Fluoroquinolone. CIPRO and AVELOX. Briefing Book. For the FDA Advisory Committee Meeting. 5 November 2015

Transcription

1 Page 1 of 121 Fluoroquinolone CIPRO and AVELOX Briefing Book For the FDA Advisory Committee Meeting 5 November 2015 Available for public disclosure without redaction This document is Bayer HealthCare s Executive Summary, prepared for the Food and Drug Administration Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on November 5, 2015 to Discuss the Benefits and Risks of Fluoroquinolones for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis in patients with chronic obstructive pulmonary disease, and uncomplicated urinary tract infections.

2 Page 2 of 121 Table of Contents Briefing Document For the FDA Advisory Committee meeting for Fluoroquinolones Briefing Book... 1 For the FDA Advisory Committee Meeting... 1 Table of Contents... 2 Table of Text Figures... 8 Abbreviations Executive Summary Introduction Development and Approval of CIPRO and AVELOX CIPRO Approved Indications Antibiotic Profile Gram-negative bacteria Gram-positive bacteria AVELOX Mechanism of action Approved Indications Antibiotic Profile Gram-negative Bacteria Gram-positive Bacteria Anaerobic organisms Atypical organisms Medical Landscape... 33

3 Page 3 of Introduction Sinusitis Bronchitis Urinary Tract Infections Susceptibility and Resistance Acute Bacterial Sinusitis (ABS) Fluoroquinolone treatment of ABS Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) COPD Exacerbation Sequelae Therapy of AECOPD AECOPD Professional Guideline Uncomplicated Urinary Tract Infection (uuti) Potential complications of failed treatment of uncomplicated UTIs: Safety Summary CIPRO Safety Bayer Global CIPRO pharmacovigilance database AVELOX Safety Bayer clinical safety data (AVELOX) Bayer Global AVELOX pharmacovigilance database oral formulations Prolongation of the QTc interval CIPRO Bayer clinical safety data pool (CIPRO) Bayer Global pharmacovigilance database (CIPRO) IV and oral formulations CIPRO Labeling for QT prolongation AVELOX Bayer clinical safety data pool (AVELOX) Bayer Global pharmacovigilance database (AVELOX) oral formulations AVELOX Labeling for QT prolongation... 63

4 Page 4 of Tendonitis and Tendon Rupture CIPRO Bayer clinical safety data pool (CIPRO) Bayer Global pharmacovigilance database (CIPRO) IV and oral formulations CIPRO Labeling for tendinopathy AVELOX Bayer clinical safety data pool (AVELOX) Bayer Global pharmacovigilance database (AVELOX) oral formulations AVELOX Labeling for tendinopathy Peripheral Neuropathy CIPRO Bayer clinical safety data pool (CIPRO) Bayer Global pharmacovigilance database (CIPRO) IV and oral formulations CIPRO Labeling for peripheral neuropathy AVELOX Bayer clinical safety data pool (AVELOX) Bayer Global pharmacovigilance database (AVELOX) oral formulations AVELOX Labeling for peripheral neuropathy Safety Conclusions Efficacy Summary Introduction Acute Bacterial Sinusitis (ABS) Treatment Guidelines CIPRO Clinical Trial Overview AVELOX Clinical Trial Overview Outcomes of Patients treated with AVELOX for ABS... 77

5 Page 5 of Placebo-controlled trials Resolution rates Bacteriological AVELOX Benefit-Risk for ABS Acute Exacerbation of COPD (AECOPD) / Acute Exacerbation of Chronic Bronchitis (AECB) CIPRO Clinical Comparisons with other treatments Bacteriological CIPRO Benefit-Risk for AECOPD AVELOX Clinical Trial Overview AVELOX data in AECOPD Bacteriological AVELOX Benefit-Risk for AECOPD Uncomplicated Urinary Tract Infections (uuti) CIPRO Clinical Trial Overview Comparisons with other treatments Resistance Resolution rates CIPRO Benefit-Risk for uuti Conclusions Appendices Adverse Effects of antibiotics prescribed for ABS, AECOPD and uuti Current Prescribing Information CIPRO

6 Page 6 of AVELOX References

7 Page 7 of 121 Text Tables Table 1: Fosfomycin Comparative Eradication Rates and Outcomes in uuti Table 2: Ciprofloxacin Susceptibility Studies Table 3: Susceptibility of Gram-negative organisms to moxifloxacin Table 4: Susceptibility of Gram-positive organisms to moxifloxacin Table 5: Susceptibility of anaerobic and atypical organisms to moxifloxacin Table 6: CIPRO Oral Tablets: Safety Data Pool Adverse Events Table 7: CIPRO Post-marketing Case Reports Summary Table 8: Subjects with treatment emergent adverse events with AVELOX 400 mg. Table 9: Overall summary of Sinusitis subjects with treatment emergent adverse events Table 10: Overall summary of Bronchitis subjects with treatment emergent adverse events Table 11: AVELOX Post-marketing case report summary Table 12: AVELOX Cardiac Safety, adapted from Haverkamp et al. Table 13: Treatment Emergent Events Considered Surrogates for TdP QTc in Phase II-IV Randomized Active Controlled Studies with Moxifloxacin Table 14: Tendinitis and Tendon Rupture related AEs in Bayer Sponsored CIPRO Studies Table 15: Tendinitis and Tendon Rupture related AEs in Bayer-Sponsored oral AVELOX Studies Table 16: Overall summary of number of treatment-emergent CIPRO peripheral neuropathy Table 17: AVELOX 400 mg Peripheral Neuropathy Events Bayer Clinical Trials Table 18: ABS Signs and Symptoms Severity Table 19: Phase III, IIIb AVELOX Clinical Trials in ABS Table 20: Moxifloxacin Resolution Rates Table 21: Infectious Etiologies of AECB Table 22: Summary of ciprofloxacin clinical research respiratory tract infection studies Table 23: Phase III-IIIb trials conducted in AECOPD with Avelox Table 24: Accumulated bacteriological success (eradication or presumed eradication) rates by patient at the primary efficacy assessment in comparative Phase III/IIIb AECB studies

8 Page 8 of 121 Table 25: Accumulated bacteriological success rates in Phase III/IIIb AECB studies by organism (bacteriological response of eradication or presumed eradication) Table 26: Bacteriological eradication rates for H. influenzae by patient provided by AVELOX and macrolide therapy at test-of-cure visit in the AECB Phase III-IIIb studies Table of Text Figures Figure 1. Outcomes in Patients Receiving Antibiotics for ABS, Adapted from Linbaeck et al Figure 2: IDSA Algorithm for the management of acute bacterial rhinosinusitis Figure 3: uuti Decision Tree Figure 4: Mean change in SNOT 16 Symptoms, Hadley at al. Figure 5: Time to first occurrence of failure/recurrence of AECB

9 Page 9 of 121 Abbreviations AAC(3)I ABS AEs AECOPD ATS BLI CAP CDRH CFU ciai COPD csssi CT ESBL ESCMID ERS EUCAST FEV1 FVC HAP IDSA MedDRA MIC MSSA MSSE NDA NI 3-N-aminoglycoside cetyltransferases Acute Bacterial Sinusitis Adverse events Acute Bacterial Exacerbations of Chronic Bronchitis in Patients with Chronic Obstructive Pulmonary Disease American Thoracic Society Bio-layer interferometry Community Acquired Pneumonia Center for Devices and Radiological Health Colony-Forming Units Complicated Intraabdominal Infections Chronic Obstructive Pulmonary Disease Complicated Skin and Skin Structure Infections Computerized Tomography Extended-Spectrum Beta-lactamase European Society for Clinical Microbiology and Infectious Diseases European Respiratory Society European Committee on Antimicrobial Susceptibility Testing Forced Expiratory Volume in 1 Second Forced Vital Capacity Hospital-Acquired Pneumonia Infectious Diseases Society of America Medical Dictionary for Regulatory Activities Minimum Inhibitory Concentration Methicillin-Susceptible Staphylococcus aureus Methicillin-Susceptible Staphylococcus epidermidis New Drug Application Non-inferiority

10 Page 10 of 121 PACTS PRSP R A S A SMART SSP TMP/SMX Topoisomerase II and IV URTI usssi UTI uuti Program to Assess Ceftolozane/Tazobactam Susceptibility Penicillin Resistant Streptococcus Pneumoniae Antibiotic Resistance Antimicrobial Susceptibility Science, Mathematics And Research for Transformation Multiple subspecies Trimethoprim/sulfamethoxazole topoisomerase II and IV DNA genes upper respiratory tract infection uncomplicated skin and skin structure infections Urinary Tract Infection Acute Uncomplicated Urinary Tract Infection

11 Page 11 of 121 This document is Bayer HealthCare s Briefing Document, prepared for the Food and Drug Administration Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on November 5, 2015 to Discuss the Benefits and Risks of Fluoroquinolones for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis in patients with chronic obstructive pulmonary disease, and uncomplicated urinary tract infections. 11

12 Page 12 of Executive Summary The Food and Drug Administration (FDA) is convening a Joint Meeting of the Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on November 5, The purpose of this meeting is to discuss the risks and benefits of fluoroquinolone antibiotics for the treatment of acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis in patients who have chronic obstructive pulmonary disease (AECOPD), and uncomplicated urinary tract infection (uuti). Bayer HealthCare Pharmaceuticals, Inc. appreciates this opportunity to provide our perspective to aid in the deliberations of the joint Committees. We are committed to antibiotic stewardship and to the appropriate use of our two fluoroquinolone products, CIPRO (ciprofloxacin) and AVELOX (moxifloxacin). Generally, each of the fluoroquinolones discussed at today s Advisory Committee has its own purpose, its own distinct activity spectrum to specific bacterial species, its own pharmacological profile, and therefore different indications. CIPRO provides broad gramnegative activity particularly suited for UTIs, including pyelonephritis, as well as potent activity against Pseudomonas aeruginosa. AVELOX provides improved activity against respiratory bacteria, especially Streptococcus pneumoniae and Haemophilus influenza. The safety profiles of these two drugs are well characterized and reflect experience gained through 600 million uses of CIPRO and 200 million uses of AVELOX. Product labeling and treatment guidelines appropriately reflect the safety profile in a way that permits physicians to make informed decisions on the use of these drugs. 12

13 Page 13 of 121 Specifically pertaining to the risks identified by the FDA for discussion at this Advisory Committee meeting (tendinopathy, peripheral neuropathy, and serious arrhythmia), these risks have been detailed in the package inserts for more than 10 years, with updates made throughout the products history. Due to the nature and inherent limitations associated with the spontaneous reporting system, it is difficult to identify an exact incidence of these adverse events. The overall event reporting rates and incidence in clinical trials support the conclusion that these three serious adverse events are either rare or very rare with CIPRO and AVELOX. When used according to treatment guidelines developed by professional societies and the FDA-approved product labeling, there is a positive risk benefit assessment in all three of the indications being discussed at this Advisory Committee meeting. This is demonstrated by analysis of data from 4 sources: Efficacy and safety derived from Bayer s clinical and post-marketing databases; Favorable conclusions in Cochrane Reviews; Treatment guidelines from professional societies; and Efficacy and safety demonstrated from clinical trials of other anti-infective drug classes in which a fluoroquinolone was used as a comparator. ABS, AECOPD and uuti are not trivial infections. Left untreated, they may progress to serious complications including brain abscess, meningitis, pneumonia and pyelonephritis. Just as each fluoroquinolone is different, each class of antibiotics has its own characteristics microbiologically and pharmacologically, as well as distinct safety and tolerability profiles. Based on treatment guidelines, fluoroquinolones are not the drug of first choice in treating these three indications. Rather, they are used when patients have not responded to other classes of antibiotics (i.e. penicillins, sulfonamides, or 13

14 Page 14 of 121 macrolides), or if treatment with those classes is considered inappropriate, e.g. due to high prevalence of bacterial resistance, patients risk factors or underlying conditions. The fluoroquinolones AVELOX and CIPRO have a positive benefit-risk profile based on demonstrated efficacy and safety and are important alternative antibacterial therapies for treatment of ABS, AECOPD, and for CIPRO, treatment of uuti. AVELOX and CIPRO are labeled appropriately, with the potency against relevant pathogens, efficacy in bacterial indications, and safety risks clearly explained. Treatment guidelines published by the ATS and IDSA place AVELOX and CIPRO as alternative therapies for ABS, AECOPD and uuti for patients who fail primary therapy, have allergies to standard therapies, have risk factors for poor outcomes, or have bacterial pathogens likely to be resistant to standard therapies. AVELOX and CIPRO have been administered to over 800 million patients since first approval, and these two fluoroquinolones remain important antibacterial therapies with proven efficacy and safety. Given the lack of any new oral antibiotics for these indications (either approved or in late stage development), patients will continue to need these antibiotics in 2015 and beyond. It is important that AVELOX and CIPRO continue to be available for these three indications, and that the complex treatment decisions regarding ABS, AECOPD, and uuti remain with the individual physician and patient. 2. Introduction Bayer has a long history of research and product development in the antibiotic and antimicrobial fields, dating back to It has a strong commitment to antibiotic stewardship, including continued support for its original antibiotics. This includes global pharmacovigilance, monitoring and evaluation of all adverse events reported in Bayer sponsored clinical trials and those in the scientific literature, as well as those that are 14

15 Page 15 of 121 spontaneously reported. Bayer s ongoing development of three late stage anti-microbial products is another example of the company s commitment to the infectious disease community. Bayer was an innovator in the clinical development of the fluoroquinolone class of antibiotics. A second generation member of the fluoroquinolone class, Bayer s ciprofloxacin (CIPRO ) was first approved as a tablet in Bayer s moxifloxacin (AVELOX ) was approved in These products have proven their value in treating or preventing a wide variety of bacterial diseases, from urinary tract infections (UTIs) and pneumonia to anthrax and plague. CIPRO and AVELOX are now largely sold generically in the United States. There are several classes of antibiotics approved by FDA for the treatment of acute bacterial sinusitis, bronchial infections, and urinary tract infections. The choices include penicillin/bli (ampicillin, amoxicillin/clavulanic acid), macrolides (azithromycin, clarithromycin), sulfonamides (trimethoprim/sulfamethoxazole), and fluoroquinolones. Each class has its strengths and weaknesses microbiologically and pharmacologically, as well as unique safety and tolerability profiles. Having and maintaining a variety of therapies with differing mechanisms is an important means to reduce the impact of disease caused by multiple bacterial strains and the threat of resistance. The variety of available antibiotics is inherently useful to physicians and beneficial to patients when bacterial sinusitis, exacerbation of COPD or chronic bronchial infection, or urinary infections (such as cystitis) are involved. Fluoroquinolones are particularly important because of the lack of ongoing development of new therapies for these indications. ABS, AECOPD and uuti are not trivial infections. Left untreated, they may progress to serious complications including brain abscess, meningitis, pneumonia and pyelonephritis. 15

16 Page 16 of 121 Fluoroquinolones should only be used for these indications when patients have not responded to other classes of antibiotics (i.e. penicillins, sulfonamides, or macrolides), or if treatment with those classes is considered inappropriate, e.g. due to high prevalence of bacterial resistance, patients risk factors or underlying conditions. Fluoroquinolones are commonly used and are considered highly effective for many conditions. Further, through ongoing monitoring of susceptibility data, we know that resistance to CIPRO and AVELOX has increased only marginally in some species (Streptococcus pneumoniae), though selected bacteria (E. coli, Pseudomonas aeruginosa) have become more resistant. FDA guidances for ABS and ABECB, finalized in 2012, now recommend placebo controlled superiority trials as the standard for approval of these indications. This is based on a FDA review of previous ABS and AECOPD trials in which it was concluded that a reliable estimate of the magnitude of benefit for antibacterial drug treatment could not be established. Clearly, this is a pivotal point in the discussion of the benefit-risk of fluoroquinolones (or any antibacterial drug) approved for these two indications. This is because all classes of approved antibiotics for use in these indications were approved based on non-inferiority (NI) studies. If the rationale is accepted that no treatment benefit has been demonstrated for fluoroquinolones in these two indications based on retroactive application of the FDA guidances, then any discussion of benefit-risk is straightforward: there can be no positive benefit-risk without treatment benefit. The assessment that antibacterials in general, and specifically fluoroquinolones, have not demonstrated accepted treatment benefit in ABS, AECOPD, and uuti is contrary to both systematic reviews of clinical data, e.g. Cochrane Reviews, as well as the published 16

17 Page 17 of 121 treatment guidelines of professional organizations such as the IDSA and ATS. The IDSA and ATS treatment guidelines consider multiple sources of information in determining the assessment of antimicrobial benefit for ABS and ABECB. Their conclusion is that antibiotics do provide benefit in selected patients and specifically that fluoroquinolones are appropriate as second or third line agents in selected patients. The version of the Cochrane Review on Antibiotics for Exacerbations of Chronic Obstructive Pulmonary Disease by Ram et al, supported the use of antibiotics in patients with COPD exacerbations with increased cough and sputum purulence who were moderately ill. Antibiotics have demonstrated superiority over placebo in properly diagnosed acute bacterial sinusitis. In 1996 Linbaeck et al 2, published results of a double blinded, placebo controlled study of 130 adult patients with a clinical diagnosis of acute sinusitis confirmed by computed tomography. They found that patients receiving antibiotics, either amoxicillin or penicillin V, had improved outcomes compared to placebo. This study illustrates the advantage of antibacterial therapies in properly diagnosed bacterial sinusitis. 17

18 Page 18 of 121 Figure 1. Outcomes in Patients Receiving Antibiotics for ABS, Adapted from Linbaeck et al The clinical trial data for fluoroquinolones is almost exclusively derived from noninferiority studies, which although intended to only demonstrate similarity to an approved active control, have also on occasion shown superiority. In the development and FDA approval of fosfomycin for the treatment of uuti, two well-controlled studies showed that fosfomycin was inferior to ciprofloxacin and trimethoprim/sulfamethoxazole. The results and conclusions are illustrated in the FDA-approved product label of fosfomycin and demonstrate the efficacy of ciprofloxacin in the treatment of uuti. 18

19 Page 19 of 121 Table 1: Fosfomycin Comparative Eradication Rates and Outcomes in uuti This briefing document will provide evidence showing the continued positive benefit-risk of using fluoroquinolones for these indications when labeling and treatment guidelines are followed. 19

20 Page 20 of Development and Approval of CIPRO and AVELOX 3.1 CIPRO Ciprofloxacin is a selective gyrase inhibitor belonging to the chemical class of fluoroquinolones. It was approved in the United States in Since then, it has been used globally with approximately 600 million treatment courses. It demonstrates rapid bactericidal activity not only during the multiplication phase, but also during the resting phase of bacteria. CIPRO is also active against intracellular sensitive organisms on biofilms and within phagocytes. Ciprofloxacin s antimicrobial spectrum includes Gramnegative and Gram-positive bacteria, including atypicals. CIPRO was one of the first fluoroquinolones to be used intravenously for the treatment of infections and it was the first orally bioavailable treatment with high activity against P.aeruginosa Approved Indications CIPRO is indicated in adults ( 18 years of age) with infections caused by designated, susceptible bacteria and in pediatric patients where indicated. Some of these approved indications have a different wording than the indications under consideration due to the different clinical standards and guidance in place during the development of CIPRO. Urinary tract infections and acute uncomplicated cystitis Chronic bacterial prostatitis Lower respiratory tract infections Acute sinusitis Skin and skin structure infections Bone and joint infections 20

21 Page 21 of 121 Complicated intra-abdominal infections Infectious diarrhea Typhoid fever (enteric fever) Uncomplicated cervical and urethral gonorrhea Complicated urinary tract infections and pyelonephritis in pediatric patients Inhalational anthrax post exposure in adult and pediatric patients Plague in adult and pediatric patients Antibiotic Profile CIPRO has in vitro activity against a wide range of Gram-negative and Gram-positive organisms. The following sections provide detail on its antibiotic activity Gram-negative bacteria Susceptibility to ciprofloxacin among Pseudomonas aeruginosa from the US remains similar to that reported in the previous update based on a recent US study that reported 76.6% susceptibility among 1081 isolates from urinary tract infection (UTI) sources. 3 From 1 non-us study, ciprofloxacin resistance rates were 29.9% for 414 P aeruginosa isolates from UTI sources. 4 For Escherichia coli, there were no US studies available during this reporting period with in vitro ciprofloxacin susceptibility rates for UTI isolates. However, 7 geographically diverse non-us studies were identified to provide current ciprofloxacin susceptibility rates for E coli isolated from UTI sources. From these 7 studies, the highest ciprofloxacin resistance rate of 5.5% was reported from a Canadian study testing E coli isolated from UTI sources of women. 12 This rate is similar to the US ciprofloxacin susceptibility rates that were reported in the previous update. From 5 other non-us studies, ciprofloxacin non-susceptibility rates ranging from 6.9 (Australia) to 39.9% (Colombia) were reported for 22,085 E coli collectively tested

22 Page 22 of A study from Czech Republic reported 8.2 and 96.7% ciprofloxacin susceptibility rates for 220 extended-spectrum Beta-lactamase (ESBL) producing E coli and 150 non-esbl producing E coli, respectively. 18 Ciprofloxacin non-susceptibility rates of 1.9 and 0.8% were reported from an Australian study for 107 Enterobacter aerogenes and 128 Enterobacter cloacae isolates, respectively. 19 From a non-us study, 300 Enterobacteriaceae (E coli and Klebsiella pneumoniae) isolates showed 55.5% ciprofloxacin resistance. 20 Ciprofloxacin continues to show good in vitro activity (<3.5% non-susceptible) against Klebsiella spp as evident from a study in Australia testing 535 Klebsiella spp from outpatient UTI sources. 21 Higher ciprofloxacin resistance (36.2%) was reported from a study in Iran testing 196 K pneumoniae isolated from inpatient UTI sources. 22 For Proteus mirabilis, 3 small non-us studies collectively tested 41 isolates and reported ciprofloxacin susceptibility rates ranging from 92.6 to 100% Gram-positive bacteria For Enterococcus faecalis and Staphylococcus saprophyticus there was no US data available. However, 1 small study from India reported 60 and 66.6% in vitro ciprofloxacin susceptibility rates for S saprophyticus and E faecalis, respectively. 26 In addition, a study from Cuba reported 52% resistance for 50 Enterococcus spp

23 Page 23 of 121 Table 2: Ciprofloxacin Susceptibility Studies Organism N %S a %R a Region Enterococcus faecalis b India Enterococcus spp Cuba Enterobacter aerogenes c Australia Enterobacter cloacae c Australia Enterobacteriaceae d Iran Escherichchia coli - ESBL Czech Republic Escherichchia coli - non ESBL Czech Republic Escherichia coli b Canada Escherichia coli Turkey Escherichia coli Germany Escherichia coli 38 17, e 7.8 France Escherichia coli 39 2, c Australia Escherichia coli f Colombia Klebsiella oxytoca c Australia Klebsiella pneumoniae c Australia Klebsiella pneumoniae Iran Proteus mirabilis Colombia Proteus mirabilis b 0 Colombia Proteus mirabilis b 0 Sudan Pseudomonas aeruginosa b Africa Pseudomonas aeruginosa g 48 1, USA Staphylococcus saprophyticus b India a Based on CLSI interpretive criteria a %S=Percent Sensitive; %R=Percent Resistant b Interpretive criteria not specified c %resistance includes intermediate and resistant isolates d Includes 245 E. coli and 55 K. pneumoniae isolates e Based on EUCAST interpretive criteria f SMART study g PACTS program (Program to Assess Ceftolozane/Tazobactam Susceptibility The bacterial genus and species which are commonly susceptible to CIPRO are: Aerobic Gram-positive microorganisms 23

24 Page 24 of 121 Bacillus anthracis, Staphylococcus aureus (methicillin-susceptible isolates), Staphylococcus Saprophyticus, Streptococcus spp Aerobic Gram-negative microorganisms Aeromonas spp., Moraxella catarrhalis, Brucella spp., Neisseria meningitides, Citrobacter koseri, Pasteurella spp, Francisella tularensis, Salmonella spp., Haemophilus ducreyi Shigella spp., Haemophilius influenzae Vibrio spp., Legionella spp., Yersinia pestis Anaerobic microorganisms Mobiluncus Other microorganisms Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma hominis Mycoplasma pneumoniae 3.2 AVELOX AVELOX oral was first approved in The IV formulation of AVELOX was approved in It is known as a respiratory fluoroquinolone because of its effectiveness in treating respiratory tract infections. AVELOX shows rapid in vitro bactericidal Mechanism of action The bactericidal action results from the interference with topoisomerase II and IV. Topoisomerases are essential enzymes which control DNA topology and assist in DNA replication, repair and transcription. AVELOX demonstrates balanced binding to topoisomerase II and topoisomerase IV, as compared to ciprofloxacin which binds 24

25 Page 25 of 121 preferentially to topoisomerase II. Minimum bactericidal concentrations are generally similar to minimum inhibitory concentrations (MIC). AVELOX is potent against β- lactam- and macrolide-resistant bacteria commonly encountered in community-acquired respiratory tract infections. Studies in animal models of infection have demonstrated high in vivo activity Approved Indications AVELOX is indicated for treating the following infections in adults 18 years of age caused by designated, susceptible bacteria. Some of these approved indications have different wording than the indications under consideration due to the different clinical standards and guidance in place during the development of AVELOX. Acute Bacterial Sinusitis Acute Bacterial Exacerbation of Chronic Bronchitis Community Acquired Pneumonia Skin and Skin Structure Infections: Uncomplicated and Complicated Complicated Intra-Abdominal Infections Plague Antibiotic Profile AVELOX has in vitro activity against a wide range of Gram-negative, Gram positive Anaerobes and other organisms. The following sections provide specific detail on its activity Gram-negative Bacteria Among Enterobacteriaceae, recent moxifloxacin susceptibility data was available from a global study testing 3,543 isolates from the Enterobacteriaceae group and 68.8% 25

26 Page 26 of 121 susceptibility was reported. 50 In vitro moxifloxacin susceptibility data for Escherichia coli was available from 3 non-us studies. A small study from Egypt reported 73% susceptibility for 35 E. coli isolated from patients with hospital-acquired pneumonia (HAP). 51 A higher moxifloxacin susceptibility rate (96.1%) was reported from a study in Chile that tested 180 E coli isolates. 52 From a study in China, MIC50/90 data was reported and values were 16/64 and 0.5/32 µg/ml for 46 extended-spectrum beta-lactamse (ESBL) producing E coli and 41 non-esbl producing E coli, respectively (4). For Klebsiella pneumoniae, one Egyptian study 53 reported susceptibility rates of 84.2, 74.6 and 92.2% for 36 community-acquired pneumonia (CAP) isolates, 45 HAP isolates, and 45 acute exacerbation of chronic bronchitis (AECB) isolates, respectively. 54 From a large global study testing 1,295 Haemophilus influenzae isolates, 99.8% moxifloxacin susceptibility was reported. 55 Slightly lower susceptibility rates (96.6%) were reported from a study in Egypt for 113 H influenzae isolates from patients with AECB. 56 There were no recent reports for Haemophilus parainfluenzae that indicate any change in moxifloxacin in vitro activity. Excellent in vitro moxifloxacin susceptibility (100%) was reported for 505 Moraxella catarrhalis tested in a large global study. 57 From a smaller Egyptian study, 94% susceptibility was reported for M catarrhalis isolated from patients with AECB

27 Page 27 of 121 Table 3: Susceptibility of Gram-negative organisms to moxifloxacin Organism N MIC50 (MIC in µg/ml) MIC9 0 %S a %R a Region Enterobacteriaceae b 59 3, > Global Escherichia coli Egypt Escherichia coli c Chile Escherichia coli - ESBL negative China Escherichia coli - ESBL positive China Klebsiella pneumoniae Egypt Klebsiella pneumoniae Egypt Klebsiella pneumoniae Egypt Haemophilus influenzae 67 1, Global Haemophilus influenzae Egypt Moraxella catarrhalis b Global Moraxella catarrhalis Egypt a) %S = % susceptible; %R = % resistant, based on CLSI interpretive criteria b) Based on EUCAST interpretive criteria c) Interpretive criteria unspecified 27

28 Page 28 of Gram-positive Bacteria Moxifloxacin continues to have excellent in vitro activity (96-99% susceptibility) against Streptococcus pneumoniae as shown from Canadian, Belgian, and global studies. Moxifloxacin also remains highly effective against Beta-haemolytic Streptococcus as evident in 1 global study reporting 98% susceptibility for 1,145 isolates. 74 Moxifloxacin susceptibility data for methicillin-susceptible Staphylococcus aureus (MSSA) was available from 3 non-us studies reporting susceptibility rates ranging from 90.1 (Canada) to 100% (Brazil) for 5,855 isolates collectively tested from studies in Brazil, Canada, and Greece For methicillin-susceptible Staphylococcus epidermidis (MSSE), a Canadian study reported 53.5% moxifloxacin susceptibility for 533 recent isolates. 78 Bayer HealthCare does not recommend moxifloxacin use for treatment of MRSA, regardless of susceptibility result. From a recent Chinese study, MIC50/90 values of 1/8 µg/ml were reported for 15 Enterocococcus faecalis isolates

29 Page 29 of 121 Table 4: Susceptibility of Gram-positive organisms to moxifloxacin (MIC in µg/ml) Organism N MIC 50 MIC 90 %S a %R a Region Enterococcus faecalis China Staphylococcus aureus - MSSA Greece Staphylococcus aureus - MSSA 82 4, Canada Staphylococcus aureus - MSSA Brazil Staphylococcus epidermidis - MSSE Canada Streptococcus- Beta- Haemolytic b 85 1, Global Streptococcus pneumoniae 86 2, Global Streptococcus pneumoniae 87 1, Canada Streptococcus pneumoniae Global Streptococcus pneumoniae Belgium a) %S = Percent sensitive; %R = Percent resistant, based on CLSI interpretive criteria; b) Based on EUCAST interpretive criteria Anaerobic organisms There was no US data available for anaerobic organisms during this reporting period. However, 4 non-us studies were identified and reported moxifloxacin non-susceptibility rates ranging from 7.8 to 47% for more than 400 Bacteroides spp collectively tested from studies in Greece, Belgium, Taiwan, and Europe. 90 From a study in Taiwan, 50 Clostridium perfringens isolates were tested and there was no moxifloxacin resistance detected. 91 For Clostridium spp, 2 studies collectively testing more than 50 isolates, 29

30 Page 30 of 121 reported % susceptibility rates for moxifloxacin For Fusobacterium nucleatum, 100% susceptibility was reported from a study in Taiwan. 94 From 2 studies in Taiwan and Belgium, 40 Fusobacterium spp isolates showed susceptibility rates ranging from 57.9 to 71% From a study in Taiwan, 50 Peptostreptococcus spp isolates showed susceptibility rates ranging from 85 to 93.3%. 97 For Prevotella spp, 3 studies reported moxifloxacin susceptibility rates ranging from 67.9 (Taiwan) to 100% (Greece) for 94 isolates collectively tested Atypical organisms There were no recent reports for Mycoplasma pneumoniae and Chlamydia pneumoniae that indicate any change in moxifloxacin in vitro activity. 30

31 Page 31 of 121 Table 5: Susceptibility of anaerobic and atypical organisms to moxifloxacin (MIC in µg/ml) Organism N MIC 50 MIC 90 %S a %R a Region Anaerobic cocci Belgium Bacteroides and Parabacteroides spp >32 62 Belgium Bacteroides fragilis >32 70 Belgium Bacteroides fragilis group Greece Bacteroides fragilis Taiwan Bacteroides 105 thetaiotaomicron Taiwan Bacteroides uniformis Taiwan Bacteroides spp - other Taiwan Bacteroides/Parabacteroides spp 109 unspecified 13.6 Europe Bacteroides/Parabacteroides spp 110 unspecified 25 Spain Bilophila wadsworthia Taiwan Clostridium perfringens Taiwan Clostridium spp - other Taiwan Clostridium spp 114 unspecified (NS) Belgium Fusobacterium nucleatum Taiwan Fusobacterium spp - other Taiwan Fusobacterium spp >32 71 Belgium Peptostreptococcus micros Taiwan Peptostreptococcus spp - other Taiwan Prevotella spp Greece Prevotella spp Taiwan Prevotella spp (and other Gram-negative bacilli) Belgium

32 Page 32 of 121 Table 5: Susceptibility of anaerobic and atypical organisms to moxifloxacin (MIC in µg/ml) Organism N MIC 50 MIC 90 %S a %R a Region a) %S = Percent sensitive; %R = Percent resistant, based on CLSI interpretive criteria; b) Based on EUCAST interpretive criteria c) Interpretive criteria unspecified AVELOX has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections Gram-positive bacteria Enterococcus faecalis, Staphylococcus aureus, Streptococcus anginosus, Streptococcus constellatus, Streptococcus pneumoniae (including multidrug resistant strains), Streptococcus pyogenes Gram-negative bacteria Enterobacter cloacae, Escherichia coli, Haemophilus influenza, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Yersinia pestis Anaerobic bacteria Bacteroides fragilis, Bacteroides thetaiotaomicron, Clostridium perfringens, Peptostreptococcus species Other microorganisms Chlamydophila pneumoniae, Mycoplasma pneumoniae *MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (MIC) 2 32

33 Page 33 of 121 mcg/ml), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. 4. Medical Landscape 4.1 Introduction CIPRO, AVELOX and the other fluoroquinolones fill a significant and ongoing medical need today for all of their many approved uses, as they have since their introduction. Patients and physicians depend on them every day for the clinical and bacteriological cure of suspected and documented bacterial infections. It is important to consider that the three major fluoroquinolones are not interchangeable. Of the three indications under consideration, CIPRO is used primarily for uuti, while AVELOX is used more commonly for ABS and AECOPD and is not indicated for uuti Sinusitis Acute sinusitis is a common infectious disease of the upper respiratory tract most often initially caused by a viral infection. Antibiotic treatment is not recommended until the patient has experienced clinical signs and symptoms for 7-10 days or has progressively worsened. These events indicate a likely bacterial secondary infection. Antibacterial therapy is considered appropriate for acute bacterial sinusitis. Amoxicillin/clavulanate is usually the antibiotic of first choice. Fluoroquinolones are part of the decision process if primary therapy fails or if the patient is allergic to penicillins. Resistance patterns have complicated ABS treatment. The macrolides and cephalosporins are no longer empiric therapy choices. Unnecessary treatment delays may prolong illness, result in chronic disease, and potentially serious complications. 33

34 Page 34 of Bronchitis There is increasing evidence for the role of bacterial infection causing acute exacerbations of chronic bronchitis. The frequency of exacerbation tends to increase with age due to the vicious cycle of infection and inflammation. This cycle is due to biofilm production which is the source of bacterial seeding in AECOPD, contributes to long term decline in lung function of patients with chronic obstructive pulmonary disease (COPD) and increases mortality. 125 Effective antibiotics are essential to bacterial eradication and patient recovery. Respiratory fluoroquinolones such as AVELOX are essential to the ongoing treatment of an acute exacerbation of COPD, especially when H. influenza or S. pneumonaie or P. aeruginosa (ciprofloxacin) is the infecting organism Urinary Tract Infections Urinary tract infections are uncomplicated if there are no structural, functional, metabolic, or neurological abnormalities that would interfere with normal urine flow and the ability to empty the bladder. In general, these infections most often occur in young, childbearing to middle-aged women. It is exceedingly rare to have uncomplicated UTIs in otherwise healthy men under age 50 and women over age 65. CIPRO is a widely used and effective treatment for UTIs as it achieves high urine and tissue concentrations, and is highly effective against Gram-negative common enteric pathogens that can cause UTI. Acute uuti remains one of the most common indications for prescribing of antibiotics to otherwise healthy communitydwelling women. Despite published guidelines for the optimal selection of an antimicrobial agent and duration of therapy, wide variation in prescribing practices are necessary based on local susceptibility patterns. 34

35 Page 35 of 121 Study: CIPRO Reduces Hospitalization for Pyelonephritis and Bronchitis The contribution of the fluoroquinolone class to medical care is uniquely demonstrated in a study done by Le Lorian and Derdarian at the time of first introduction of CIPRO to the Saskatchewan and Quebec provincial formularies. 127 When it was introduced, CIPRO was considered more expensive than alternative antimicrobials. Thus, it was restricted in Saskatchewan but not Quebec. The use in Quebec was 50 times greater per person than in Saskatchewan. The authors retrospectively studied the ecological correlation between hospital admissions in the two provinces using public domain data. The authors found a significant direct correlation between market entry of CIPRO into Quebec and a decline in hospitalization rates for chronic bronchitis and pyelonephritis. A similar decline in hospitalization rates in Saskatchewan during the same period was not found. Ecological correlations are notoriously poor models to establish a cause and effect relationship, but the results strongly suggest that CIPRO was at least partly responsible for the decline in hospitalizations noted in Quebec. 4.2 Susceptibility and Resistance In vitro resistance to CIPRO and AVELOX is commonly due to target site mutations in topoisomerase IV and DNA gyrase through multiple-step mutations. Single mutations may result in reduced susceptibility rather than clinical resistance, but multiple mutations generally result in clinical resistance and cross-resistance across the fluoroquinolone class. Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect fluoroquinolone susceptibility. Plasmid-mediated resistance encoded by the qnr gene has been reported. In fact plasmids which carry the AAC3I gene de-activate both aminoglycosides and fluoroquinolones. Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines are different from those that interfere with the antibacterial 35

36 Page 36 of 121 activity of the fluoroquinolones. Organisms resistant to those drugs may be susceptible to a fluoroquinolone. Susceptibility and resistance patterns vary between members of the fluoroquinolone class. For example, cross-resistance has been observed between fluoroquinolones against Gram negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to AVELOX. When compared with levofloxacin, AVELOX was found to be active against resistant S. pneumoniae and thus is of use in ABS, especially recalcitrant ABS, and community acquired bacterial pneumonia. Differences in susceptibility patterns like these are due to differing binding to topoisomerase II and IV among the fluoroquinolones. 4.3 Acute Bacterial Sinusitis (ABS) Acute sinusitis, an inflammation of the mucosal lining of the nasal passage and paranasal sinuses, is one of the most common reasons for people to seek medical care. Proper diagnosis is key to the effective management of acute bacterial sinusitis (ABS). ABS is a clinical diagnosis, generally followed by empiric antimicrobial therapy. A laboratory bacterial culture is desirable but not often obtained because nasopharyngeal cultures are unreliable. Direct aspiration is the only way to obtain a reliable culture result. The prevalence of a bacterial infection during acute rhinosinusitis is estimated to be 2% 10%, whereas viral cases, which do not respond to antibiotic drugs, account for 90% 98%. 128 ABS is most often preceded by a viral upper respiratory tract infection (URTI). Bacterial secondary infection may occur at any time during the course of a viral URTI. In general, the clinical diagnosis of ABS is made in adults or children with symptoms of a viral URTI and who have not improved after 10 days or worsen after 5 to 7 days and are accompanied by some or all of the following signs or symptoms: nasal drainage, nasal congestion, facial pressure, postnasal drainage, hyposmia/anosmia, fever, cough, fatigue, maxillary dental pain, 36

37 Page 37 of 121 and ear pressure 129. A course of antibiotics is beneficial for known or suspected episodes of bacterial sinusitis. The physician s primary goal is to eradicate the bacterial pathogens from the site of infection, which helps: Decrease the duration of symptoms to allow patients to resume daily activities more quickly, Return the sinuses to health, Prevent severe complications (e.g., meningitis, brain abscess) and, Decrease the likelihood of developing chronic disease. To meet this goal, appropriate therapies, providing rapid resolution of symptoms with a low risk of recurrence, are needed. During the course of a viral upper respiratory tract infection, three common clinical presentations should prompt the clinician to consider that the patient is experiencing an episode of acute bacterial sinusitis: Onset with persistent symptoms, Onset with severe symptoms, or Onset with worsening symptoms. Persistent symptoms, in the context of acute bacterial sinusitis, are respiratory symptoms that last more than 10 days but less than 30 days and which have not begun to improve. Such symptoms include nasal discharge (of any quality, e.g., thick or thin, serous, mucoid or purulent) or daytime cough (which may be worse at night) or both. Poorly treated ABS can lead to: 37

38 Page 38 of 121 Asthma flare-ups. Chronic sinusitis, lasting 8 weeks or more. Meningitis. Vision problems. Ear infection. The Infectious Disease Society of America s guideline statement published in Clinical Infectious Diseases makes a strong recommendation that clinicians must distinguish between acute rhinosinusitis caused by bacterial causes and those episodes caused by viral upper respiratory infections and noninfectious conditions. 130 They recommend that empiric antibacterial therapy should be started as soon as a clinical diagnosis is made because appropriate specimens for bacteriologic testing are rarely taken in the community. Amoxicillin-clavulanate is recommended as the first choice for empiric therapy in the nonpenicillin allergic patient. Doxycycline or a respiratory fluoroquinolone is recommended for penicillin allergic patients as initial empiric therapy. Penicillin allergy is reported by 10% of adult patients in the US. 131 The ATS-IDSA algorithm for treatment of ABS is shown below: 38

39 Fluoroquinolones for ABS, AECOPD, uuti Page 39 of Figure 2: ATS-IDSA Algorithm for the management of acute bacterial rhinosinusitis Fluoroquinolone treatment of ABS In recent years, empiric treatment of ABS has become challenging owing to a marked rise in the incidence of infections caused by penicillin resistant S. pneumoniae (PRSP). A secondary concern is that the development of resistance to penicillin in S. pneumoniae often parallels its

40 Page 40 of 121 development of resistance to other antimicrobial agents, such as the macrolides or the cephalosporins, which are no longer recommended for empiric management. 132 In order to assist physicians in their decision making process, the Centers for Disease Control (CDC) maintains a map of resistance patterns throughout the US for multidrug resistant streptococcus. Use of empiric therapy to which the infecting bacteria are resistant, can lead to adverse medical outcomes. Patients infected with PRSP had a significantly longer median hospital stay compared with those infected with penicillin susceptible S. pneumoniae (PSSP; 14 versus 10 days, respectively; p< 0.05). 133 In the case of PRSP infections, there is less likelihood of adverse medical outcomes attributable to drug resistance if patients receive empiric therapy with an agent that has shown activity against S. pneumoniae (e.g., a respiratory fluoroquinolone). 134 If a potent broad-spectrum antimicrobial agent is considered necessary, use of a targeted approach to therapy (i.e., one that emphasizes the correct spectrum of activity plus the best pharmacodynamic profile) may curtail the development of antimicrobial resistance. 135 Patients who are seriously ill, immunocompromised, continue to deteriorate clinically despite extended courses of antimicrobial therapy, or have recurrent bouts of acute rhinosinusitis with clearing between episodes should be referred to a specialist (otolaryngologist, infectious disease specialist, or allergist) for consultation. Prompt and appropriate referral should hasten the recovery in patients with complicated ABS. Delay in appropriate referral to specialists may prolong illness, result in chronic disease, and occasionally lead to serious consequences if complications are not recognized. 40

41 Page 41 of Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) The incidence and overall importance of COPD has been rising, increasing the urgent need for effective prevention and management of its complications and exacerbations. 136 Fluoroquinolone antibacterial medicines play a major role in the management of AECOPD. There is increasing evidence for the role of bacterial infection causing acute exacerbations of chronic bronchitis (AECB), particularly in patients who present with all three cardinal symptoms defined by Anthonisen. 137 The frequency of exacerbations adversely affects disease progression and overall health status. 138 Indeed, the frequency of exacerbations contributes to long term decline in lung function of patients with chronic obstructive pulmonary disease (COPD) and increases mortality. 141 Studies involving sputum analysis, bronchoscopic sampling, molecular epidemiology of bacterial strains, and immunology have linked the presence of bacterial infection with AECB and bacterial eradication with recovery. Chronic inflammation has been associated with bacterial persistence and the number of bacteria present in the airway with disease progression. 145 The Allegra study 146 is the only double-blind, placebo-controlled, adequately powered, prospective clinical trial of antibiotic therapy ever conducted in ambulatory patients with AECOPD. The study, briefly summarized here, demonstrates a clinical benefit of antibiotic treatment, the magnitude of which is 36.1% absolute and 72% relative. Although there was no microbiologic confirmation of a bacteriologic etiology of the AECB episode, the requirement for a microbiologically evaluable subset should be necessary only in the context of noninferiority studies in order to ensure that non-inferiority was not established due to inclusion of subjects with viral or other non-bacterial causes of AECB. The Allegra study demonstrated that in a well-characterized patient population with COPD and chronic bronchitis, with a 41

42 Page 42 of 121 well-characterized acute exacerbation, antibiotic treatment provided a statistically and clinically significant benefit which can be estimated as 36% based on clinical response. Thus, a non-inferiority margin of -10%, if established in an appropriately designed study (if the control agent were amoxicillin/clavulanate), would ensure preservation of at least a 26% benefit over no treatment. This study was conducted in Italy at 44 hospital-based pulmonary clinics. This study demonstrated the superiority of antibiotic treatment. Placebo patients failed in 49.7% of cases. Only 13.6% of patients who received antibiotic treatment failed; p< All clinical parameters (signs and symptoms, clinical score, and FEV1 ) supported the superiority of antibiotic treatment. Saint et al conducted a meta-analysis of placebo-controlled trials of AECOPD. Antibiotic treatment had a small but significant benefit on overall recovery and change in peak flow In view of the limits of the spectrum of activity of some antibiotics, as well as the increasing prevalence of bacterial resistance to older generation agents, there is a continued need to find antibiotics that can be used as empiric treatment regimens while limiting the risk of development of resistance COPD Exacerbation Sequelae Exacerbation is a common cause of morbidity in COPD patients. Patients who experience more than 2 exacerbations per year (the frequent exacerbators) are at a greater risk of lung function decline. In America, COPD annually accounts for 16 billion office visits, 500,000 hospitalizations and $18 billion in direct healthcare costs. 148 Approximately half of exacerbations are not reported to clinicians and the majority are managed at home by the patient or primary care team. Moderate-to-severe COPD patients with frequent exacerbations 42

43 Page 43 of 121 have a faster decline in lung function and are more often admitted to hospital with longer lengths of stay. Accelerated decline in lung function is the single most important feature of COPD, a generally progressive disease, especially if the patient s exposure to noxious substances, most often tobacco smoking, continues. If noxious exposure is stopped, the disease may still progress, mainly due to the decline in lung function that normally occurs with aging. Nevertheless, stopping exposure to noxious agents, even after significant airflow limitation is present, can result in some improvement in function and will slow or even hold the progression of the disease. Symptoms of an exacerbation include increased symptom severity that frequently requires a change in usual medications. These episodes vary in severity from mild exacerbations, normally managed at home by the patient, to moderate exacerbations, requiring consultation with primary care physicians, and severe exacerbations requiring hospitalization Therapy of AECOPD Surrogate endpoints for the efficacy of therapy (bronchodilators, corticosteroids and antibiotics) in exacerbations include symptoms and bacteriological resolution at 2 4 weeks. These endpoints have been used to evaluate new drugs but may lack clinical relevance. Other endpoints, such as an exacerbation-free interval, resource utilization, including hospitalization, clinic visits, medication use, lost work days, etc. and improved quality of life may be more suitable endpoints in this patient population. 43

44 Page 44 of 121 In the ambulatory patient, infectious processes involving viruses (Rhinovirus spp., influenza); or bacteria (H. influenzae, S. pneumoniae, Moraxella catarrhalis, Enterobacteriaceae spp., Pseudomonas spp.) are a principal risk factor for exacerbation of COPD AECOPD Professional Guideline The ATS/ERS guidelines 149 document offers the following for antibiotic treatment in the event of an exacerbation: Antibiotic therapy may be initiated in patients with altered sputum characteristics Medication choice should be based on local bacterial resistance patterns and the local prevalence of bacterial β-lactamases o Amoxicillin/ampicillin, cephalosporins o Doxycycline o Macrolides o If the patient has failed prior antibiotic therapy consider: Amoxicillin/clavulanate, a respiratory fluoroquinolone (AVELOX, levofloxacin) or a cephalosporin (cefdinir, cefprozil, cefuroxime) In a meta-analysis of placebo-controlled trials of AECOPD, antibiotic treatment had a small but significant benefit on overall recovery and change in peak flow. 150 In view of the limits of the spectrum of activity of some antibiotics, as well as the increasing prevalence of bacterial resistance to older generation agents, there is a continued need to find antibiotics that can be used as empiric treatment regimens while limiting the risk of development of resistance to existing medicines, including the fluoroquinolones. 44

45 Page 45 of Uncomplicated Urinary Tract Infection (uuti) The usual cause of uutis is the normal enteric (gastrointestinal) bacteria that populate the anal area and colonize the vagina. The most prevalent of these bacteria is E. coli, a Gram negative pathogen that is responsible for up to 80% of uuti infections. The second most common bacterial cause of uutis is Staphylococcus saprophyticus, a Gram-positive bacterium. S. saprophyticus is most often found in the vagina, and women with a uuti. Evolving bacterial resistance patterns are changing the way antimicrobial agents are used in the management of uuti. Effective management hinges on knowledge and utilization of resistance patterns in the local treatment area. According to the 2011 IDSA/ESCMID guidelines, 153 optimal treatment of uuti can be obtained with the following regimens, depending on susceptibility and resistance patterns: Nitrofurantoin monohydrate/macrocrystals (100 mg twice daily for 5 days) is an appropriate choice for therapy due to minimal resistance and propensity for adverse effects and efficacy comparable to 3 days of trimethoprim-sulfamethoxazole. Trimethoprim-sulfamethoxazole (160/800 mg [1 double strength tablet] twice-daily for 3 days) is an appropriate choice for therapy, given its efficacy as assessed in numerous clinical trials, if local resistance rates of uropathogens causing acute uncomplicated cystitis do not exceed 20% or if the infecting strain is known to be susceptible. o The threshold of 20% as the resistance prevalence at which the agent is no longer recommended for empirical treatment of acute cystitis is based on expert opinion derived from clinical, in vitro, and mathematical modeling studies. 45

46 Page 46 of 121 o In some countries and regions, trimethoprim (100 mg twice daily for 3 days) is the preferred agent and is considered equivalent to trimethoprimsulfamethoxazole on the basis of data presented in the original guideline. o Data are insufficient to make a recommendation for other cystitis antimicrobials as to what resistance prevalence should be used to preclude their use for empirical treatment of acute cystitis. Fosfomycin trometamol (3 g in a single dose) is an appropriate choice for therapy where it is available due to minimal resistance and propensity for collateral damage, but it appears to have inferior efficacy compared with standard short course regimens according to data submitted to the US Food and Drug Administration (FDA) and summarized in the Medical Letter. 154 Resistance to fosfomycin develops relatively rapidly. The fluoroquinolones are highly efficacious in 3-day regimens but should be reserved, and thus should be considered alternative antimicrobials for acute cystitis. β-lactam agents, including amoxicillin-clavulanate, cefdinir, cefaclor, and cefpodoxime-proxetil, in 3 7-day regimens are appropriate choices for therapy when other recommended agents cannot be used. Other β-lactams, such as cephalexin, are less well studied but may also be appropriate in certain settings. However, the β- lactams generally have inferior efficacy and more adverse effects, compared with other UTI antimicrobials. For these reasons, β-lactams should be used with caution for uncomplicated cystitis. Amoxicillin or ampicillin should not be used for empirical treatment given the relatively poor efficacy, and the very high prevalence of antimicrobial resistance to these agents worldwide. The diagram below illustrates the IDSA treatment guidance for uncomplicated UTI. 46

47 Page 47 of 121 Figure 3: uuti Decision Tree UTIs frequently recur, especially in women. Between 27 48% of healthy women experience this and it may be due to either a relapse or a recurrence. 155 A relapse is a re-infection that 47

48 Page 48 of 121 occurs within 2 weeks of a course of therapy, is usually the same strain of bacteria, and is often due to an incomplete resolution of the initial infection. This relapse may result from: Persistent vaginal or intestinal colonization that leads to rapid re-infection Incomplete course of antibiotic therapy with reemergence of colonization A more serious, unresolved renal infection. Recurrent infection may occur anytime within 4 months of the initial infection. It refers to an infection-free period followed by re-infection, usually via the same route as the initial infection, which may be caused by the same or a different organism. Patients with recurrent infection need to be evaluated for underlying causes. Recurrent infections are sometimes considered to be complicated UTIs. Postmenopausal women may have frequent re-infections. These can be caused by residual urine after voiding, which is associated with bladder or uterine prolapse. Lack of estrogen can alter the vaginal microflora (bacteria and fungi that are normally found in the area) and promote growth of E. coli Potential complications of failed treatment of uncomplicated UTIs: Recurrent infections, especially in women who experience three or more UTIs. Permanent kidney damage from an acute or chronic kidney infection (pyelonephritis) due to an untreated UTI. Increased risk in pregnant women of delivering low birth weight or premature infants. Urethral narrowing (stricture) in men from recurrent urethritis, previously seen with gonococcal urethritis. Sepsis, especially if the infection works its way to the kidneys. 48

49 Page 49 of Safety Summary Fluoroquinolones are widely prescribed. Considering oral and IV dosage forms of CIPRO, 600 million patients 156 worldwide are estimated to have been treated since initial product approval in CIPRO is included on the World Health Organization s List of Essential Medicines. AVELOX was approved for marketing in the United States in It is estimated to have been prescribed to more than 200 million patients worldwide since its introduction, most often as the oral formulation (185 million patients). 157 CIPRO and AVELOX are safe and effective for the vast majority of patients who have used them over the years. Although a wide variety of different adverse events have been reported to Bayer Global pharmacovigilance, they represent a small portion of the 800 million patients treated with these products since their introduction. Placing the safety of the fluoroquinolone class into perspective requires a review of the serious adverse events associated with other antibiotic drugs used in the treatment of ABS, AECOPD and uuti. Appendix II lists a summary of serious adverse effects of these antibiotics. When compared to the potentially serious risks and changing resistance patterns of other antibiotics, CIPRO and AVELOX, when used as directed in labeling and treatment guidelines, offer important safety and efficacy benefits to patients. Serious adverse events under consideration at today s meeting are all considered events subject to class labeling, though their frequency and degree may vary among class members. QT prolongation and Torsade de Pointes (TdP) are considered class effects of fluoroquinolones and they do occur with CIPRO and AVELOX. However, QT prolongation is considered a marker for TdP and other arrhythmias. No TdP event was observed in clinical studies with oral CIPRO and AVELOX formulations, though elderly and seriously ill patients may be at greater risk. 49

50 Page 50 of 121 Tendinitis and tendon rupture are very rare events after CIPRO and rare to very rare after AVELOX in clinical studies. Based on all clinical studies, the frequency of peripheral neuropathy and polyneuropathy among patients taking CIPRO is rare. The safety profile of patients treated with CIPRO and AVELOX in the three indications under review, uuti, ABS and AECOPD, is presented based on the following data sources: CIPRO clinical safety data pool consisting of 51,621 patients treated with CIPRO in phase 2 to 4 studies between 1983 and This pool includes more than 800 controlled and uncontrolled clinical studies dating back into the 1980s, with a subset of 38,869 patients treated with oral tablet formulations. AVELOX clinical safety data pool consisting of 14,746 patients treated with oral AVELOX in controlled and uncontrolled phase II to IV studies between 1996 and This pool includes patients from 16 studies of patients with ABS, and 20 studies in patients with AECB, besides studies in other indications, with a subset of 14,190 patients treated with oral AVELOX 400 mg. Post-marketing data from Bayer s Global Pharmacovigilance database as of 01 September This data includes adverse event reports received spontaneously from healthcare professionals and consumers, from the literature and noninterventional trials. All three databases were re-analyzed with a focus on three fluoroquinolone class effects identified as topics of interest during preparation for this meeting: serious cardiac arrhythmias, tendinopathy and peripheral neuropathy. 50

51 Page 51 of 121 The known safety concerns are discussed in detail in the US CIPRO and AVELOX labels This includes Black Box warnings for tendinitis or tendon rupture and aggravation of myasthenia gravis. 5.1 CIPRO Safety The CIPRO clinical safety data pool consists of 51,621 patients treated with CIPRO in phase II to IV controlled and uncontrolled studies between 1983 and This pool includes more than 800 studies dating back into the 1980s. As the indications are not coded in this pool, the data does not allow a breakdown to the three indications of interest. The dataset of 38,869 patients treated with CIPRO tablets is considered the most relevant for the patient population and the indications under review. Table 6: CIPRO Oral Tablets: Safety Data Pool Adverse Events CIPRO Oral N=38,869 (100%) Number of subjects (%) with: Any AE 6783 (17.5%) Any study drug-related AE 4335 (11.2%) Any SAE 258 (0.7%) Any study drug-related Serious AE 45 (0.1%) Study drug-related AE leading to death 9 (<0.1%) Discontinuation of study drug due to AE 827 (2.1%) Discontinuation of study drug due to Serious AE 22 (<0.1%) 51

52 Page 52 of 121 The CNS adverse reaction profile in CIPRO pivotal trials was comparable to the control drugs. In all, 49,038 patients received courses of the drug during approval studies. The most frequently reported adverse reactions, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of CIPRO therapy were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1%), and rash (1%) Bayer Global CIPRO pharmacovigilance database Limitations of post-marketing AE reporting are well known, accepted and described. The spontaneous ADR reporting system from post-marketing is known to be susceptible to both reporting bias and under-reporting. In addition, the individual case reports often provide scarce information despite follow-up attempts. Therefore, the true incidences cannot be derived from the reporting frequencies. Risk estimation requires adequate denominator information on drug utilization which, if taken from sales data, may not accurately reflect prescribing and usage levels. The numerator is also inaccurate, as it is subject to reporting bias. Reporting rates may also vary over time and be influenced by factors such time of introduction into the market, media attention and new medical publications. There are also limits regarding identification of indications of interest, as in about a third of the post-marketing adverse event reports, no indications for use of CIPRO was reported. Nevertheless, to give an overview regarding adverse event reporting in the three indications of interest, a broad search strategy was used to account for non-standardized indication terminology in the post marketing setting. For example, to present the indication of acute bacterial sinusitis, not only the MedDRAPT term acute sinusitis was used but also further terms linked to this medical condition such as rhinitis, nasal congestion, nasopharyngitis etc. were chosen. Using a comparable approach to find case reports of acute exacerbation of chronic bronchitis, also medical conditions such as bronchiolitis, (upper or lower) respiratory 52

53 Page 53 of 121 tract infection, bronchial obstruction, chronic respiratory disease etc. were also chosen. For UTI, the search included terms such as cystitis, urethritis, and urinary tract disorders. For the sake of simplicity, the three indications are described as sinusitis, bronchitis and UTI. The majority of cases are spontaneous case reports (90%). About 28% were from the US vs ~72% from rest of the world. The following summary table shows the number of serious and non-serious case reports in the pharmacovigilance database as percentage of the overall received case reports for CIPRO. Table 7: CIPRO Post-marketing Case Reports Summary Total Case Reports Non-serious Serious CIPRO (100%) (100%) (100%) Sinusitis 801 (2.3%) 512 (2.7) 289 (1.8%) Bronchitis 2304 (6.6%) 1210 (6.4%) 1094 (6.8%) UTI 5962 (17.0%) 3322 (17.5%) 2640 (16.3%) Based on an estimated patient exposure of 600 million patients treated with CIPRO oral and IV formulations, the overall cumulative case reporting rate of 59 case reports (serious and non-serious) per million patients. 5.2 AVELOX Safety Bayer clinical safety data (AVELOX) 53

54 Page 54 of 121 The AVELOX global integrated analysis pool contains all Bayer-sponsored phase 2 to 4 interventional clinical studies performed between 1996 and 2010 with the exception of two very specific trials (a study in cirrhotic patients, and a study testing AVELOX p.o. as a 5-day course every 8 weeks). The overall clinical safety data pool of patients treated with 400 mg oral AVELOX consists of 14,190 patients valid for safety, as described in the following table. Table 8: Subjects with treatment emergent adverse events. Population: all controlled and uncontrolled clinical trials with oral AVELOX 400 mg (Data Lock Point: 23SEP2015) AVELOX 400MG Number of subjects (%) with the specified AE: N=14,190 (100%) Any AE 5834 (41.1%) Any study drug-related AE 3167 (22.3%) Any SAE 538 (3.8%) Any study drug related SAE 72 (0.5%) Any study drug related AE with fatal outcome 3 (<0.1%) Discontinuation of study drug due to AE 537 (3.8%) Discontinuation of study drug due to SAE 125 (0.9%) The following two tables present the overall summary of safety for the patients included in clinical trials with oral AVELOX for two indications of interest, sinusitis and bronchitis: 54

55 Page 55 of 121 Table 9: Overall summary of Sinusitis subjects with treatment emergent adverse events controlled and uncontrolled clinical trials with 400 mg oral AVELOX (Data Lock Point: 23SEP2015) AVELOX 400MG N=3,974 (100%) Number of subjects (%) with the specified AE: Any AE 1630 (41.0%) Any study drug-related AE 947 (23.8%) Any SAE 41 (1.0%) Any study drug related SAE 5 (0.1%) Any study drug related AE with fatal outcome 0 Discontinuation of study drug due to AE 126 (3.2%) Discontinuation of study drug due to SAE 10 (0.3%) Table 10: Overall summary of Bronchitis subjects with treatment emergent adverse events controlled and uncontrolled clinical trials with 400 mg oral AVELOX (Data Lock Point:23SEP2015) AVELOX 400MG 55 N=5219 (100%) Any AE 1878 (36.0%) Any study drug-related AE 861 (16.5%) Any SAE 245 (4.7%) Any study drug related SAE 14 (0.3%) Any study drug related AE with fatal outcome 1 (<0.1%) Discontinuation of study drug due to AE 163 (3.1%) Discontinuation of study drug due to SAE 32 (0.6%)

56 Page 56 of Bayer Global AVELOX pharmacovigilance database oral formulations The limitations of the pharmacovigilance database regarding estimations of a true incidence, and reliable identification of patients treated for indications of interest are laid out in the chapter for CIPRO, and are also applicable for AVELOX. An identical search strategy was applied. Case reports for oral AVELOX formulations are presented, and need to be seen in the light of an estimated patient exposure of 185 million patients treated with oral AVELOX since introduction into the global market in The majority of cases represent spontaneous case reports (89%). About 37% come from the US vs ~63% from rest of the world. As for CIPRO, in about a third of the Post-marketing adverse event reports, no indications for use of AVELOX was reported. The below summary tables shows the number of serious and non-serious case reports to the pharmacovigilance database as percentage of the overall received case reports for AVELOX. Table 11: AVELOX Post-marketing case report summary AVELOX (Oral) Total Case Reports (100%) Non-serious (100%) Serious 16373(100%) Sinusitis 4717 (16.5%) 2713 (22.2%) 2004 (12.2%) Bronchitis 6972 (24.4%) 3263 (26.7%) 3709 (22.7%) Based on an estimated patient exposure of 185 million patients treated with oral AVELOX, these numbers translate into an overall cumulative case reporting rate of 155 case reports (serious and non-serious) per million patients. Next, this book addresses the specific serious safety concerns raised by FDA for discussion at this meeting: 56

57 Page 57 of Prolongation of the QTc interval The QT interval encompasses the ventricular depolarization and ventricular repolarization phase of the cardiac action potential. It should be corrected for heart rate in order to determine whether it is prolonged relative to baseline (QTc). The QT interval is gender and age specific. For adult men QTc intervals of <430 ms and for adult women of <450 ms are considered normal. Congenital long QT syndrome is an inherited disease which may result in syncope and sudden death. Current estimates suggest that 1 in 10,000 persons are gene carriers and that the congenital long QT syndrome causes 3000 to 4000 sudden deaths in children and young adults each year in the US. Torsades de Pointes (TdP) are often associated with a prolonged QT interval and are defined as a potentially fatal polymorphic ventricular tachyarrhythmia. QT prolongation and TdP are considered class effects of fluoroquinolones. However, it is accepted that the risk for such undesirable effects differs for individual drugs within the class of fluoroquinolones. Fluoroquinolones prolong the QT interval by blocking the rapidly activating component (I Kr) of the voltage-gated potassium channels in ventricular cardiomyocytes CIPRO The pivotal trials for CIPRO approval did not include routine ECG monitoring. Thus, cases of QT prolongation and TdP with CIPRO were identified only through post marketing surveillance for which a frequency could not be estimated. However, there are special risk groups or risk factors: As women tend to have a longer baseline QTc interval compared with men, they may be more sensitive to QTc prolonging medications. Elderly patients may also be more susceptible to drug-associated effects on the QT interval. Precaution should be taken when using CIPRO with concomitant drugs that can result in prolongation with the QT interval (e.g. class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, 57

58 Page 58 of 121 antipsychotics) or in patients with risk factors for QT prolongation or Torsades de Pointes (e.g. congenital long QT syndrome, uncorrected electrolyte imbalance such as hypokalemia or hypocalcemia and cardiac disease such as heart failure, myocardial infarction, or bradycardia). A review of the literature shows that the risk for QT prolongation and TdP with CIPRO is rather low, as confirmed through in vitro and in vivo models. CIPRO belongs to the group of fluoroquinolones which do not exhibit an action-potential prolonging effect except in very high concentrations as shown in pre-clinical investigations Bayer clinical safety data pool (CIPRO) Serious cardiac disorders were reported as SAEs with an incidence (<0.1%) in 38,869 patients treated with oral tablet formulations of CIPRO. No TdP event was found in the overall CIPRO clinical data pool Bayer Global pharmacovigilance database (CIPRO) IV and oral formulations Of all reported SAEs of serious arrhythmia in the pharmacovigilance database, including reported events such as cardiac arrest, Torsade de Pointes, ventricular tachycardia or fibrillation and other arrhythmia-associated events, 2 came from a patient with sinusitis, 18 came from bronchitis patients and 36 from patients treated for UTI. Considering the overall estimated patient exposure to CIPRO oral and IV formulations, the overall cumulative reporting rate for all patients regardless of indication was 0.3 SAEs of serious arrhythmia per million exposed patients. Of all reported serious adverse events of Torsades de Pointes in the database, none came from a sinusitis patient, 4 from bronchitis patients and 12 from UTI patients. 58

59 Page 59 of CIPRO Labeling for QT prolongation Cardiac effects of CIPRO have been noted in product labeling for more than 20 years. The current warning can be found in the CIPRO product labeling, section AVELOX It is well established that AVELOX produces a predictable small prolongation of the corrected QT (QTc) interval 166 by reversible and dose-dependent but weak blockage of the rapidly activating delayed rectifier potassium channel, IKr 167 or human cloned counterpart, the herg potassium channels. 168 The predictability of AVELOX-induced QTc changes has led to its use as a positive control in thorough Phase I QT/QTc studies. Based on all clinical studies of AVELOX, the frequency of QT prolongation is uncommon ( 1/1,000 to < 1/100) overall and common for QT prolongation in patients with hypokalemia ( 1/100 to < 1/10). The Torsades de Pointes and cardiac arrest cases are ADRs derived only from post marketing reports. These ADRs are especially likely to develop in patients with severe underlying pro-arrhythmic conditions. A meta-analysis of nine trials involving QT-prolongation (and employing AVELOX as positive control) investigated the most appropriate covariance structure for modeling the data. The authors concluded that Fridericia s method for correction of differences in heart rate (QTcF) was more appropriate in their data set, as Bazett s method resulted in an overcorrection (QTcB). In the large population investigated, 400 mg AVELOX resulted in a change 30 msec in QTcF in 85.2% of subjects (no subject had a change > 60 msec), 97.1% of subjects had a QTcF 450 msec. In studies with a 24 hour baseline, the mean change from baseline (difference between AVELOX and placebo) was 4.60 to msec, while in studies without 24 hour baseline, the mean change was to msec. The peak effect was observed 2 to 4 hours after dosing, corresponding to the time of maximum AVELOX plasma concentrations

60 Page 60 of Bayer clinical safety data pool (AVELOX) Haverkamp et al. 172 presented the totality of treatment emergent cardiac AEs based on randomized active controlled studies with 400 mg PO or IV/PO AVELOX that were included in the Bayer safety pool at that time. The author s analysis confirmed the favorable cardiac safety profile of AVELOX versus a range of currently available antimicrobial agents. The established small QTc interval prolongation that occurs with AVELOX did not translate into a higher risk of developing clinical cardiac adverse events. Therefore, although AVELOX should not be used in patients with known pro-arrhythmic conditions, its overall cardiac safety, orally or intravenously, appears to be comparable to that of other commonly used antibiotics. The overall incidence of treatment-emergent cardiac AEs considered potential surrogates for TdP/QTc prolongation was lower in the PO group than the IV/PO group, probably reflecting differences in severity of illness and underlying conditions. There was no evidence of any excess of cardiac AEs with AVELOX versus comparators in the oral treatment group. Of note, no event of Torsades de Pointes was reported in the AVELOX treatment groups. Tables 12 and 13 below are adapted from Haverkamp et al. to detail the cardiac safety of oral AVELOX formulations. 60

61 Page 61 of 121 Table 12: AVELOX Cardiac Safety, adapted from Haverkamp et al. AE Moxifloxacin n (%) Comparator n (%) PO Studies All N=10613 Cardiac AE 698 (6.6%) Drug related cardiac AE Serious cardiac AE Serious drug related cardiac AE Cardiac AE w fatal outcome Drug related cardiac AE w fatal outcome 342 (3.2%) 75 (<0.7%) Women N= (7.1%) 248 (4.3%) 21 (0.4%) 7 (0.1%) 3 12 (0.1%) (<0.1%) 3 (<0.1%) 66 Years N=2451 All N= (8.6%) 619 (5.8%) 76 (3.1%) 256 (2.4%) 42 (1.7%) 72 (0.7%) 3 (0.1%) 9 (0.4%) 6 (<0.1%) 21 (0.2%) (<0.1%) Women N= (6.1%) 185 (3.2%) 66 Years N= (7.3%) 36 (1.5%) 27 (0.5%) 35 (1.5%) 3 (<0.1%) 3 (<0.1%) 4 (0.1%) 12 (0.5%)

62 Page 62 of 121 The following table details the cardiac safety findings in the AVELOX Phase II-IV clinical study data pool: Table 13: Treatment Emergent Events Considered Surrogates for TdP QTc in Phase II-IV Randomized Active Controlled Studies with Moxifloxacin Moxifloxacin N=10,613 Comparator N=10,685 Any AE 25 (0.2) 23 (0.2) Cardiac Disorders Cardiac Arrest 1 (<0.1) 1 (<0.1) Cardiac flutter 2 (<0.1) 1 (<0.1) Cardiorespiratory Arrest 2 (<0.1) 1 (<0.1) Torsade de Point 0 0 Ventricular arrhythmia 2 (<0.1) 0 Ventricular fibrillation 1 (<0.1) 0 Ventricular tachycardia 0 2 (<0.1) General Disorders and Administration Death 2 (<0.1) 2 (<0.1) Sudden death 2 (<0.1) 1 (<0.1) Sudden cardiac death 0 0 Nervous system disorders Loss of consciousness 4 (<0.1) 5 (<0.1) Syncope 9 (<0.1) 10 (<0.1) Surgical and medical procedures Resuscitations 0 0 The clinical safety data pool of oral AVELOX Phase II-IV was re-analyzed for cardiac events in the two indications of interest. 62

63 Page 63 of 121 No serious arrhythmia or TdP was reported in 3974 patients in controlled and uncontrolled clinical sinusitis trials with oral AVELOX 400 mg. 3 (<0.1%) events of serious arrhythmia were reported in 5219 patients in controlled and uncontrolled clinical bronchitis trials with oral AVELOX 400 mg. No event of TdP was reported for AVELOX 400 mg Bayer Global pharmacovigilance database (AVELOX) oral formulations Of all reported SAEs of serious arrhythmia in the pharmacovigilance database, including reported events such as cardiac arrest, Torsades de Pointes, ventricular tachycardia or fibrillation and other arrhythmia-associated events, 19 came from patients with sinusitis and 85 came from bronchitis patients. Considering the overall estimated patient exposure to AVELOX oral of 185 million patients, the cumulative reporting rate, regardless of indication, was 1.4 serious arrhythmia per million exposed patients. Of all reported events of Torsades de Pointes in the database of 185 million patients, 1 came from a sinusitis patient and 15 from bronchitis patients treated with oral AVELOX AVELOX Labeling for QT prolongation AVELOX product labeling has included a warning on the prolongation of the QT interval since initial approval in 1999, and the current warning can be found in the AVELOX product labeling, section Tendonitis and Tendon Rupture Fluoroquinolones have the potential to damage connective tissue structures as tendons, and are thus associated with unusual forms of adverse drug reactions such as tendinitis and tendon rupture. The mechanism is poorly understood; direct toxic effects on collagen fibers, ischemic processes, magnesium chelation, and increased expression of matrix metalloproteinases and 63

64 Page 64 of 121 formation of reactive oxygen species have been hypothesized. 173 An abnormal healing response to fluoroquinolone-associated inflammation reaction has been deduced to produce a delayed effect several months after completion of even a short course of a fluoroquinolone therapy. A review of the literature shows that tendon ruptures can occur bilaterally. Fluoroquinolonerelated tendon rupture affects preferentially, but not exclusively, the Achilles tendon. The overall estimated incidence of fluoroquinolone-related tendon rupture ranges from 0.14% to 0.4%. Risk factors include age, concomitant use of corticosteroids, renal failure, sporting activities, and rheumatic disease CIPRO Evidence from the literature and post marketing cases suggest that even several months after discontinuation of CIPRO therapy, there is a possibility of tendon rupture or tendon inflammation occurring. Literature and post marketing cases also show that tendinitis and tendon rupture may already occur within the first 48 hours of CIPRO treatment. As addressed in the product label, at any sign of tendinitis (e.g. painful swelling, inflammation), a physician should be consulted and the antibiotic treatment be discontinued. Care should be taken to keep the affected extremity at rest and avoid any inappropriate physical exercise (as the risk for tendon rupture might increase otherwise). CIPRO should not be used by patients with a history of tendon disorders related to fluoroquinolone treatment Bayer clinical safety data pool (CIPRO) In preparation for this meeting, the Bayer clinical safety pool was reviewed for tendinopathy reported in patients treated with oral CIPRO. Five (<0.1%) events (composite of tendon disorders, tendonitis and tendon rupture) were reported in 38,869 patients treated with oral CIPRO, including only one tendon rupture. 64

65 Page 65 of 121 Table 14: Tendinitis and Tendon Rupture related AEs in Bayer Sponsored CIPRO Studies Overall summary of number of selected treatment-emergent adverse events by Risk: Tendinitis and tendon rupture (safety analysis set) Number of subjects (%) with CIPRO P.O. N=38,869 (100%) Any AE 5 (<0.1%) Any SAE 0 Discontinuation of study drug due to AE 1 (<0.1%) Discontinuation of study drug due to SAE Bayer Global pharmacovigilance database (CIPRO) IV and oral formulations Of all reported serious events of tendinopathy in the pharmacovigilance database, including reported events such as tendon pain, tendonitis, tendon rupture, unspecific tendon disorders and other tendon related events, 60 came from patients with sinusitis, 267 from patients with bronchitis and 307 from patients with UTI. Considering the overall estimated patient exposure to CIPRO oral and IV formulations, the overall cumulative reporting rate, regardless of indication, was 2.8 serious events of tendinopathy per million exposed patients. Of all reported serious tendon rupture events, 22 came from patients with sinusitis, 124 patients with bronchitis and 115 patients treated for UTI CIPRO Labeling for tendinopathy Product labeling related to tendon effects seen in animals was included in CIPRO labeling starting in A warning regarding tendon ruptures in patients was added in 1996 and the 65

66 Page 66 of 121 current warning can be found in the CIPRO product labeling, section 5.1. A Black Box Warning on tendon effects was added in AVELOX Bayer clinical safety data pool (AVELOX) In preparation for this meeting, the Bayer clinical safety pool was reviewed for tendinopathy (including events such as tendon disorders, tendonitis and tendon rupture) in patients treated with oral AVELOX 400mg. A total of 4 (0.1%) events of tendinopathy occurred in the 3974 patients included in sinusitis clinical studies, and 2 (<0.1%) occurred in the 5219 patients included in bronchitis clinical studies with AVELOX 400mg, with no report of tendon rupture for either indication Table 15: Tendinitis and Tendon Rupture related AEs in Bayer-Sponsored oral AVELOX Studies Tendinitis & Tendon Rupture AVELOX 400 mg (n=14190) Any AE 10 (<0.1%) Any study drug-related AE 5 (<0.1%) Maximum intensity for any AE MILD 4 (<0.1%) MODERATE 6 (<0.1%) Any Serious AE 0 Any study drug related Serious AE 0 Discontinuation of study drug due to AE 2 (<0.1%) Discontinuation of study drug due to Serious AE 0 66

67 Page 67 of Bayer Global pharmacovigilance database (AVELOX) oral formulations Of all reported serious events of tendinopathy in the pharmacovigilance database, including reported events such as tendon pain, tendonitis, tendon rupture, unspecific tendon disorders and other tendon related events, 110 came from patients with sinusitis and 107 from patients with bronchitis. Considering the overall estimated patient exposure to oral AVELOX, the overall cumulative reporting rate regardless of indication was 2.6 serious events of tendinopathy per million exposed patients. From all reported serious events of tendon rupture, 45 came from patients with sinusitis and 54 from patients with bronchitis AVELOX Labeling for tendinopathy AVELOX product labeling related to tendon effects was included in the original label upon product approval in 1999, and the current warning can be found in the AVELOX product labeling, section 5.1. A Black Box Warning on tendon effects was added in Peripheral Neuropathy Fluoroquinolones have been associated with peripheral neuropathy, but the mechanism is still unknown. Axonal degeneration with secondary breakdown of the myelin sheath or possibly primary segmental demyelination has been demonstrated. 181 Various mechanisms including toxic, metabolic, or immunological mechanisms, may play a role in causing distal axonopathies, myelinopathies, neuronopathies or focal neuropathies. 182 Some reports can be found in the published literature describing cases of fluoroquinolone associated sensory or sensorimotor polyneuropathy The Swedish adverse drug reactions advisory committee, for example, analyzed 37 cases of peripheral sensory disturbances submitted to the Swedish health authority between 1987 and For CIPRO, the number of reports was insufficient for incidence estimation and most cases described mild events such as paresthesia (81%), hypoesthesia (51%) and hyperesthesia (27%). Two publications provided 67

68 Page 68 of 121 neurophysiological data in form of electromyographic (EMG) results to support the diagnosis of drug-induced peripheral neuropathy The prompt recognition of polyneuropathy-related symptoms and withdrawal of the fluoroquinolone is important, especially since no curative treatment is known for drug induced neuropathy CIPRO Bayer clinical safety data pool (CIPRO) In preparation for this meeting, the Bayer clinical safety pool was reviewed for neuropathy events in patients treated with oral CIPRO; 5 (<0.1%) neuropathy events were reported in 38,869 patients treated with oral CIPRO. None were reported as a Serious Adverse Event and all improved or resolved. Table 16: Overall summary of number of selected treatment-emergent adverse events Peripheral neuropathy (safety analysis set) CIPRO P.O. Number of subjects (%) with: N=38,869 (100%) Any AE 5 (<0.1%) Any SAE 0 Discontinuation of study drug due to AE 2 (<0.1%) Discontinuation of study drug due to SAE Bayer Global pharmacovigilance database (CIPRO) IV and oral formulations Considering the overall estimated patient exposure to CIPRO oral and IV formulations, the overall cumulative reporting rate regardless of indication was 0.5 serious neuropathy events per million exposed patients. Of all reported serious events of neuropathy in the 68

69 Page 69 of 121 pharmacovigilance database, including reported events such as neuropathy peripheral, polyneuropathy, peripheral sensory neuropathy and other sensory (motor) events, 9 came from patients with sinusitis, 4 from patients with bronchitis and 69 from patients with UTI. Patients under treatment with any fluoroquinolone antibiotic should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop CIPRO Labeling for peripheral neuropathy A Warning related to effects on peripheral neuropathy was included in CIPRO labeling starting in 2004, and the current warning can be found in the CIPRO product labeling, section AVELOX Bayer clinical safety data pool (AVELOX) Cases of sensory or sensorimotor polyneuropathy resulting in paresthesias, hypoesthesias, dysesthesias, or weakness have been reported in patients receiving quinolones, including AVELOX. The following table describes reported neuropathy events for 14,190 patients included in all Bayer sponsored controlled and uncontrolled clinical studies with oral AVELOX 400 mg. None of these 2 (<0.1%) events occurred in the patients included in clinical trials studying sinusitis or bronchitis. 69

70 Page 70 of 121 Table 17: AVELOX 400 mg Peripheral Neuropathy Events Bayer Clinical Trials Peripheral Neuropathy Number of subjects (%) with the specified AE: AVELOX 400MG N=14190 Any AE 2 (<0.1%) Any study drug-related AE 0 Maximum intensity for any AE MILD 2 (<0.1%) Any Serious AE 0 Any study drug related Serious AE 0 Discontinuation of study drug due to AE 0 Discontinuation of study drug due to Serious AE Bayer Global pharmacovigilance database (AVELOX) oral formulations Of all reported serious events of neuropathy in the pharmacovigilance database, including reported events such as neuropathy peripheral, polyneuropathy, peripheral sensory neuropathy and other sensori (motor) events, 16 came from patients with sinusitis and 16 from patients with bronchitis. Considering the overall estimated patient exposure to AVELOX oral, the overall cumulative reporting rate regardless of indication was 0.6 serious events of neuropathy per million exposed patients AVELOX Labeling for peripheral neuropathy A Warning related to effects on peripheral neuropathy was included in AVELOX labeling starting in 2004, and the current warning can be found in the AVELOX product labeling, section

71 Page 71 of Safety Conclusions The risks identified by FDA for discussion at this Advisory Committee meeting (tendinopathy, peripheral neuropathy, and serious arrhythmia) have been detailed in the package inserts for more than 10 years, with updates made throughout the products history. Due to the nature and inherent limitations associated with the spontaneous reporting system, it is difficult to identify a true incidence of these adverse events. The overall event reporting rates and incidence in clinical trials support the conclusion that these three serious adverse events are either rare or very rare with CIPRO and AVELOX. 6. Efficacy Summary 6.1 Introduction Fluoroquinolone antibiotics have demonstrated proven activity atgainst a wide variety of community-acquired infectious organisms. Their efficacy was established in comparative non-inferiority trials, the standard for antibiotic efficacy trials at the time of their approval. The level of proof achieved in these non-inferiority studies and the millions of patients successfully treated over the years, demonstrates that these trials led to the introduction of safe and effective antibiotics to treat infected patients. Bayer believes strongly in antibiotic stewardship. We must protect the efficacy of our existing antibiotic drugs to reduce selection for multi-drug resistant strains. Bayer supports the medically appropriate use of CIPRO, AVELOX and all other antibiotics. The efficacy of CIPRO and AVELOX in acute bacterial sinusitis has been previously established. Currently, CIPRO and AVELOX are recommended for patients who have not responded to other therapies or who cannot take another antibiotic because of hypersensitivity or allergy, or those who cannot tolerate other drug classes due to adverse effects. Acute exacerbation of COPD can be a serious concern, since exacerbation is directly linked to patient decline. AVELOX and CIPRO have demonstrated efficacy in treatments of AECOPD. 71

72 Page 72 of 121 Uncomplicated urinary tract infection (uuti) is one of the most common infections in women. Managing these infections has been made more complicated by changing resistance patterns to standard treatments for uuti, especially to β-lactams and trimethoprimsulfamethoxazole. CIPRO has been proven effective against the most common organisms involved in uuti and is widely used after other therapies have failed. 6.2 Acute Bacterial Sinusitis (ABS) Most cases of acute sinusitis are caused by viral infections. Mucosal edema leads to obstruction of the sinus ostia. In addition, viral and bacterial infections impair the cilia, which transport mucus. There is increasing evidence that Biofilm formation also seeds bacteria in the sinuses. The obstruction and slowed mucus transport cause stagnation of secretions and lowered oxygen tension within the sinuses. This environment is an excellent culture medium for viruses and bacteria, though viral rhinosinusitis is complicated by acute bacterial infection in only a minority of the cases. The clinical signs and symptoms of ABS are not trivial. For example, in a Bayer study, over 90% of the patients experienced moderate to severe purulent nasal drainage, over 80% experienced moderate to severe facial pain, and over 75% experienced moderate to severe frontal headache. 72

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74 Page 74 of 121 antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to CIPRO. CIPRO may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some isolates of P. aeruginosa may develop resistance fairly rapidly during CIPRO treatment. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance. The most common bacterial organisms seen in community-acquired acute bacterial rhinosinusitis are Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis. CIPRO is indicated in adult patients for the treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis Clinical Trial Overview Approval was based on randomized, double-blind controlled clinical trials comparing CIPRO tablets [500 mg two times daily (BID)] to cefuroxime axetil (250 mg 500 mg BID) 195 and to clarithromycin (500 mg BID) 196 in patients with sinus infections. In treating patients with acute bacterial sinusitis, antibiotic coverage must include resistant S. pneumonia, H. influenza, M. catarrhalis, and S. aureus. Resistant Pseudomonas aeruginosa occurs very infrequently and may need to be treated with drugs such as antibacterials with anti-pseudomonal activity. In some patients treatment may be necessary with a respiratory fluoroquinolone drug such as AVELOX or levofloxacin. However, changing bacterial resistance patterns demand a large armamentarium of effective antibiotics. 74

75 Page 75 of Resolution rates Patients taking CIPRO for ABS experienced a high rate of resolution of their infection. Rates vary with the infectious organism and specific patient circumstances. Overall, CIPRO is very effective for ABS patients who have failed on other antibiotic treatments Comparisons with other treatments In clinical non-inferiority trials, CIPRO was found to be non-inferior to comparator medicines. The use of ciprofloxacin in Acute Bacterial Sinusitis has been limited because, as recommended by treatment guidelines, ciprofloxacin has generally been reserved for patients who have failed first line therapy and who are suffering from proven or suspected sensitive organisms, based on the physician s clinical judgement CIPRO Benefit-Risk for ABS CIPRO offers an important benefit to ABS patients with a relatively small risk of serious adverse drug effects. CIPRO is an established antibiotic for situations when first line therapy has failed. The disease process in ABS patients is such that they will likely have been suffering for 10 days or more before CIPRO is considered. Bacteriologic eradication data provide the most accurate indication of antimicrobial effect in ABS. CIPRO rapidly eradicates key pathogens of ABS, leading to rapid improvement in sinusitis symptoms. CIPRO has a positive benefit-risk for use in ABS due to the second line nature of CIPRO use in more serious patients, and the rare frequency of serious adverse events observed in clinical trials and in post approval studies. 75

76 Page 76 of AVELOX Clinical Trial Overview The efficacy of AVELOX in treating ABS has been proven in Phase III-IIIb clinical studies using various comparators (cefuroxime, trovafloxacin, amoxicillin- clavulanic acid). Table 19: Phase III, IIIb AVELOX Clinical Trials in ABS The overall clinical success rates for the 7 day or 10 day AVELOX 400 mg od regimen were non-inferior to those obtained with comparators. However, in Bayer studies 0116 and , the clinical success rates at the end of treatment in the evaluable population were significantly higher in the AVELOX group than in the comparator group (vs. cefuroxime axetil or trovafloxacin). 76

77 Page 77 of Outcomes of Patients treated with AVELOX for ABS Because there are few data concerning outcomes in patients with ABS caused by PRSP infection, a retrospective analysis was done by Johnson et al. to assess the efficacy of AVELOX in this subpopulation infected with highly resistant organisms. 197 This pooled analysis found that AVELOX was both clinically and bacteriologically effective in the treatment of moderate to severe episodes of ABS caused by PRSP Study Description The analysis used pooled data from two prospective, multicenter, open-label, noncomparative US trials of AVELOX in the treatment of ABS. Patients received AVELOX 400 mg OD for 7 days in one trial (N = 372) and for 10 days in the other (N = 434). Adults presenting with a clinical and radiological diagnosis of ABS of < 4 weeks duration, with microbiological confirmation of S. pneumoniae as the causative pathogen, were included in this pooled analysis. The investigators rated the current episode of ABS as mild, moderate, or severe based on the presenting signs and symptoms, using the criteria of Lanza and Kennedy Results Of the 69 isolates of S. pneumoniae cultured at baseline, 54 were penicillin susceptible (range of penicillin MICs, ) and 15 were categorized as PRSP (penicillin MIC 2 mg/l). The MIC90 for AVELOX against the 54 PSSP strains was 0.25 mg/l (range, mg/l). MIC90s for AVELOX against the 15 PRSP strains ranged from 0.06 to 0.25mg/L. 77

78 Page 78 of 121 For all patients with broth dilution confirmed S. pneumoniae, regardless of penicillin susceptibility, clinical and bacteriologic success was reported in 88.4% (61/69) of AVELOX recipients at the test-of-cure visit (95%CI, 0.82 to 0.95). Seven of the 8 clinical/microbiologic failures occurred in patients infected with PSSP. Among these 7 patients, 3 had no organism present on a culture performed after the end of therapy. The rate of clinical resolution/bacteriologic eradication in those with PSSP was 87.0% (47/54). In the 15 cases of confirmed PRSP infection, 93.3% (14) were classified as clinical and bacteriologic successes. The pre-therapy AVELOX MIC against PRSP in the one patient who failed to respond to treatment was 0.25 mg/l. In this patient, it is of note that bacteriologic eradication was documented by antral puncture at the end-of-therapy visit. Four days after the end of therapy, this patient s symptoms, which were considered severe before therapy, had improved to mild; nonetheless, the patient was considered a clinical failure Placebo-controlled trials Moxifloxacin 400 mg QD was compared to placebo in the treatment of acute bacterial rhinosinusitis (Hadley et al, 2010). Patients with ABRS defined by clinical, radiologic, and bacteriologic criteria were recruited to the study. The overall effect of moxifloxacin versus placebo was: Numerically better clinical response in the moxifloxacin group. Moxifloxacin 78.1%, 57/73) versus placebo (66.7%, 30/45); (P =.189). Significantly greater mean reductions in SNOT-16, a patient-reported outcome measurement, scores occurred in moxifloxacin- versus placebo-treated patients (17.54 vs ; P =.032). Overall concomitant medication use was lower in moxifloxacin versus placebo patients (38.4%, 28/73 vs. 55.6%, 25/45 respectively). 78

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80 Page 80 of Resolution rates Accumulated clinical resolution rates after end of treatment in Phase III-IIIb clinical trials in acute bacterial sinusitis (per protocol population) ranged from 87.1 to 96.9% for AVELOX administered 400 mg QD for 7 or 10 days. The clinical resolution rate for comparator ranged from 89.2% to 94.6%. Table 20: Moxifloxacin Resolution Rates Bacteriological AVELOX has in vitro activity against MDRSP, PSSP and PRSP (MIC90, 0.25 μg/ml), as well as against other common respiratory tract pathogens. Among the available oral fluoroquinolones, AVELOX is considered to have relatively low potential for inducing resistance in S pneumoniae. Furthermore, sinus mucosal levels of AVELOX have been shown 80

81 Page 81 of 121 to greatly exceed (i.e., 5 30 times) the MIC90 for of S pneumoniae isolates, suggesting that it may provide bactericidal rapid activity at the site of infection AVELOX Benefit-Risk for ABS AVELOX offers effective treatment for patients suffering from ABS who have not responded to other treatments or who suffer from sinusitis caused by bacteria known or suspected to be susceptible. The risk of serious adverse events is small. In a placebo controlled trial of ABRS, AVELOX demonstrated numerically higher clinical response and statistically better reduction in clinical symptoms and significantly lower discontinuation due to failure. Moxifloxacin had numerically fewer concurrent medication use, and similar (numerically fewer) adverse events. Moxifloxacin also demonstrated non-inferiority to accepted antibacterial treatments in multiple non-inferiority trials, with similar response and adverse event rates. Therefore, AVELOX has a positive benefit-to-risk ratio when used appropriately for treatment of ABS. 6.3 Acute Exacerbation of COPD (AECOPD) / Acute Exacerbation of Chronic Bronchitis (AECB) On average, a patient with chronic bronchitis experiences 1 to 4 exacerbations per year 201, with symptoms lasting up to 2 weeks per episode. Patients with an acute exacerbation of chronic bronchitis will usually have increasing symptoms of cough, dyspnea, and/or sputum production before they seek treatment from a health care provider. There are multiple types of therapy available for AECOPD (e.g., antimicrobial, bronchodilator, and/or systemic corticosteroid therapy). However, because there is no rapid or reliable method to predict etiology based on patient history, physical examination, or routine laboratory test results, physicians must rely on epidemiologic data to predict the most likely pathogens. The majority of patients (about 90%) will not require hospitalization for treatment of AECB. 81

82 Page 82 of 121 Table 21: Infectious Etiologies of AECB A review of the clinical aspects of AECB suggests: The etiology of a specific AECOPD episode is difficult to determine, Patients at high risk for treatment failure or early recurrence of AECB can be identified using clinical history, and Individualizing treatment decisions in patients with AECB may prove cost-effective. 82

83 Page 83 of CIPRO Clinical Ciprofloxacin has been studied in respiratory tract infections, both in clinical development, and as a positive control in trials of other agents. These trials have consistently demonstrated the efficacy of ciprofloxacin Clinical Trial Overview Three controlled clinical trials comparing CIPRO, 750 mg BID (n=77) to ampicillin, 500 mg QID (N=78), for patients with bronchitis or other bronchopulmonary infections. The infectious organisms were sensitive to both antibiotics. One of these, which enrolled 14 patients, was a crossover design where each patient received both drugs, one each during successive exacerbations at least one month apart. The second series of studies was comprised of 4 non-controlled trials which studied patients with respiratory infections caused by any organism sensitive to CIPRO patients were enrolled. Treatment courses were valid for 135 of the 168 patients. A summary of CIPRO pivotal respiratory approval trials are listed in the table below. Efficacy data for all patients treated with CIPRO for only respiratory tract infections was culled from all controlled and uncontrolled trials monitored by the sponsor. Of the 306 patients in this group, 169 had bronchitis, 91 had pneumonia and 27 had an acute pulmonary exacerbation of CF. Pseudomonas aeruginosa was cultured most often. Other frequently cultured organisms were H. influenzae, H. parainfluenzae, S. pneumoniae and Klebsiella pneumoniae. The overall response to CIPRO in non-cf patients was: 221 (74.9%) Cure 49 (16.6%) Partial cure 14 (4.7%) Failure 11 (3.7%) Indeterminate response. 83

84 Page 84 of 121 Investigator/ Location Khan, Jamaica NY Phillips Columbiana AL Chodosh Boston MA Muhar Vienna Aus. Khan Jamaica NY Phillips Columbiana Study/ Report Table 22: Summary of ciprofloxacin clinical research Number D D Ampicillin D (P) D Respiratory Tract Infection Studies Study Design Double blind compariso n vs ampicillin Double blind compariso n vs ampicillin Double blind crossover compariso n vs ampicillin Comparis on vs cephalexin Noncompa r-ative Patients valid/ evaluabl e 84 Age & Gender 116 (92) M=51 F41 25 (22) M=12 F=13 20 (18) M=10 F=8 60 (51) (56.6) M=10 F=8 80 (62) M=47 F=33 CIPRO dose 750 bid 750 mg cap 750 bid 750 mg cap 750 bid 750 mg cap 500 bid 500 mg cap 750 bid 750 mg cap Control drug Ampi- cillin 500 q6h 500 q6h 500 q6h Ampicillin Cephalexin 1000 bid Duration (days) 5-20 Cip (8.8) Amp (8.7) 5-16 Cip (14.8) Amp (13.9) Cip (15.1) Amp (14.9) 7-13 Cip (8) Ceph (8) None 5-19 (8.6) D84- Noncompa 48 (45) bid None 6-24

85 Page 85 of 121 AL r-ative (65.8) Krist Bronx, NY Mogabgab New Orleans Klein Netherlands Mahar Vienna Aus. Marks Oklahoma City Blumer Cleveland OH Herbst & Black Salt Lake City D D Noncompa r-ative Noncompa rative 3349 (P) Noncompa rative (P) D D D Noncompa rative Double blind crossover 2 dose levels Noncontro lled Double blind compariso n vs azlocillin and tobramyci 85 M=25 F=23 29 (20) M=8 F=3 11 (8) M=8 F=3 27 (27) (54.4) M=17 F=10 20 (20) M=20 F=0 30 (28) M=20 F=8 28 (25) M=2 F=4 6 (6) M=2 F=4 750 mg cap 750 bid 750 mg cap 750 bid 750 mg cap 500 bid 500 mg cap 500 bid 500 mg cap 1000 bid 750 bid 750 tid 750 mg cap 750 bid 750 mg cap (14) None 5-12 (8) None 5-19 None 10 (12.8) (10) None 6-11 (8.3) None (14.1) 750- (14.5) None Tobra 6mg/kg divided tid Azlocillin (14.9) 7-14 Cip (10.5) Tob/Azl o

86 Page 86 of 121 n 300 mg/kg (12.8) divided q6h Goldfarrb Valhalla NY D Double blind compariso n vs azlocillin and tobramyci n 4 (2) M=2 F=2 750 bid 750 mg cap Tobra 6mg/kg divided tid Azlocillin 300 mg/kg 7-14 Cip (14.5) Tob/ Azlo divided q6h Bixbie Norfolk VA D Double blind compariso n vs azlocillin and tobramyci n 3 (3) M=2 F=1 750 bid 750 mg cap Tobra 6mg/kg divided tid Azlocillin 300 mg/kg Cip (45) Tob/ Azlo (20) divided q6h Congeni Akron OH D Double blind compariso n vs azlocillin and tobramyci n 3 (2) M=2 F=3 750 bid 750 mg capamp Tobra 6mg/kg divided tid Azlocillin 300 mg/kg Cip (15) Tob/ Azlo (12) divided q6h 86

87 Page 87 of Results CIPRO has been used in multiple clinical trials of respiratory tract infections. Clinical responses generally ranged from 80 to 90%. During clinical development, CIPRO demonstrated non-inferiority to comparator agents and similar adverse event rates Comparisons with other treatments Ciprofloxacin has been compared to many respiratory antibiotics. The clinical development featured comparisons to ampicillin and tobramycin, but many other drugs and classes have been compared including cephalosporins, macrolides, and tetracyclines. The trials are extensive in number Bacteriological The primary bacterial pathogens of AE-COPD are S. pneumoniae, H. influenzae, and various enterobacteriaceae including K. pneumoniae. Resistance development has been non-existent in H. influenzae, very low (<3%) in S. pneumoniae, and moderate in K. pneumoniae and other enterobacteriaceae CIPRO Benefit-Risk for AECOPD CIPRO has demonstrated a positive benefit risk in the treatment of lower respiratory infections, including acute exacerbations of chronic bronchitis. Due to differing clinical trial standards at the time of its approval, ciprofloxacin was not formally studied in AECOPD. CIPRO has demonstrated potency against the pathogens of AECOPD and efficacy in studies of respiratory infections. CIPRO is currently not used as the quinolone of choice for respiratory infections, except in cases of known P. aeruginosa infections. 87

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89 Page 89 of 121 Table 24: Accumulated bacteriological success (eradication or presumed eradication) rates by patient at the primary efficacy assessment in comparative Phase III/IIIb AECB studies Study/ Report 400 mg OD x5 Moxiflox acin 400 mg OD x10 Clarithro -mycin 500 mg X 7-10 Moxifloxacin Cefuroxime axetil 500 mg BID x 10 Azithro mycin 250 mg OD X5 Levo- floxacin 500 mg OD X 10 Amoxi/ Clav 500/125 TID X / /251 PH % 91.6% / /327 PH % 88.4% / / /251 MMRR % 91.4% 89.2% / /185 MMRR % 87.0% / /216 PH % 94% / /243 MMRR % 88.1% / /150 MMRR % 79.3% / /234 MMRR % 94% / /222 PH % 85.6% Total 1665/ / / / / / / % 91.8% 87.9% 87.0% 84.7% 94% 91.6% 89

90 Page 90 of 121 With regards to H. influenzae, the predominant organism causing bacterial exacerbation of chronic bronchitis, AVELOX was associated with a higher bacteriological success rate when compared with macrolide and β-lactam therapy. The superior bacteriological success rate provided by AVELOX over macrolide therapy against H. influenzae has been shown in a pooled analysis of the four Phase III-IIIb trials comparing AVELOX with macrolide therapy (clarithromycin or azithromycin), AVELOX data in AECOPD The results of initial Phase III-IIIb studies are in line with a published probability model which showed that fluoroquinolones were among the antimicrobials with the highest predicted clinical efficacy rates, whereas macrolides had the lowest predicted clinical efficacy rates for the treatment of AECOPD. 204 AVELOX has consistently demonstrated efficacy in acute exacerbations of chronic bronchitis. Post-approval studies have been designed to evaluate the efficacy of AVELOX in different patient populations with exacerbations of CB Study The aim of this multicenter, open-label, randomized Phase IV study conducted in Italy was to compare the efficacy of a 5-day treatment course of oral AVELOX with that of a 7-day course of intramuscular ceftriaxone (1 g once daily). Both short and long-term outcomes were assessed. At the test-of cure visit, AVELOX- and ceftriaxone-treated patients achieved similar clinical success rates (AVELOX, 90.6% [193/213], ceftriaxone, 89.0% [187/210]). During the 6-month follow-up period, relapse rates were lower for AVELOX (23.3%) than for ceftriaxone (28.3%), however, the difference was not statistically significant. 90

91 Page 91 of Study This was a Phase IV study conducted in Canada and the United-States aimed at comparing the efficacy of AVELOX (given for 5 days) with that of azithromycin (5 days) or cefuroximeaxetil (7 days) in the treatment of AECB. The primary efficacy outcome was the rate of patients having a new exacerbation within one year after treatment with study medication. A total of 226 patients were enrolled and randomized, with 76 in the AVELOX group, 78 in the azithromycin group, and 72 in the cefuroxime-axetil group. There was no statistically significant difference (p = 0.98) between the AVELOX (65.8%) and the combined comparator groups (66.0%) with regard to the rate of patients who had a new exacerbation episode within one year after the end of study drug treatment. However, the rate of exacerbation episodes in patients with cardiovascular disease was lower in the AVELOX group (38.5%) than in the comparator groups: azithromycin, 59.1%; cefuroxime-axetil, 85.7%. It was also lower in the subgroup of patients with 2 or more prior exacerbation episodes within 1 year: AVELOX, 55.3%; azithromycin, 61.5%; cefuroxime-axetil, 60.6% MOSAIC (Study ) This study demonstrated that AVELOX was equivalent to the comparator regimen for the primary outcome measure, i.e., clinical success at 7 to 10 days after therapy. Clinical superiority with AVELOX versus comparator antibiotics was shown for both short-term and long-term efficacy variables including: cure rate, need for additional antimicrobial treatment of AECB, rate of bacteriologic eradication, and time to next exacerbation. 91

92 Page 92 of 121 MOSAIC was a Phase IV, multicenter, multinational, randomized, double-blind study in two parallel treatment arms of patients, comparing the effectiveness of oral AVELOX, 400 mg OD for 5 days, with standard oral 7-day antibiotic treatment regimens as first-line therapy for infectious AECB (Anthonisen Type 1). The study was original in that it incorporated several design features that had never been used together before in an antibiotic trial. The choice of comparator (amoxicillin 500 mg TID, or clarithromycin 500 mg BID or cefuroxime 250 mg BID) was left to the investigator, while the double-blind design maintained a high degree of internal validity. Pre-exacerbation health status was established to allow measuring the postexacerbation return to baseline. The concomitant use of corticosteroids was taken into account by stratification; and a long-term follow-up was performed up to 9 month, including administration of post-therapy antibiotics and time to next exacerbation. The primary outcome measure was clinical success assessed 7 to 10 days after the end of treatment, defined as the proportion of patients with clinical cure or improvement. Secondary efficacy measures included the frequency of additional antimicrobial therapy, time to the next AECB, and bacteriologic success. A total of 1935 patients were enrolled in 103 centers from 19 European and non-european countries, 733 of whom were randomized. Treatment arms were comparable for all variables at both enrollment and randomization visits in the ITT population (Table 1-21). In the PP population, the mean age was statistically higher in the AVELOX than in the comparator group (64.5 years compared to 62.5 years), p value = No other comparison of baseline variables showed any significant differences. AVELOX and the comparator regimens were equivalent in terms of clinical success (cure plus improvement) rates at 7-10 days after therapy. This was confirmed in the subgroup of 92

93 Page 93 of 121 subjects with bacteriologically documented AECB. AVELOX showed superiority over comparator on clinical cure in both the ITT and PP populations. When clinical failure was analyzed in subjects who required additional antibiotics, failure rates were significantly lower in the AVELOX group (27/354, 7.6%) than in the comparator group (53/376, 14.1%) in the ITT population (95% CI, 2.3 to 11.6) and in the PP population (24/274, 8.8%, versus 44/298, 14.8%; CI, 0.6 to 11.1). Clinical cure was achieved in a significantly higher proportion of subjects (p = 0.03) with AVELOX than a comparator in the subgroup receiving no concomitant steroid treatment in the ITT population. Both the clinical success and cure rates were lower in both groups in subjects with the greatest degree of airway obstruction; for the ITT population, AVELOX had a significantly (p = 0.03) higher clinical cure rate in subjects with a FEV1 50%. In the microbiologically valid population, the bacteriological success rate with AVELOX was significantly higher than that with the comparator. There were 3 persisting organisms in the AVELOX regimen and 11 persisting organisms in the comparator regimen. During the follow-up period, and after exclusion of ITT subjects who received a further antibiotic to the study treatment course for the presenting AECB, a new AECB was documented in 179 of 324 subjects in the AVELOX group and in 176 of 319 patients in the comparator arm. In this population, median times to the next AECB episode were days (range, 18 to 289 days) and days (range, 14 to 280 days) for AVELOX and comparator, respectively. Mean times to the next AECB were ± 67.5 days and ± 67.9 days for AVELOX and comparator, respectively; the difference was statistically significant (p = 0.03). 93

94 Page 94 of 121 In a Kaplan Meier analysis (Figure, below) of the time to the first composite event (treatment failure and/or new exacerbation and/or any further antibiotic treatment), the log-rank test showed a significant difference in favor of AVELOX for up to 5 months of follow-up (p = 0.03). This difference was no longer significant over the entire study follow-up of 9 months (p = 0.11). When the same analysis was stratified according to the date of the last exacerbation, AVELOX was superior to comparator in the subgroup of subjects who had an exacerbation < 6 months prior to randomization (p=0.01). Figure 5: Kaplan-Meier analysis of time to the first composite event (treatment failure, and/or new exacerbation and/or any further antibiotic treatment) stratified according to the time of the last exacerbation prior to randomization 94

95 Page 95 of MAESTRAL The Moxifloxacin in Acute Exacerbations of Chronic Bronchitis TriaL (MAESTRAL) was a multiregional, randomized, double-blind non-inferiority outpatient study. 205 The primary objective of MAESTRAL was to compare the efficacy of a 5-day course of moxifloxacin to that of a 7-day course of amoxicillin/clavulanic acid in the treatment of outpatients with chronic bronchitis experiencing AECOPD who are at high risk of treatment failure. Following stratification by steroid use patients received moxifloxacin 400 mg p.o. q.d. (5 days) or amoxicillin/clavulanic acid 875/125 mg p.o. b.i.d. (7 days). The primary endpoint was clinical failure 8 weeks post-therapy in the per protocol population. Moxifloxacin was noninferior to amoxicillin/clavulanic acid at the primary endpoint (111 (20.6%) out of 538, versus 114 (22.0%) out of 518, respectively; 95% CI %). In patients with confirmed bacterial AECOPD, moxifloxacin led to significantly lower clinical failure rates than amoxicillin/clavulanic acid (in the intent-to-treat with pathogens, 62 (19.0%) out of 327 versus 85 (25.4%) out of 335, respectively; p=0.016). Confirmed bacterial eradication at end of therapy was associated with higher clinical cure rates at 8 weeks posttherapy overall (p=0.0014) and for moxifloxacin (p=0.003). Patients treated with oral corticosteroids had more severe disease and higher failure rates Bacteriological AVELOX is active against a wide variety of bacteria, as indicated by the following data. 95

96 Page 96 of 121 Table 25: Accumulated bacteriological success rates in Phase III/IIIb AECB studies by organism (bacteriological response of eradication or presumed eradication) Pathogen Moxifloxacin 400 mg PO for 5 days H.influenzae 238/263 (90.5%) S. 129/148 pneumoniae (87.2%) Moraxella 136/147 catarrhalis (92.6%) Moxiflo xacin 400 mg PO for 10 days 49/51 (96.1%) 25/26 (96.2%) 33/35 (94.3% Levofloxacin 500 mg PO for 5 days 64/66 (97%) 27/27 (100%) 35/35 (100%) Clarithr omycin 500mg BID For 7 days 32/63 (50.8%) 48/52 (92.3%) 31/34 (91.2%) Clarithr omycin 500mg BID For 10 days 31/41 (75.6%) 21/23 (91.3% 24/24 (100%) Cefuroxime 500 mg BID for 10 days 22/27 (81.5%) 8/9 (88%) 7/10 (70%) Amoxici llin/ clavulani c acid 500/125 TID for 7 days 28/32 (87.5%) 10/10 (100%) 11/11 (100%) Azithrom ycin 250 mg OD for 5 days 30/36 (83.3%) 18/21 (85.7%) 20/20 (100%) The superior bacteriological success rate provided by AVELOX over macrolide therapy against H. influenzae has been shown in a pooled analysis of the four Phase III-IIIb comparing AVELOX with macrolide therapy (clarithromycin or azithromycin). 206 Table 26: Bacteriological eradication rates for H. influenzae by patient provided by AVELOX and macrolide therapy at test-of-cure visit in the AECB Phase III-IIIb studies 96

97 Page 97 of AVELOX Benefit-Risk for AECOPD AVELOX offers a significant benefit to AECOPD patients with a relatively small risk of serious adverse drug effects. Newly generated data confirm the efficacy of AVELOX observed in initial AECOPD studies. AVELOX resulted in better outcomes than its comparators in terms of treatment failure and recurrence rates. Bacteriologic eradication data provide the most accurate indication of antimicrobial effect. AVELOX was shown to rapidly eradicate key pathogens of AECOPD and this bacterial clearance was associated with a rapid sinusitis symptom improvement. AVELOX is recommended the ATS/ERS Guidelines on the Management of COPD. 207 Results for a cohort of patients with AECOPD of various severities caused by PRSP demonstrated the effectiveness of AVELOX in antimicrobial resistant infections. 6.4 Uncomplicated Urinary Tract Infections (uuti) CIPRO Clinical Trial Overview Uncomplicated UTIs (cystitis) are among the most commonly encountered bacterial infections in women. Management of these infections has been made more complicated in recent years by increasing antimicrobial resistance, especially to β-lactams and trimethoprimsulfamethoxazole. The current standard for the empirical treatment of acute uncomplicated cystitis is trimethoprim/ sulfamethoxazole for 3 days. Because the prevalence of resistance to trimethoprim/sulfamethoxazole among uropathogens is increasing, fluoroquinolones are being used as empiric therapy for the management of cystitis. The clinical efficacy of CIPRO in uncomplicated and complicated UTI is demonstrated in a large number of clinical studies, and supported by extensive use in clinical practice. 97

98 Page 98 of 121 Increasing concern about fluoroquinolone resistance in many pathogens causing health care associated and community acquired infections has raised concerns about the future usefulness of this class of antibiotics. In order to address these concerns, CIPRO prescribing for uuti should be guided by regional and individual resistance data and professional society guidelines. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Culture and susceptibility testing will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance. Initial approval for UTI was based on pivotal trials comparing the effectiveness of CIPRO against comparator antibiotics with known effectiveness against urinary pathogens. As resistance patterns have evolved over the years, most CIPRO uuti use has also evolved from primary to secondary therapy after initially prescribed antibiotics have failed, per current prescribing guidelines Comparisons with other treatments CIPRO has been compared with other antibiotics in numerous studies. Effective fluoroquinolone sparing agents would permit the reservation of CIPRO and other fluoroquinolones for more seriously ill patients. We have summarized several of these comparison studies Hooton 2005 Hooton and colleagues 208 conducted the first comparison of a 3-day regimen of amoxicillinclavulanate vs a 3-day regimen of a fluoroquinolone for the treatment of acute uncomplicated 98

99 Page 99 of 121 cystitis in women. This was a randomized, single-blind treatment trial of 370 women, aged 18 to 45 years, with symptoms of acute uncomplicated cystitis and a urine culture with at least 102 colony-forming units of uropathogens per milliliter. Subjects were drawn from a university student health center or a health maintenance organization at the University of Washington Student Health Center and the Group Health Cooperative from July 1998 to May Study participants were randomly assigned to receive amoxicillin-clavulanate (500 mg/125 mg twice daily) or CIPRO (250 mg twice daily) for 3 days and were followed up for 4 months. The primary study outcome was study drug efficacy based on clinical cure. Women were considered to have clinical cure if they did not have symptomatic, persistent or recurrent UTI. A persistent or recurrent UTI was considered to be culture-confirmed if there were at least 10 3 colony-forming units (CFU) of uropathogens per milliliter of urine. Secondary study outcomes of interest were microbiological cure and vaginal E coli colonization at the 2-week follow-up visit. Clinical cure was observed in 124 (77%) of 162 women treated with CIPRO compared with 93 (58%) of 160 women treated with amoxicillin/clavulanate (P=0.001). Amoxicillin/clavulanate was not as effective as CIPRO even among women infected with strains susceptible to amoxicillin/clavulanate; 114 [77%] of 149 women in the CIPRO group vs 65 [60%] of 109 women in the amoxicillin-clavulanate group; P=.004. The difference in clinical cure rates occurred almost entirely within the first 2 weeks after initiating therapy. Microbiological cure at 2 weeks was observed in 153 (95%) of 161 women treated with CIPRO vs 118 (76%) of 156 women treated with amoxicillin-clavulanate (P=0.001). At the 2- week visit, 45% of women in the amoxicillin-clavulanate group had vaginal colonization group with E coli vs. 10% in the CIPRO group (P=0.001). 99

100 Page 100 of 121 Of some concern was the fact that 2 women developed same-strain pyelonephritis soon after treatment with amoxicillin-clavulanate (same-strain is presumed in 1 woman based on a urine culture 5 days before the episode of pyelonephritis). This study found that the 3-day regimen of amoxicillin-clavulanate was not as effective as CIPRO for the treatment of acute uncomplicated cystitis, even in women infected with susceptible strains. This difference may be due to the inferior ability of amoxicillin/clavulanate to maintain MIC levels in the urine, facilitating early reinfection Hooton 2012 In a 2012 study published in JAMA, Hooton and colleagues found cefpodoxime inferior to CIPRO for the treatment of uuti. 209 The purpose of the study was to investigate cefpodoxime as a possible fluoroquinolone sparing agent. This was a randomized, double-blind trial of 300 women aged 18 to 55 years with acute uncomplicated cystitis comparing CIPRO the comparator - (n=150) with cefpodoxime (n=150); patients were from a student health center in Seattle, Washington, and a referral center in Miami, Florida. The study was conducted from 2005 to 2009 and outcomes were assessed at 5 to 9 days and 28 to 30 days after completion of therapy. Intent-to-treat and perprotocol analyses were performed; 15 women in the CIPRO group and 17 women in the cefpodoxime group were lost to follow-up. The overall clinical cure rate at the 30-day visit with the intent-to-treat approach in which patients lost to follow-up were considered as having clinical cure was 93% (139/150) for CIPRO compared with 82% (123/150) for cefpodoxime (difference of 11%; 95% CI, 3% 18%); and for the intent-to-treat approach in which patients lost to follow-up were considered as having not responded to treatment, the clinical cure rate was 83% (124/150) for CIPRO 100

101 Page 101 of 121 compared with 71% (106/150) for cefpodoxime (difference of 12%; 95% CI, 3% 21%). The microbiological cure rate was 96% (123/128) for CIPRO compared with 81% (104/129) for cefpodoxime (difference of 15%; 95% CI, 8% 23%). At first follow-up, 16% of women in the CIPRO group compared with 40% of women in the cefpodoxime group had vaginal E coli colonization. Among women with uncomplicated cystitis, a 3-day regimen of cefpodoxime compared with CIPRO did not meet criteria for noninferiority for achieving clinical cure. These findings, along with concerns about possible adverse ecological effects associated with other broadspectrum β-lactams, do not support the use of cefpodoxime as a first-line fluoroquinolonesparing antimicrobial for acute uncomplicated cystitis Additional Studies Knotterus et al 210 compared the efficacies and adverse effects of all relevant antibiotics for UTI treatment simultaneously by performing a network meta-analysis using direct and indirect treatment comparisons. The data was analyzed by regression analysis. After review by the investigators, 12 studies were selected from different regions of the world: Latin America, Europe, North America, Asia, and Scandinavia. Overall, CIPRO and gatifloxacin (no longer marketed in the US) appeared to be the most effective of all treatments, and amoxicillin clavulanate appeared the least effective treatment. There were no significant differences in terms of adverse effects. Talan and co-workers compared 7 days of CIPRO therapy against 14 days of trimethoprimsulfamethoxazole in women with uncomplicated pyelonephritis. 211 The objective of the study was to optimal antimicrobial regimen and treatment duration for acute uncomplicated pyelonephritis. 101

102 Page 102 of 121 Three hundred seventy-eight premenopausal women at 25 outpatient centers in the United States were enrolled in the study. Of these, 255 were included in the analysis. Patients were randomized to CIPRO 500 mg twice a day for 7 days with or without an initial IV dose followed by a placebo for 7 days or trimethoprim-sulfamethoxazole 160/800 mg twice a day for 14 days with or without IV ceftriaxone. The main outcome measures were continued bacteriologic and clinical cure. In this study, greater clinical and bacteriologic cure was achieved with the 7 day CIPRO regimen than with the 14 day trimethoprim-sulfamethoxazole regimen Resistance Antibiotic resistance among uropathogens causing uncomplicated cystitis has increased and there is greater appreciation of the importance of the ecological adverse effects of antimicrobial therapy. Fluoroquinolones have high rates of efficacy, high rates of susceptibility among pathogens causing uncomplicated urinary tract infection (UTI), and minimal adverse drug reactions when used in a 3-7 day regimen as recommended. Increasing rates of fluoroquinolone-resistant E. coli are being reported worldwide, including in some areas of the United States and Canada. Although fluoroquinolones are highly efficacious and preferred in some clinical circumstances, guidelines from the Infectious Disease Society of America 212 for the treatment of uncomplicated cystitis recommend limiting fluoroquinolone use to second or third line for patients who have failed on other antibiotics Resolution rates In the comparative clinical trials described above, CIPRO was consistently shown to offer patients an important treatment benefit. Because of its recognized effectiveness, CIPRO has 102

103 Page 103 of 121 often been used as the comparator drug to establish non-inferiority, as in the Hooton et al study published in uuti resolution rates in studies of CIPRO where it has been compared to another antibiotic or is the comparator antibiotic, have remained in the 85-95% range, comparable to resolution rates in the earliest pivotal trials. When evaluating CIPRO s place in the infectious disease armamentarium, one must take into account changing resistance patterns for all antibiotics prescribed in the management of uuti. Local sensitivity and resistance information should always a principal factor in the physician s decision making process about which antibiotic to prescribe CIPRO Benefit-Risk for uuti CIPRO offers a significant benefit to uuti patients with a relatively small risk of serious adverse drug events. Overall rates of serious adverse reactions are very low with CIPRO in patients treated according to the approved dosing regimens and utilized in line with professional society guidelines. Newly generated data has verified the benefits of CIPRO versus other antibiotics. In these trials, CIPRO use resulted in better outcomes than comparators in terms of treatment failure and recurrence rates. Symptom relief and bacteriologic cure data provide the most accurate indication of antimicrobial effect in uuti. CIPRO is recommended as alternative therapy in the International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Disease Society of America and the European Society for Microbiology and Infectious DiseasesGuidelines for the Management of Urinary Tract Infection. 103

104 Page 104 of Conclusions The development of fluoroquinolones in the 1980 s provided a new class of antibiotics to U.S. physicians that are both powerful and highly effective across a broad spectrum of bacterial pathogens. In the intervening years, additional fluoroquinolone products have been developed and each has found a niche in which it has a strong benefit-risk. In conformity with FDA-approved labeling and the treatment guidelines of professional societies, fluoroquinolones, as a class, are used as a primary therapy against the most serious, intractable and dangerous infections. The use and success of fluoroquinolones as therapy for these serious infections is well-documented. For most other indications including the three under consideration the fluoroquinolones, used according to treatment guidelines, are recommended as alternative therapies. This includes use when other treatments fail, in cases of allergies to other drug therapies, or when specific resistance patterns are present. Bayer market research data shows very low use of ciprofloxacin and moxifloxacin in respiratory indications where they are recommended by the treatment guidelines as alternative therapies. An important consideration is to preserve antibacterial treatment options, even for infections deemed mild. Sinusitis is one example that illustrates the effectiveness of treatment guidelines. In sinusitis, the overwhelming likelihood is that the infection is viral, with only a low risk of a bacterial infection. The IDSA treatment guideline specifies antibiotic use only if the infection becomes worse or persists for more than 10 days. The patient should then be placed on an antibiotic other than a fluoroquinolone. If the patient fails on the first antibiotic, or is at high risk of complications, then a fluoroquinolone may be prescribed. This decision remains, appropriately, in the physician s hands. 104

105 Page 105 of 121 Fluoroquinolones efficacy was established by pivotal non-inferiority trials, and efficacy is also attested to by Cochrane Reviews of the literature and supported by important clinical trial guidelines from the IDSA and ATS professional societies. The safety profiles of both CIPRO and AVELOX have been well characterized and are well known to doctors who prescribe them. Overall event reporting rates and incidence in clinical trials support the conclusion that the risks identified by FDA for discussion at this Advisory Committee meeting (tendinopathy, peripheral neuropathy, and serious arrhythmia) are either rare or very rare with CIPRO and AVELOX. This safety profile is detailed in package inserts, including a detailed Medication Guide for the patient, Patient Counseling information for the physician, and specific Warnings on serious events including arrhythmias, tendon effects, and peripheral neuropathy. The safety profile is also well-characterized by the 600 million uses of CIPRO and 200 million uses of AVELOX worldwide and appropriately reflected in labeling to permit physicians to make informed decisions on the use of these drugs. The overall efficacy and safety profile of the fluoroquinolones CIPRO and AVELOX in ABS, AECOPD, and uuti support the continued use of these two drugs as alternative therapies in these three indications. The labeling information, along with recommended guidelines for treatment, facilitates appropriate use of these drugs. 105

106 Page 106 of Appendices 8.1 Adverse Effects of antibiotics prescribed for ABS, AECOPD and uuti 8.2 Current Prescribing Information CIPRO AVELOX 106

107 Page 107 of References 1 Steverding Parasites & Vectors 2010, 3:15; 2 Lindbaeck M, Hjortdahl P, Johnsen U. Randomised, double blind, placebo controlled trial of penicillin V and amoxicillin in treatment of acute sinus infections in adults. BMJ 1996; 313: Farrell DJ, H. S. Sader, M. Castanheira, R. N. Jones. Antimicrobial Activity of Ceftolozane/Tazobactam (TOL/TAZ) and Comparator Agents Tested against Pseudomonas aeruginosa Isolates from United States (U.S.A.) Medical Centers (2013). C th ICAAC; Washington, D.C Zerouali K, Ramdani-Bouguessa N, Boye C, Hammami A, The Active G. Multicentric study in five African countries of antibiotic susceptibility for three main pathogens: Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Journal of chemotherapy. 2014: Y Epub 2014/11/05 5 Grignon O, Montassier E, Corvec S, Lepelletier D, Hardouin JB, Caillon J, et al. Escherichia coli antibiotic resistance in emergency departments. Do local resistance rates matter? European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology Epub 2014/10/24. 6 Kresken M, Pfeifer Y, Hafner D, et al. Working Party 'Antimicrobial Resistance' of the Paul-Ehrlich-Society for C. Occurrence of multidrug resistance to oral antibiotics among Escherichia coli urine isolates from outpatient departments in Germany: extended-spectrum beta-lactamases and the role of fosfomycin. International journal of antimicrobial agents. 2014;44(4): Epub 2014/09/17 7 Lemos Luengas E, E. Castro, J. Ruiz, et al. Monitoring of Trends of Ertapenem and Imipenem Activity In Vitro against E. coli in Complicated Urinary Tract Infections (cuti) in Emergency Rooms in Colombia: SMART C-156. ICAAC 2014; Washington, D.C McIsaac WJ, Moineddin R, Meaney C, Mazzulli T. Antibiotic-resistant Escherichia coli in women with acute cystitis in Canada. The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada. 2013;24(3): Epub 2014/01/15. 9 Siskova P, Cernohorska L, Mahelova M, Turkova K, Woznicova V. Phenotypes of Escherichia coli isolated from urine: Differences between extended-spectrum beta-lactamase producers and sensitive strains. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi Epub 2014/05/ Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Community-onset Gramnegative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/20 11 Demir T, Milletli Sezgin F, Buyukguclu T. Antibiotic susceptibility of E. coli strains related to communityacquired urinary tract infections. R th ECCMID; Barcelona, Spain

108 Page 108 of McIsaac WJ, Moineddin R, Meaney C, Mazzulli T. Antibiotic-resistant Escherichia coli in women with acute cystitis in Canada. The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada. 2013;24(3): Epub 2014/01/15 13 Grignon O, Montassier E, Corvec S, et al. Escherichia coli antibiotic resistance in emergency departments. Do local resistance rates matter? European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology Epub 2014/10/24 14 Kresken M, Pfeifer Y, Hafner D, et al. Working Party 'Antimicrobial Resistance' of the Paul-Ehrlich-Society for C. Occurrence of multidrug resistance to oral antibiotics among Escherichia coli urine isolates from outpatient departments in Germany: extended-spectrum beta-lactamases and the role of fosfomycin. International journal of antimicrobial agents. 2014;44(4): Epub 2014/09/17 15 Lemos Luengas E, E. Castro, J. Ruiz, et al. Monitoring of Trends of Ertapenem and Imipenem Activity In Vitro against E. coli in Complicated Urinary Tract Infections (cuti) in Emergency Rooms in Colombia: SMART C-156. ICAAC 2014; Washington, D.C Turnidge JD, Gottlieb T, Mitchell DH, et al. Community-onset Gram-negative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/20 17 Demir T, Milletli Sezgin F, Buyukguclu T. Antibiotic susceptibility of E. coli strains related to communityacquired urinary tract infections. R th ECCMID; Barcelona, Spain Siskova P, Cernohorska L, Mahelova M, Turkova K, Woznicova V. Phenotypes of Escherichia coli isolated from urine: Differences between extended-spectrum beta-lactamase producers and sensitive strains. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi Epub 2014/05/29 19 Turnidge JD, Gottlieb T, Mitchell DH, et al. Community-onset Gram-negative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/ Gholipour A, Soleimani N, Shokri D, et al.. Phenotypic and Molecular Characterization of Extended-Spectrum beta-lactamase Produced by Escherichia coli, and Klebsiella pneumoniae Isolates in an Educational Hospital. Jundishapur journal of microbiology. 2014;7(10):e Epub 2015/01/30 21 Turnidge JD, Gottlieb T, Mitchell DH, et al. Community-onset Gram-negative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/ Raei F, Eftekhar F, Feizabadi MM. Prevalence of Quinolone Resistance Among Extended-Spectrum bers- Lactamase Producing Uropathogenic Klebsiella pneumoniae. Jundishapur journal of microbiology. 2014;7(6):e Epub 2014/11/06 23 Lemos Luengas E, E. Castro, J. Ruiz, F. et al. Monitoring of Trends of Ertapenem and Imipenem Activity In Vitro against E. coli in Complicated Urinary Tract Infections (cuti) in Emergency Rooms in Colombia: SMART C-156. ICAAC 2014; Washington, D.C Velez Echeverri C, Serna-Higuita LM, Serrano AK, et al. Resistance profile for pathogens causing urinary tract infection in a pediatric population, and antibiotic treatment response at a university hospital, Colombia medica. 2014;45(1): Epub 2014/06/28 25 Alsammani MA, Ahmed MI, Abdelatif NF. Bacterial uropathogens isolates and antibiograms in children under 5 years of age. Medical archives. 2014;68(4): Epub 2015/01/

109 Page 109 of Sibi G, Kumari P, Kabungulundabungi N. Antibiotic sensitivity pattern from pregnant women with urinary tract infection in Bangalore, India. Asian Pacific journal of tropical medicine. 2014;7S1:S Epub 2014/10/15 27 Medell M, Hart M, Batista ML. [In vitro antimicrobial susceptibility in Enterococcus faecalis and Enterococcus faecium isolated from hospitalized patients]. Biomedica : revista del Instituto Nacional de Salud. 2014;34 Suppl 1:50-7. Epub 2014/06/27. Sensibilidad antimicrobiana in vitro en aislamientos de Enterococcus faecalis y Enterococcus faecium obtenidos de pacientes hospitalizados 28 Sibi G, Kumari P, Kabungulundabungi N. Antibiotic sensitivity pattern from pregnant women with urinary tract infection in Bangalore, India. Asian Pacific journal of tropical medicine. 2014;7S1:S Epub 2014/10/ Medell M, Hart M, Batista ML. [In vitro antimicrobial susceptibility in Enterococcus faecalis and Enterococcus faecium isolated from hospitalized patients]. Biomedica : revista del Instituto Nacional de Salud. 2014;34 Suppl 1:50-7. Epub 2014/06/27. Sensibilidad antimicrobiana in vitro en aislamientos de Enterococcus faecalis y Enterococcus faecium obtenidos de pacientes hospitalizados 30 Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Community-onset Gramnegative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/ ibid 32 Gholipour A, Soleimani N, Shokri D, Mobasherizadeh S, Kardi M, Baradaran A. Phenotypic and Molecular Characterization of Extended-Spectrum beta-lactamase Produced by Escherichia coli, and Klebsiella pneumoniae Isolates in an Educational Hospital. Jundishapur journal of microbiology. 2014;7(10):e Epub 2015/01/ Siskova P, Cernohorska L, Mahelova M, Turkova K, Woznicova V. Phenotypes of Escherichia coli isolated from urine: Differences between extended-spectrum beta-lactamase producers and sensitive strains. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi Epub 2014/05/ ibid 35 McIsaac WJ, Moineddin R, Meaney C, Mazzulli T. Antibiotic-resistant Escherichia coli in women with acute cystitis in Canada. The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada. 2013;24(3): Epub 2014/01/ Demir T, Milletli Sezgin F, Buyukguclu T. Antibiotic susceptibility of E. coli strains related to communityacquired urinary tract infections. R th ECCMID; Barcelona, Spain Kresken M, Pfeifer Y, Hafner D, Wresch R, Korber-Irrgang B, Working Party 'Antimicrobial Resistance' of the Paul-Ehrlich-Society for C. Occurrence of multidrug resistance to oral antibiotics among Escherichia coli urine isolates from outpatient departments in Germany: extended-spectrum beta-lactamases and the role of fosfomycin. International journal of antimicrobial agents. 2014;44(4): Epub 2014/09/17 38 Grignon O, Montassier E, Corvec S, Lepelletier D, Hardouin JB, Caillon J, et al. Escherichia coli antibiotic resistance in emergency departments. Do local resistance rates matter? European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology Epub 2014/10/24 109

110 Page 110 of Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Community-onset Gramnegative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/ Lemos Luengas E, E. Castro, J. Ruiz, F. Lozano, R. Badal. Monitoring of Trends of Ertapenem and Imipenem Activity In Vitro against E. coli in Complicated Urinary Tract Infections (cuti) in Emergency Rooms in Colombia: SMART C-156. ICAAC 2014; Washington, D.C Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Community-onset Gramnegative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/20 42 Turnidge JD, Gottlieb T, Mitchell DH, Coombs GW, Daly DA, Bell JM, et al. Community-onset Gramnegative Surveillance Program annual report, Communicable diseases intelligence quarterly report. 2014;38(1):E54-8. Epub 2014/11/20 43 Raei F, Eftekhar F, Feizabadi MM. Prevalence of Quinolone Resistance Among Extended-Spectrum bers- Lactamase Producing Uropathogenic Klebsiella pneumoniae. Jundishapur journal of microbiology. 2014;7(6):e Epub 2014/11/ Lemos Luengas E, E. Castro, J. Ruiz, F. Lozano, R. Badal. Monitoring of Trends of Ertapenem and Imipenem Activity In Vitro against E. coli in Complicated Urinary Tract Infections (cuti) in Emergency Rooms in Colombia: SMART C-156. ICAAC 2014; Washington, D.C Velez Echeverri C, Serna-Higuita LM, Serrano AK, Ochoa-Garcia C, Rojas Rosas L, Maria Bedoya A, et al. Resistance profile for pathogens causing urinary tract infection in a pediatric population, and antibiotic treatment response at a university hospital, Colombia medica. 2014;45(1): Epub 2014/06/ Alsammani MA, Ahmed MI, Abdelatif NF. Bacterial uropathogens isolates and antibiograms in children under 5 years of age. Medical archives. 2014;68(4): Epub 2015/01/09 47 Zerouali K, Ramdani-Bouguessa N, Boye C, Hammami A, The Active G. Multicentric study in five African countries of antibiotic susceptibility for three main pathogens: Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Journal of chemotherapy. 2014: Y Epub 2014/11/05 48 Farrell DJ, H. S. Sader, M. Castanheira, R. N. Jones. Antimicrobial Activity of Ceftolozane/Tazobactam (TOL/TAZ) and Comparator Agents Tested against Pseudomonas aeruginosa Isolates from United States (U.S.A.) Medical Centers (2013). C th ICAAC; Washington, D.C Sibi G, Kumari P, Kabungulundabungi N. Antibiotic sensitivity pattern from pregnant women with urinary tract infection in Bangalore, India. Asian Pacific journal of tropical medicine. 2014;7S1:S Epub 2014/10/ Agmy G, Mohamed S, Gad Y, Farghally E, Mohammedin H, Rashed H. Bacterial profile, antibiotic sensitivity and resistance of lower respiratory tract infections in upper egypt. Mediterranean journal of hematology and infectious diseases. 2013;5(1):e Epub 2013/10/10 51 ibid 110

111 Page 111 of Padilla C, Padilla A, Lobos O. Virulence genes and antimicrobial susceptibility of Escherichia coli taken from women with vaginitis in Talca, Chile. Journal of infection in developing countries. 2014;8(3): Epub 2014/03/13 53 Agmy G, Mohamed S, Gad Y, Farghally E, Mohammedin H, Rashed H. Bacterial profile, antibiotic sensitivity and resistance of lower respiratory tract infections in upper egypt. Mediterranean journal of hematology and infectious diseases. 2013;5(1):e Epub 2013/10/10 54 ibid 55 Flamm RK, D. J. Farrell, H. S. Sader, Jones RN. Activity of the Fluoroquinolone JNJ-Q2 Tested Against Contemporary (2012) Pathogens Isolated from the Global SENTRY Surveillance Platform. C ICAAC Denver, CO ibid 57 Flamm RK, D. J. Farrell, H. S. Sader, Jones RN. Activity of the Fluoroquinolone JNJ-Q2 Tested Against Contemporary (2012) Pathogens Isolated from the Global SENTRY Surveillance Platform. C ICAAC Denver, CO Agmy G, Mohamed S, Gad Y, Farghally E, Mohammedin H, Rashed H. Bacterial profile, antibiotic sensitivity and resistance of lower respiratory tract infections in upper egypt. Mediterranean journal of hematology and infectious diseases. 2013;5(1):e Epub 2013/10/10 58 Padilla C, Padilla A, Lobos O. Virulence genes and antimicrobial susceptibility of Escherichia coli taken from women with vaginitis in Talca, Chile. Journal of infection in developing countries. 2014;8(3): Epub 2014/03/13 59 Ibid 60 Agmy G, Mohamed S, Gad Y, Farghally E, Mohammedin H, Rashed H. Bacterial profile, antibiotic sensitivity and resistance of lower respiratory tract infections in upper egypt. Mediterranean journal of hematology and infectious diseases. 2013;5(1):e Epub 2013/10/10 61 Padilla C, Padilla A, Lobos O. Virulence genes and antimicrobial susceptibility of Escherichia coli taken from women with vaginitis in Talca, Chile. Journal of infection in developing countries. 2014;8(3): Epub 2014/03/ Qiao LD, Chen S, Yang Y, Zhang K, Zheng B, Guo HF, et al. Characteristics of urinary tract infection pathogens and their in vitro susceptibility to antimicrobial agents in China: data from a multicenter study. BMJ open. 2013;3(12):e Epub 2013/12/ ibid 64 Agmy G, Mohamed S, Gad Y, Farghally E, Mohammedin H, Rashed H. Bacterial profile, antibiotic sensitivity and resistance of lower respiratory tract infections in upper egypt. Mediterranean journal of hematology and infectious diseases. 2013;5(1):e Epub 2013/10/10 65 ibid 66 ibid 111

112 Page 112 of Flamm RK, D. J. Farrell, H. S. Sader, Jones RN. Activity of the Fluoroquinolone JNJ-Q2 Tested Against Contemporary (2012) Pathogens Isolated from the Global SENTRY Surveillance Platform. C ICAAC Denver, CO Agmy G, Mohamed S, Gad Y, Farghally E, Mohammedin H, Rashed H. Bacterial profile, antibiotic sensitivity and resistance of lower respiratory tract infections in upper egypt. Mediterranean journal of hematology and infectious diseases. 2013;5(1):e Epub 2013/10/10 69 Flamm RK, D. J. Farrell, H. S. Sader, Jones RN. Activity of the Fluoroquinolone JNJ-Q2 Tested Against Contemporary (2012) Pathogens Isolated from the Global SENTRY Surveillance Platform. C ICAAC Denver, CO Agmy G, Mohamed S, Gad Y, Farghally E, Mohammedin H, Rashed H. Bacterial profile, antibiotic sensitivity and resistance of lower respiratory tract infections in upper egypt. Mediterranean journal of hematology and infectious diseases. 2013;5(1):e Epub 2013/10/10 71 Flamm RK, D. J. Farrell, H. S. Sader, Jones RN. Activity of the Fluoroquinolone JNJ-Q2 Tested Against Contemporary (2012) Pathogens Isolated from the Global SENTRY Surveillance Platform. C ICAAC Denver, CO Zhanel GG, H. Adam, P. Lagacé-Wiens, J. Karlowsky, M. Baxter, K. Nichol, et al. Antimicrobial susceptibility of pathogens isolated from patients in Canadian hospitals: CANWARD study P ECCMID; Barcelona, Spain Vandevelde NM, Tulkens PM, Diaz Iglesias Y, et al. Characterisation of a collection of Streptococcus pneumoniae isolates from patients suffering from acute exacerbations of chronic bronchitis: in vitro susceptibility to antibiotics and biofilm formation in relation to antibiotic efflux and serotypes/serogroups. International journal of antimicrobial agents. 2014;44(3): Epub 2014/08/ Flamm RK, D. J. Farrell, H. S. Sader, Jones RN. Activity of the Fluoroquinolone JNJ-Q2 Tested Against Contemporary (2012) Pathogens Isolated from the Global SENTRY Surveillance Platform. C ICAAC Denver, CO Zhanel GG, H. Adam, P. Lagacé-Wiens, J. Karlowsky, M. Baxter, K. Nichol, et al. Antimicrobial susceptibility of pathogens isolated from patients in Canadian hospitals: CANWARD study P ECCMID; Barcelona, Spain Souli M, H. Giamarellou. Comparative in vitro efficacy of ceftaroline and other anti-staphylococcal antibiotics against a nationwide collection of nosocomial Staphylococcus aureus clinical isolates from Greece. ep th ECCMID; Barcelona, Spain Vola ME, Moriyama AS, Lisboa R, Vola MM, Hirai FE, Bispo PJ, et al. Prevalence and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus in ocular infections. Arquivos brasileiros de oftalmologia. 2013;76(6): Epub 2014/02/11 78 Nichol KA, H. J. Adam, N. Laing, B. et al. Activity of Telavancin against Gram-Positive Cocci from CANWARD using Previously Established and Revised CLSI Guidelines. C-826. ICAAC; Washington, DC

113 Page 113 of Qiao LD, Chen S, Yang Y, Zhang K, Zheng B, Guo HF, et al. Characteristics of urinary tract infection pathogens and their in vitro susceptibility to antimicrobial agents in China: data from a multicenter study. BMJ open. 2013;3(12):e Epub 2013/12/18 80 ibid 81 Souli M, H. Giamarellou. Comparative in vitro efficacy of ceftaroline and other anti-staphylococcal antibiotics against a nationwide collection of nosocomial Staphylococcus aureus clinical isolates from Greece. ep th ECCMID; Barcelona, Spain Zhanel GG, H. Adam, P. Lagacé-Wiens, J. Karlowsky, M. Baxter, K. Nichol, et al. Antimicrobial susceptibility of pathogens isolated from patients in Canadian hospitals: CANWARD study P ECCMID; Barcelona, Spain Vola ME, Moriyama AS, Lisboa R, Vola MM, Hirai FE, Bispo PJ, et al. Prevalence and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus in ocular infections. Arquivos brasileiros de oftalmologia. 2013;76(6): Epub 2014/02/11 84 Nichol KA, H. J. Adam, N. Laing, B. Weshnoweski, R. Vashisht, M. R. Baxter, et al. Activity of Telavancin against Gram-Positive Cocci from CANWARD using Previously Established and Revised CLSI Guidelines. C-826. ICAAC; Washington, DC Flamm RK, D. J. Farrell, H. S. Sader, Jones RN. Activity of the Fluoroquinolone JNJ-Q2 Tested Against Contemporary (2012) Pathogens Isolated from the Global SENTRY Surveillance Platform. C ICAAC Denver, CO ibid 87 Zhanel GG, H. Adam, P. Lagacé-Wiens, J. et al. Antimicrobial susceptibility of pathogens isolated from patients in Canadian hospitals: CANWARD study P ECCMID; Barcelona, Spain Vandevelde NM, Tulkens PM, Diaz Iglesias Y, et al. Characterisation of a collection of Streptococcus pneumoniae isolates from patients suffering from acute exacerbations of chronic bronchitis: in vitro susceptibility to antibiotics and biofilm formation in relation to antibiotic efflux and serotypes/serogroups. International journal of antimicrobial agents. 2014;44(3): Epub 2014/08/ ibid 90 Wybo I, Van den Bossche D, Soetens O, et al. Fourth Belgian multicentre survey of antibiotic susceptibility of anaerobic bacteria. The Journal of antimicrobial chemotherapy. 2014;69(1): Epub 2013/09/07 91 Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 92 Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 113

114 Page 114 of Boyanova L, Kolarov R, Mitov I. Recent evolution of antibiotic resistance in the anaerobes as compared to previous decades. Anaerobe Epub 2014/05/31 94 Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 95 Wybo I, Van den Bossche D, Soetens O, et al. Fourth Belgian multicentre survey of antibiotic susceptibility of anaerobic bacteria. The Journal of antimicrobial chemotherapy. 2014;69(1): Epub 2013/09/07 96 Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 97 Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 98 Wybo I, Van den Bossche D, Soetens O, et al. Fourth Belgian multicentre survey of antibiotic susceptibility of anaerobic bacteria. The Journal of antimicrobial chemotherapy. 2014;69(1): Epub 2013/09/07 99 Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 100 Wybo I, Van den Bossche D, Soetens O, et al. Fourth Belgian multicentre survey of antibiotic susceptibility of anaerobic bacteria. The Journal of antimicrobial chemotherapy. 2014;69(1): Epub 2013/09/ ibid 102 ibid 103 Orfanidou M, E. Vagiakou, M. Kamperogianni, L. et al. Isolation of anaerobic bacteria and susceptibility to antimicrobials from burn wounds in plastic surgery and burns unit in a Greek hospital during a two year period. P th ECCMID; Barcelona, Spain Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 2014/06/ ibid 106 ibid 107 ibid 108 ibid 114

115 Page 115 of Boyanova L, Kolarov R, Mitov I. Recent evolution of antibiotic resistance in the anaerobes as compared to previous decades. Anaerobe Epub 2014/05/ ibid 111 Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 2014/06/ ibid 113 ibid 114 Boyanova L, Kolarov R, Mitov I. Recent evolution of antibiotic resistance in the anaerobes as compared to previous decades. Anaerobe Epub 2014/05/ Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 2014/06/ ibid 117 Wybo I, Van den Bossche D, Soetens O, Vekens E, Vandoorslaer K, Claeys G, et al. Fourth Belgian multicentre survey of antibiotic susceptibility of anaerobic bacteria. The Journal of antimicrobial chemotherapy. 2014;69(1): Epub 2013/09/ Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 2014/06/ ibid 120 Orfanidou M, E. Vagiakou, M. Kamperogianni, L. et al. Isolation of anaerobic bacteria and susceptibility to antimicrobials from burn wounds in plastic surgery and burns unit in a Greek hospital during a two year period. P th ECCMID; Barcelona, Spain Wang FD, Liao CH, Lin YT, et al.. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, , northern Taiwan. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014;33(11): Epub 2014/06/ Wybo I, Van den Bossche D, Soetens O, Vekens E, Vandoorslaer K, Claeys G, et al. Fourth Belgian multicentre survey of antibiotic susceptibility of anaerobic bacteria. The Journal of antimicrobial chemotherapy. 2014;69(1): Epub 2013/09/07 115

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118 Page 118 of Czaja, C.A., et al., Population-based epidemiologic analysis of acute pyelonephritis. Clin Infect Dis, (3): p Echols, R.M., et al., Demographic, clinical, and treatment parameters influencing the outcome of acute cystitis. Clin Infect Dis, (1): p Gupta K, Hooton TM, Naber KG et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clinical Infectious Diseases 2011;52(5):e103 e Fosfomycin for urinary tract infections. Med Lett Drugs Ther 1997; 39: Foxman, B., et al., Risk factors for second urinary tract infection among college women. Am J Epidemiol, (12): p Bayer Global Pharmacovigilance data. 157 ibid 158 Cipro prescribing information, Revised Feb Avelox prescribing information. Revised Dec Moss, A.J., Measurement of the QT interval and the risk associated with QTc interval prolongation: a review. Am J Cardiol, (6): p. 23B-25B. 161 Briasoulis, A., V. Agarwal, and W.J. Pierce, QT prolongation and torsade de Pointeesinduced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology, (2): p Wehrens, X.H., et al., Novel insights in the congenital long QT syndrome. Ann Intern Med, (12): p Briasoulis, A., V. Agarwal, and W.J. Pierce, QT prolongation and torsade de Pointes induced by fluoroquinolones: infrequent side effects from commonly used medications.cardiology, (2): p Owens, R.C., Jr. QT prolongation with antimicrobial agents: understanding the significance. Drugs, (10): p Owens, R.C., Jr. and T.D. Nolin, Antimicrobial-associated QT interval prolongation: Pointes of interest. Clin Infect Dis, (12): p van Bambeke F, Tulkens PM. Safety profile of the respiratory fluoroquinolone AVELOX: comparison with other fluoroquinolones and other antibacterial classes. Drug Saf. 2009;32: Chen X, Cass JD, Bradley JA, et al. QT prolongation and proarrhythmia by AVELOX: concordance of preclinical models in relation to clinical outcome. Br J Pharmacol. 2005;146: Alexandrou AJ, Duncan RS, Sullivan A, et al. Mechanism of herg K+ channel blockade by the fluoroquinolone antibiotic AVELOX. Br J Pharmacol. 2006;147:

119 Page 119 of Malik M, Garnett CE, Zhang J. Thorough QT studies: questions and quandaries. Drug Saf. 2010;33: Malik M, Hnatkova K, Schmidt A, Smetana P. Electrocardiographic QTc changes due to AVELOX infusion. J Clin Pharmacol. 2009;49: Stylianou, A., J. Roger, and K. Stephens, A statistical assessment of QT data following placebo and AVELOX dosing in thorough QT studies. J Biopharm Stat, (3): p Haverkamp W, Kruesmann F, Fritsch A. Update on the Cardiac Safety of AVELOX. Current Drug Safety, 2012, 7, Mehlhorn, A.J. and D.A. Brown, Safety concerns with fluoroquinolones. Ann Pharmacother, (11): p Casparian, J.M., et al., Quinolones and tendon ruptures. South Med J, (5): p Movin, T., et al., Pathology of the Achilles tendon in association with CIPRO treatment. Foot Ankle Int, (5): p Van Bambeke, F. and P.M. Tulkens, Safety profile of the respiratory fluoroquinolone AVELOX: comparison with other fluoroquinolones and other antibacterial classes. Drug Saf, (5): p Khanzada, Z., et al., Bilateral spontaneous non-traumatic rupture of the Achillestendon: a case report. J Med Case Rep, : p Stahlmann, R. and H. Lode, Toxicity of quinolones. Drugs, Suppl 2: p McGarvey, W.C., D. Singh, and S.G. Trevino, Partial Achilles tendon ruptures associated with fluoroquinolone antibiotics: a case report and literature review. Foot Ankle Int, (8): p Fluoroquinolones and tendon disorders: even after single-dose therapy. Prescrire Int, (129): p Hedenmalm, K. and O. Spigset, Peripheral sensory disturbances related to treatment with fluoroquinolones. Journal of Antimicrobial Chemotherapy, (4): p Olesen, L. and T. Jensen, Prevention and Management of Drug-Induced Peripheral Neuropathy. Drug Safety, (4): p Cohen, J.S., Peripheral Neuropathy Associated with Fluoroquinolones. Annals of Pharmacotherapy, (12): p Hedenmalm, K. and O. Spigset, Peripheral sensory disturbances related to treatment with fluoroquinolones. Journal of Antimicrobial Chemotherapy, (4): p Rollof, J. and E. Vinge, Neurologic Adverse Effects during Concomitant Treatment with CIPRO, Nsaids, and Chloroquine: Possible Drug Interaction. Annals of Pharmacotherapy, (9): p Schwartz, M.T. and F.J. Calvert, Potential neurologic toxixity related to CIPRO. DICP Ann Pharmacother, : p Singh, J., CIPRO-related acute peripheral neuropathy in a patient with lupus nephritis. Journal of Clinical Rheumatology, (3): p

120 Page 120 of Aoun, M., et al., Peripheral neuropathy associated with fluoroquinolones. The Lancet, (8811): p Rollof, J. and E. Vinge, Neurologic Adverse Effects during Concomitant Treatment with CIPRO, Nsaids, and Chloroquine: Possible Drug Interaction. Annals of Pharmacotherapy, (9): p Cohen, J.S., Peripheral Neuropathy Associated with Fluoroquinolones. Annals of Pharmacotherapy, (12): p Olesen, L. and T. Jensen, Prevention and Management of Drug-Induced Peripheral Neuropathy. Drug Safety, (4): p Chow AW, Benninger MS, Brook I, et al. IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults. CID. March 20, Weis M 1, Hendrick K, Tillotson G, Gravelle K. Multicenter comparative trial of ciprofloxacin versus cefuroxime axetil in the treatment of acute rhinosinusitis in a primary care setting. Rhinosinusitis Investigation Group. Clin Ther Sep-Oct;20(5): Klein GL 1, Whalen E, Echols RM, Heyd A.Ciprofloxacin versus cefuroxime axetil in the treatment of adult patients with acute bacterial sinusitis. J Otolaryngol Feb;27(1): Johnson PA 1, Rodriguez HP, Wazen JJ, et al.ciprofloxacin versus cefuroxime axetil in the treatment of acute bacterial sinusitis. Sinusitis Infection Study Group. J Otolaryngol Feb;28(1): Clifford K, Huck W, Shan M, et al.double-blind comparative trial of ciprofloxacin versus clarithromycin in the treatment of acute bacterial sinusitis. Sinusitis Infection Study Group. Ann Otol Rhinol Laryngol Apr;108(4): Johnson P, Cihon C, Herrington J et al. Efficacy and Tolerability of AVELOX in the Treatment of Acute Bacterial Sinusitis Caused by Penicillin-Resistant Streptococcus pneumoniae: A Pooled Analysis. Clin Ther, 2004; 26: Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Surg, 1997;117: S1-S Scheid DC and Hamm RM., M.D. Acute Bacterial Rhinosinusitis in Adults: Part II. Treatment. Am Fam Physician 2004;70: , Johnson P, Cihon C, Herrington J et al. Efficacy and Tolerability of AVELOX in thetreatment of Acute Bacterial Sinusitis Caused by Penicillin-Resistant Streptococcus pneumoniae: A Pooled Analysis. Clin Ther, 2004; 26: Saint S, Fluherty KR, Abrahamse M, et al. Acute Exacerbation of Chronic Bronchitis: Disease-Specific Issues That Influence the Cost-Effectiveness of Antimicrobial Therapy. Clin Thel: 2001;23: Ram FS, Rodriguez-Roisin R, Granados-Navarrete A et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev, 2006; 2: CD Niederman MS, Anzueto A, Sethi S et al. Eradication of H. influenzae in AECB: A pooled analysis of AVELOX phase III trials compared with macrolide agents. Respir Med, 2006; 100;

121 Page 121 of Canut A, Martin-Herrero JE, Labora A et al. What are the most appropriate antibiotics for the treatment of acute excerbation of chronic obstructive pulmonary disease. A therapeutic outcomes model. J Antimicrob Chemother, 2007; 60: Wilson R, Anzueto A, Miravitles M, et al. Moxifloxacin versus amoxicillin/clavulanic acid in outpatient acute exacerbations of COPD: MAESTRAL results. Eur Respir J Jul; 40(1): Saint S, Bent S, Vittinghoff E et al. Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. JAMA, 1995; 273: [Guideline] Standards for the diagnosis and management of patients with COPD. Amer Thoracic Soc and European Thoracic Soc Hooton TM, Scholes D, Gupta K et al. Amoxicillin-Clavulanate vs CIPRO for the Treatment of Uncomplicated Cystitis in Women: A Randomized Trial. JAMA. 2005;293: Hooton TM, Roberts PL and Stapleton AE. Cefpodoxime vs CIPRO for Short-Course Treatment of Acute Uncomplicated Cystitis: A Randomized Trial. JAMA February 8; 307(6): Knottnerus BJ, Grigoryan L Geerlingsd SE, Moll EP et al. Comparative effectiveness of antibiotics for uncomplicated urinary tract infections: Network meta-analysis of randomized trials. Family Practice. 29: Talan DA, Stamm, WE, Hooton, TM et al. Comparison of ciprofloxacin (7 days) and trimethoprimsulfamethoxazole (14 days) for uncomplicated pyelonephritis in women: A randomized trial. JAMA 2000;283: Gupta K, Hooton TM, Naber KG et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Inf Dis. 2011;52(5):e103 e

122 Adverse Effects of Antibiotics Employed in Treatment of ABS, AECOPD, uuti Adverse Reaction Summary Drug Class Indication Black Box Warnings/Precautions Azithromycin Clarithromycin Amikacin Gentamicin Tonbramycin Azalide, a macrolide subclass Macrolide aminoglycoside ABS AECOPD uncomplicated initial UTI if the causative organisms are not susceptible to antibiotics having less potential toxicity; serious bacterial infections of the urinary tract. Aztreonam Monobactam UTI (complicated & uncomplicated), including pyelonephritis and cystitis (initial and recurrent) Cefipime Cefixime Cefotaxime Cefpodoxime Ceftazidime Ceftizoxime Ceftriaxone Cephalosporin Uncomplicated & complicated UTI (including pyelonephritis) None Ototoxicity; nephrotoxicity; Neuromuscular blockade; respiratory paralysis; None None - Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson - Clostridium difficile associated diarrhea - Contraindicated in pregnant women, unless benefit exceeds risk - Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity. Also numbness, skin tingling, muscle twitching and convulsions; - Contraindicated in pregnancy; bisulfite allergy; C. difficile associated diarrhea - Hypersensitivity reactions, with or w/o prior exposure. Administer with caution to any patient w a history of hypersensitivity to penicillins, cephalosporins, and/or carbapenems; - Clostridium difficile-associated diarrhea; - Rare cases of toxic epidermal necrolysis - Hypersensitivity reactions. Serious and occasionally fatal anaphylaxis has been reported Cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy; - Dose adjustment in renal impairment. - Neurotoxicity: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and nonconvulsive status epilepticus. - Clostridium difficile Associated Diarrhea

123 Cefdinir Cefuroxime Cefaclor Cefixime Cefpodoxime Cefprozil Ceftibuten Cefuroxime Demeclocycline Doxycycline Minocycline HCl Tetracycline Amoxicillin/ clavulanate potassium Imipenem/ cilastatin Nitrofurantoin monohydrate & nitrofurantoin macrocrystalline Piperacillin Tetracycline beta-lactam with a metabolic inhibitor Imidazolidine dione Beta lactamase inhibitor ABS; Sinusitis in children 6 months to 12 years AECOPD UTI caused by Klebsiella species None - Hemolytic anemia - Risk of Developing Drug-Resistant Bacteria - Reduced prothrombin time. - Cephalosporins should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis - Potentially life-threatening arrhythmia (Cefotaxime) - Renal insufficiency can lead to seizures, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia (Ceftazidime) - Gall stones and kidney stones (Ceftriaxone) - Pancreatitis (Ceftriaxone) - Fetal harm when taken by a pregnant woman. - Tooth discoloration (in utero) and up to age 8 - Aggravate existing renal failure - Photosensitivity reactions - Diabetes insipidus - Clostridium difficile associated diarrhea - Central nervous system effects including light-headedness, dizziness, or vertigo (minocycline) ABS None - Anaphylaxis in patients w penicillin allergy - Seizures and other CNS adverse experiences, such as confusional states and Complicated and uncomplicated UTI Acute uncomplicated UTI Urinary Tract Infections caused by susceptible gram negative None None myoclonic activity - Hepatic dysfunction - Clostridium difficile associated diarrhea - Acute, subacute or chronic pulmonary reactions. Pulmonary reactions have been cited as a cause of death. - Hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis occur rarely; Fatalities have been reported. - Peripheral neuropathy, which may become severe or irreversible;. Fatalities have been reported. Optic neuritis has been reported rarely in postmarketing experience - Hemolytic anemia - Clostridium difficile-associated diarrhea - Serious and potentially fatal hypersensitivity reactions. - Clostridium difficile associated diarrhea

124 Trimethoprim/ Sulfamethoxazol e Sulfonamide antibacterial bacteria. - UTI due to susceptible organisms - AECOPD None -Fatalities, though rare, are associated with sulfonamide antibacterials due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. -skin rash may progress to Stevens Johnson-Syndrome - Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of a serious reaction -Sulfonamide hypersensitivity reactions of the respiratory tract include cough, shortness of breath, and pulmonary infiltrates. - Severe cases of thrombocytopenia that are fatal or life threatening have been reported in patients taking a sulfonamide antibacterial. - Sulfonamides should not be used for the treatment of group A β-hemolytic streptococcus. They will not eradicate an established infection. -Clostridium difficile associated diarrhea

125 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CIPRO safely and effectively. See full prescribing information for CIPRO. CIPRO (ciprofloxacin hydrochloride) tablet for oral use CIPRO (ciprofloxacin hydrochloride) for oral suspension Initial U.S. Approval: 1987 WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS See full prescribing information for complete boxed warning. Fluoroquinolones, including CIPRO, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. (5.1) Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis. (5.2) RECENT MAJOR CHANGES Indications and Usage, Plague (1.14) 2/2015 Dosage and Administration, Adults (2.1), Pediatrics (2.2) 2/ INDICATIONS AND USAGE CIPRO is a fluoroquinolone antibacterial indicated in adults ( 18 years of age) with infections caused by designated, susceptible bacteria and in pediatric patients where indicated. Urinary tract infections (1.1) and Acute uncomplicated cystitis (1.2) Chronic bacterial prostatitis (1.3) Lower respiratory tract infections (1.4) Acute sinusitis (1.5) Skin and skin structure infections (1.6) Bone and joint infections (1.7) Complicated intra-abdominal infections (1.8) Infectious diarrhea (1.9) Typhoid fever (enteric fever) (1.10) Uncomplicated cervical and urethral gonorrhea (1.11) Complicated urinary tract infections and pyelonephritis in pediatric patients (1.12) Inhalational anthrax postexposure in adult and pediatric patients (1.13) Plague in adult and pediatric patients (1.14) To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO and other antibacterial drugs, CIPRO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.16) DOSAGE AND ADMINISTRATION Adult Dosage Guidelines Infection Dose Frequency Duration Urinary Tract mg every 12 hours 7 to 14 days Acute Cystitis 250 mg every 12 hours 3 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract mg every 12 hours 7 to 14 days Acute Sinusitis 500 mg every 12 hours 10 days Skin and Skin Structure mg every 12 hours 7 to 14 days Bone and Joint mg every 12 hours 4 to 8 weeks Intra-Abdominal 500 mg every 12 hours 7 to 14 days Infectious Diarrhea 500 mg every 12 hours 5 to 7 days Typhoid Fever 500 mg every 12 hours 10 days Uncomplicated Gonorrhea 250 mg single dose single dose Inhalational anthrax (postexposure) 500 mg every 12 hours 60 days Plague mg every 12 hours 14 days Adults with creatinine clearance ml/min mg q 12 h Adults with creatinine clearance 5 29 ml/min mg q 18 h Patients on hemodialysis or peritoneal dialysis mg q 24 h (after dialysis) Pediatric Oral Dosage Guidelines Infection Dose Frequency Duration Complicated Urinary Tract Pyelonephritis (1 to 17 years of age) Inhalational Anthrax (Post-Exposure) Plague mg/kg (maximum 750 mg per dose) 15 mg/kg (maximum 500 mg per dose) 15mg/kg (maximum 500 mg per dose) Every 12 hours Every 12 hours Every 12 to 8 hours days 60 days days DOSAGE FORMS AND STRENGTHS Tablets: 250 mg, 500 mg (3) Oral Suspension: 5% (250 mg/5 ml), 10% (500 mg/5 ml) (3) CONTRAINDICATIONS Known sensitivity to CIPRO or other quinolones (4.1, 5.3) Concomitant administration with tizanidine (4.2) WARNINGS AND PRECAUTIONS Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions may occur after first or subsequent doses. Discontinue at first sign of skin rash, jaundice or any sign of hypersensitivity. (4.1, 5.3, 5.4) Hepatotoxicity: Discontinue immediately if signs and symptoms of hepatitis occur. (5.5) Central nervous system effects, including convulsions, increased intracranial pressure (pseudotumor cerebri) and toxic psychosis have been reported. Caution should be taken in patients predisposed to seizures. (5.7) Clostridium difficile-associated diarrhea: Evaluate if colitis occurs. (5.8) Peripheral neuropathy: Discontinue if symptoms occur in order to prevent irreversibility. (5.9) QT Prolongation: Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval. (5.10, 7, 8.5) ADVERSE REACTIONS The most common adverse reactions 1% were nausea, diarrhea, liver function tests abnormal, vomiting, and rash. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at or FDA at FDA-1088 or DRUG INTERACTIONS Interacting Drug Interaction Theophylline Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7) Warfarin Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7) Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7) Phenytoin Monitor phenytoin level (7) Methotrexate Monitor for methotrexate toxicity (7) Cyclosporine May increase serum creatinine. Monitor serum creatinine (7) Multivalent cation-containing products including antacids, metal cations or didanosine Decreased CIPRO absorption. Take 2 hours before or 6 hours after CIPRO (7) USE IN SPECIFIC POPULATIONS See full prescribing information for use in pediatric and geriatric patients (8.4, 8.5) 1

126 See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 2/2015 2

127 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: TENDON EFFECTS AND MYASTHENIA GRAVIS 1 INDICATIONS AND USAGE 1.1 Urinary Tract Infections 1.2 Acute Uncomplicated Cystitis 1.3 Chronic Bacterial Prostatitis 1.4 Lower Respiratory Tract Infections 1.5 Acute Sinusitis 1.6 Skin and Skin Structure Infections 1.7 Bone and Joint Infections 1.8 Complicated Intra-Abdominal Infections 1.9 Infectious Diarrhea 1.10 Typhoid Fever (Enteric Fever) 1.11 Uncomplicated Cervical and Urethral Gonorrhea 1.12 Complicated Urinary Tract Infections and Pyelonephritis 1.13 Inhalational Anthrax (post-exposure) 1.14 Plague 1.15 Limitation of Use 1.16 Usage 2 DOSAGE AND ADMINISTRATION 2.1 Dosage in Adults 2.2 Dosage in Pediatric Patients 2.3 Dosage Modifications in Patients with Renal Impairment 2.4 Important Administration Instructions 2.5 Directions for Reconstitution of the CIPRO Microcapsules for Oral Suspension 3 DOSAGE FORMS AND STRENGTHS 3.1 Tablets 3.2 Oral Suspension 4 CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Tizanidine 5 WARNINGS AND PRECAUTIONS 5.1 Tendinopathy and Tendon Rupture 5.2 Exacerbation of Myasthenia Gravis 5.3 Hypersensitivity Reactions 5.4 Other Serious and Sometimes Fatal Reactions 5.5 Hepatotoxicity 5.6 Serious Adverse Reactions with Concomitant Theophylline 5.7 Central Nervous System Effects 5.8 Clostridium Difficile-Associated Diarrhea 5.9 Peripheral Neuropathy 5.10 Prolongation of the QT Interval 5.11 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals 5.12 Crystalluria 5.13 Photosensitivity/Phototoxicity 5.14 Development of Drug Resistant Bacteria 5.15 Potential Risks With Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2 Enzymes 5.16 Interference with Timely Diagnosis of Syphilis 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 6.3Adverse Laboratory Changes 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 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 14.1 Complicated Urinary Tract Infection and Pyelonephritis Efficacy in Pediatric Patients 14.2 Inhalational Anthrax in Adults and Pediatrics 14.3 Plague 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed 3

128 FULL PRESCRIBING INFORMATION WARNING: TENDON EFFECTS and MYASTHENIA GRAVIS Fluoroquinolones, including CIPRO, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart, or lung transplants [see Warnings and Precautions (5.1)]. Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE CIPRO is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below. 1.1 Urinary Tract Infections CIPRO is indicated in adult patients for treatment of urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter koseri, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis. 1.2 Acute Uncomplicated Cystitis CIPRO is indicated in adult female patients for treatment of acute uncomplicated cystitis caused by Escherichia coli or Staphylococcus saprophyticus. 1.3 Chronic Bacterial Prostatitis CIPRO is indicated in adult patients for treatment of chronic bacterial prostatitis caused by Escherichia coli or Proteus mirabilis. 1.4 Lower Respiratory Tract Infections CIPRO is indicated in adult patients for treatment of lower respiratory tract infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or Streptococcus pneumoniae. Also, CIPRO is indicated for the treatment of acute exacerbations of chronic bronchitis caused by Moraxella catarrhalis [see Indications and Usage (1.15)]. 1.5 Acute Sinusitis CIPRO is indicated in adult patients for treatment of acute sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis. 4

129 1.6 Skin and Skin Structure Infections CIPRO is indicated in adult patients for treatment of skin and skin structure infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillinsusceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes. 1.7 Bone and Joint Infections CIPRO is indicated in adult patients for treatment of bone and joint infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa. 1.8 Complicated Intra-Abdominal Infections CIPRO is indicated in adult patients for treatment of complicated intra-abdominal infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. 1.9 Infectious Diarrhea CIPRO is indicated in adult patients for treatment of infectious diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii, Shigella dysenteriae, Shigella flexneri or Shigella sonnei when antibacterial therapy is indicated. Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients Typhoid Fever (Enteric Fever) CIPRO is indicated in adult patients for treatment of typhoid fever (enteric fever) caused by Salmonella typhi. The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated Uncomplicated Cervical and Urethral Gonorrhea CIPRO is indicated in adult patients for treatment of uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae [see Warnings and Precautions (5.16)] Complicated Urinary Tract Infections and Pyelonephritis CIPRO is indicated in pediatric patients one to 17 years of age for treatment of complicated urinary tract infections (cuti) and pyelonephritis due to Escherichia coli [see Indications and Usage (1.15) and Use in Specific Populations (8.4)] Inhalational Anthrax (post-exposure) CIPRO is indicated in adults and pediatric patients from birth to 17 years of age for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. 5

130 Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication. 1 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October [See Clinical Studies (14.2).] 1.14 Plague CIPRO is indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17 years of age. Efficacy studies of ciprofloxacin could not be conducted in humans with plague for feasibility reasons. Therefore this indication is based on an efficacy study conducted in animals only [see Clinical Studies (14.3)] Limitation of Use Use in Pediatric Patients Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues. CIPRO, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals [see Warnings and Precautions (5.11), Adverse Reactions (6.1), Use in Specific Populations (8.4) Nonclinical Toxicology (13.2)]. Lower Respiratory Tract Infections CIPRO is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae [see Indications and Usage (1.4)] Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO and other antibacterial drugs, CIPRO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance. 2 DOSAGE AND ADMINISTRATION CIPRO Tablets and Oral Suspension should be administered orally as described in the appropriate Dosage Guidelines tables. 6

131 2.1 Dosage in Adults The determination of dosage and duration for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative microorganism, the integrity of the patient s host-defense mechanisms, and the status of renal and hepatic function. Table 1: Adult Dosage Guidelines Infection Dose Frequency Usual Durations 1 Urinary Tract mg every 12 hours 7 to 14 days Acute Uncomplicated Cystitis 250 mg every 12 hours 3 days Chronic Bacterial Prostatitis 500 mg every 12 hours 28 days Lower Respiratory Tract mg every 12 hours 7 to 14 days Acute Sinusitis 500 mg every 12 hours 10 days Skin and Skin Structure mg every 12 hours 7 to 14 days Bone and Joint mg every 12 hours 4 to 8 weeks Complicated Intra Abdominal mg every 12 hours 7 to 14 days Infectious Diarrhea 500 mg every 12 hours 5 to 7 days Typhoid Fever 500 mg every 12 hours 10 days Uncomplicated Urethral and Cervical Gonococcal Infections 250 mg single dose single dose Inhalational anthrax (postexposure) 500 mg every 12 hours 60 days 3 Plague mg every 12 hours 14 days 1. Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure). 2. Used in conjunction with metronidazole. 3. Begin drug administration as soon as possible after suspected or confirmed exposure. Conversion of IV to Oral Dosing in Adults Patients whose therapy is started with CIPRO IV may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of the physician (Table 2) [see Clinical Pharmacology (12.3)]. Table 2: Equivalent AUC Dosing Regimens CIPRO Oral Dosage Equivalent CIPRO IV Dosage 250 mg Tablet every 12 hours 200 mg intravenous every 12 hours 500 mg Tablet every 12 hours 400 mg intravenous every 12 hours 750 mg Tablet every 12 hours 400 mg intravenous every 8 hours 2.2 Dosage in Pediatric Patients Dosing and initial route of therapy (that is, IV or oral) for cuti or pyelonephritis should be determined by the severity of the infection. CIPRO should be administered as described in Table 3. 7

132 Table 3: Pediatric Dosage Guidelines Infection Dose Frequency Total Duration 10 mg/kg to 20 mg/kg Complicated Urinary Tract or (maximum 750 mg per dose; not to be Pyelonephritis exceeded even in patients weighing more (patients from 1 to 17 years of age) than 51 kg) Every 12 hours days 1 Inhalational Anthrax (Post- 15 mg/kg Exposure) 2 (maximum 500 mg per dose) Every 12 hours 60 days Plague 2,3 15 mg/kg Every 12 to 8 (maximum 500 mg per dose) hours days 1. The total duration of therapy for cuti and pyelonephritis in the clinical trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days). 2. Begin drug administration as soon as possible after suspected or confirmed exposure. 3. Begin drug administration as soon as possible after suspected or confirmed exposure to Y. pestis. 2.3 Dosage Modifications in Patients with Renal Impairment Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. Dosage guidelines for use in patients with renal impairment are shown in Table 4. Table 4: Recommended Starting and Maintenance Doses for Adult Patients with Impaired Renal Function Creatinine Clearance (ml/min) Dose > 50 See Usual Dosage mg every12 hours mg every 18 hours Patients on hemodialysis or Peritoneal dialysis mg every 24 hours (after dialysis) When only the serum creatinine concentration is known, the following formulas may be used to estimate creatinine clearance: Men - Creatinine clearance (ml/min) = Weight (kg) x (140 age) 72 x serum creatinine (mg/dl) Women x the value calculated for men. The serum creatinine should represent a steady state of renal function. In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored. Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of cuti and pyelonephritis. No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 ml/min/1.73m 2 ). 8

133 2.4 Important Administration Instructions With Multivalent Cations Administer CIPRO at least 2 hours before or 6 hours after magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate; Videx (didanosine) chewable/buffered tablets or pediatric powder for oral solution; other highly buffered drugs; or other products containing calcium, iron or zinc. With Dairy Products Concomitant administration of CIPRO with dairy products (like milk or yogurt) or calcium-fortified juices alone should be avoided since decreased absorption is possible; however, CIPRO may be taken with a meal that contains these products. Hydration of Patients Receiving CIPRO Assure adequate hydration of patients receiving CIPRO to prevent the formation of highly concentrated urine. Crystalluria has been reported with quinolones. Instruct the patient of the appropriate CIPRO administration [see Patient Counseling Information (17)]. 2.5 Directions for Reconstitution of the CIPRO Microcapsules for Oral Suspension CIPRO Oral Suspension is supplied in 5% (5 g ciprofloxacin in 100 ml) and 10% (10 g ciprofloxacin in 100 ml) strengths. CIPRO oral suspension is composed of two components (microcapsules and diluent) that must be combined prior to dispensing. Table 5: Appropriate Dosing Volumes of the Reconstituted Oral Suspensions Dose 5% 10% 250 mg 5 ml 2.5 ml 500 mg 10 ml 5 ml 750 mg 15 ml 7.5 ml Preparation of the suspension: Step1 The small bottle contains the microcapsules, the large bottle contains the diluent. Step 2 Open both bottles. Child-proof cap: Press down according to instructions on the cap while turning to the left. Step 3 Pour the microcapsules completely into the larger bottle of Step 4 Remove the top layer of the diluent bottle label (to reveal the CIPRO Oral 9

134 diluent. Do not add water to the suspension. Suspension label). Close the large bottle completely according to the directions on the cap and shake vigorously for about 15 seconds. The suspension is ready for use. Step 5: Write the expiration date of the re-constituted oral suspension on the bottle label. Reconstituted product may be stored below 30 C (86 F) for 14 days. Protect from freezing. No additions should be made to the mixed final ciprofloxacin suspension. CIPRO Oral Suspension should not be administered through feeding or NG (nasogastric) tubes due to its physical characteristics. 3 DOSAGE FORMS AND STRENGTHS 3.1 Tablets 250 mg slightly yellowish, film-coated, round, imprinted with BAYER on one side and CIP 250 on the other 500 mg, slightly yellowish, film-coated, capsule shaped, imprinted with BAYER on one side and CIP 500 on the other 3.2 Oral Suspension 5% Oral Suspension: 250 mg ciprofloxacin per 5 ml after reconstitution 10% Oral Suspension: 500 mg ciprofloxacin per 5 ml after reconstitution 4 CONTRAINDICATIONS 4.1 Hypersensitivity CIPRO is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components [see Warnings and Precautions (5.3)]. 4.2 Tizanidine Concomitant administration with tizanidine is contraindicated [see Drug Interactions (7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Tendinopathy and Tendon Rupture Fluoroquinolones, including CIPRO, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing 10