patients enrolled in the clinical trials was 1.5 years; 62% of patients were 6 months through 2 years of age and 38% of patients were greater than 2 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 a blinded assessor on or after 3 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 2 presents the results from each Phase 3 trial. Table 2: Cumulative Proportion of Treatment Failures Through Day 15 in Phase 3 Trials OTIPRIO Treatment Failure 25% (44/179) Reason for Failure 1 Trial 1 (N=266) Sham 45% (39/87) Difference (Sham OTIPRIO) (95% CI) OTIPRIO 20% (8%, 32%) 2 21% (38/178) Trial 2 (N=266) Sham 45% (40/88) Otorrhea 7% 11% 7% 27% Otic antibacterial drugs Systemic antibacterial drugs Lost-to-follow-up and missed visit 6% 17% 5% 8% 2% 5% 3% 3% 10% 11% 6% 7% Difference (Sham OTIPRIO) (95% CI) 24% (12%, 36%) 2 1 the earliest occurring treatment failure event, and patients were classified as a treatment failure due only to that component for the remainder of the study 2 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. 16 HOW SUPPLIED/STORAGE AND HANDLING OTIPRIO is a sterile, preservative-free, otic suspension of 6% (60 mg/ml, w/v) ciprofloxacin in a neutral ph buffered, isotonic solution containing poloxamer 407. Each OTIPRIO carton contains 1 ml of 6% (60 mg/ml, w/v) ciprofloxacin in a 2 ml single-patient use glass vial fitted with a rubber stopper. (NDC-69251-201-01) OTIPRIO should be stored at 2 to 8 C (36 to 46 F) until prior to use to prevent thickening during preparation. Protect from light. Store in the original carton until dose preparation. 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 a fever, advise patients and their caregiver(s) to consult their physician. Distributed by: Otonomy, Inc. San Diego, CA 92121 www.otiprio.com OTIPRIO TM is a Trademark of Otonomy. U.S. Patent Nos: 8,318,817 and 9,205,048 1-OTI15193 3