Avalox in Aecb: PP-AVE-JO-0006-1

Avalox® in AECB
CONTENTS
PP-AVE-JO-0006-1
L.SA.MKT.04.2017.0137
Contents
…click on a hyperlink to go straight to the section
Introduction to AECB
Preclinical activity of Avalox®
Efficacy of Avalox® against resistant bacterial strains
Safety and tolerability of Avalox®
Avalox®
key clinical trials in AECB
Avqlox®
health economics data in AECB
Current AECB guidelines
Other antibiotics in AECB
References
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Avalox® in AECB
INTRODUCTION TO AECB
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Relationship between major respiratory
conditions
CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
CHRONIC
EMPHYSEMA
BRONCHITIS
AIRFLOW
OBSTRUCTION
ACUTE EXACERBATION
OF CHRONIC
BRONCHITIS
Increase in baseline
symptoms:
 Dyspnea
 Sputum volume
 Sputum purulence ASTHMA
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Adapted from: ATS. Am J Respir Crit Care 1995; 152: S77–S120 L.SA.MKT.04.2017.0137
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Chronic bronchitis and acute exacerbation
of chronic bronchitis
Chronic bronchitis
• The presence of cough and sputum production for 3 consecutive
months in each of 2 consecutive years in a patient in whom other
causes of chronic cough have been excluded1,2
• Chronic bronchitis is present in ~85% of patients with COPD3
Acute exacerbation of chronic bronchitis2
• Acute aggravation of the symptoms of chronic bronchitis
• Diagnosis based on the presence of a number of symptoms
– Presence of or increase in dyspnea
– Increase in sputum production
– Purulent sputum
– Less commonly – fever or febricula
• Severity of exacerbation defined by number of concurrent symptoms
using the Anthonisen criteria4
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1) ATS. Am J Respir Crit Care 1995; 152: S77–S120
2) Miravitlles et al. Arch Bronchoneumol 2004; 40: 315–25
3) Balter et al. Can Respir J 2003; 10 (Suppl B): 3B–32B
4) Anthonisen et al. Ann Intern Med 1987; 106: 196–204 L.SA.MKT.04.2017.0137
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Stratification of AECB patients – the
Anthonisen criteria
Increase in:
• dyspnea
• sputum volume
• sputum purulence
TYPE I TYPE II TYPE III

Two of three present, One of three present,
All three present,
antibiotic recommended antibiotic
antibiotic recommended
if includes purulence not recommended
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Anthonisen et al. Ann Intern Med 1987 [Adapted from Woodhead et al. Clin Microbiol Infect 2011;17 (Suppl 6):E1-E59) 6
Causes of AECB
Infection
Bacterial Allergy
Viral
AECB
Pollution Weather
Cigarette smoke
Fall in temperature
Industrial dusts
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Ball. CHEST 1995; 108: 43S–52S; Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press
Communications, 2004; Donaldson et al. Eur Respir J 1999; 13: 844–9 L.SA.MKT.04.2017.0137
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Most exacerbations are due to infection
80% of all exacerbations are infectious
• Predominant bacterial pathogens: 40–50% of infectious exacerbations
– Haemophilus influenzae
– Moraxella catarrhalis
– Streptococcus pneumoniae
• Atypical bacteria: 5–10% of infectious exacerbations
– Chlamydia pneumoniae
– Mycoplasma pneumonia
• Occasional causes of infectious exacerbations
– Haemophilus parainfluenzae
– Pseudomonas aeruginosa
– Staphylococcus aureus
– Enterobacteriaceae
• Viral infection: 30% of infectious exacerbations
20% of all exacerbations are non-infectious
• Environmental factors
• Non-compliance with medications
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Sethi. CHEST 2000; 117: 380S–385S; Miravitlles et al. Arch Bronchoneumol 2004; 40: 315–25 L.SA.MKT.04.2017.0137
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Bacterial pathogens isolated from sputum in studies
of acute exacerbations of chronic bronchitis
Gram-negative Gram-positive
pathogens pathogens
Enteric pathogens S. pneumoniae
11.4% (3–19) 14.2% (7–26)
P. aeruginosa
5.8% (1–13)
S. aureus
6.4% (1–20)
H. parainfluenzae
9.4% (0–32)
M. catarrhalis
Non-typeable H. influenzae
14.0% (4–21)
31.2% (13–50)
Data are mean (range) percentage of total bacterial isolates

Number of patients: 687 (140–2180)
Sputum culture positive for potentially pathogenic bacteria: 53.7 (28.1–88.6)
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Sethi. Clin Infect Dis 2005; 40: S489–97 L.SA.MKT.04.2017.0137

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Profile of bacterial infection in exacerbations
of differing severity
Group 1: S. pneumoniae
and S. aureus
Group 1 Group 2 Group 3 Group 2: H. influenzae
80 and M. catarrhalis
Group 3: P. aeruginosa,
Percent of patients (%)
Pseudomonas spp., Serratia

60
marcesens, Klebsiella
pneumoniae, Proteus vulgaris,
40 Escherichia coli, Citrobacter
spp., Enterobacter spp.,
20 Stenotrophomonas maltophilia
0
The distribution of the three
groups of bacteria causing
All patients FEV ≥50% FEV >35% FEV ≤35%
n=112 1
predicted, to1 <50% 1
predicted,
infective exacerbations by lung
n=30 predicted, n=52 function severity was significant
n=30 (p=0.016, 2 test)
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Eller et al. CHEST 1998; 113: 1542–8 L.SA.MKT.04.2017.0137

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AECB is associated with bacterial infection with new strains of H.
influenzae, M. catarrhalis and S. pneumoniae in patients with COPD
Percent of clinic visits when an Percent of clinic visits for

exacerbation was present related to exacerbations that were associated
the presence or absence of with presence or absence of new
pathogens strains
p<0.001
Exacerbations/visit (%)
40
33.0
p<0.001
30
23.6
20 18.0
15.4
10
Pathogen No pathogen New strain No new strain
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Sethi et al. N Engl J Med 2002; 347: 465–71 L.SA.MKT.04.2017.0137

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Impact of AECB
COPD patients with significant levels of obstruction

experience 2–3 exacerbations/year1
Some patients experience up to 8 exacerbations/year2
In one study of patients experiencing an average of 1.5
exacerbations/year 31% required hospital treatment3
Mortality of AECB patients admitted to ICU varies from 24
to 46%4
Exacerbations result in a deterioration in lung function
and have a prolonged effect on quality of life4
Exacerbations increase healthcare costs
• Physician visits, hospitalization, medication2
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1) Miravitlles et al. Arch Bronchoneumol 2004; 40: 315–25
2) Sethi & File Curr Med Res Opin 2004; 20: 1511–21
3) Miravitlles et al. Thorax 2004; 59: 387–95
4) Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press Communications, 2004 L.SA.MKT.04.2017.0137
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Frequent exacerbations hasten lung
function decline
The decline in FEV1 of 16 frequent exacerbators* (40.1 mL/year)
was significantly faster than in the 16 infrequent exacerbators**
(32.1 mL/year); p<0.05
The percentage decline in FEV1 of frequent exacerbators was greater
than for those with infrequent exacerbations
Infrequent exacerbators (3.59% decline in FEV /year)

Percent change in FEV1 (L)
Frequent exacerbators (4.22% decline in FEV /year)
0.95
0.9
0.85
0.8
0.75
0 1 2 3 4
Time (years)
*Infrequent exacerbators: less than the median rate of 2.92 exacerbations/year
**Frequent exacerbators: more than the median rate of 2.92 exacerbations/year
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Donaldson et al. Thorax 2002; 57: 847–52 L.SA.MKT.04.2017.0137

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Exacerbations have a sustained detrimental
effect on health status
Exacerbators Non-exacerbators *
60
Questionnaire total score
St George’s Respiratory
55
50
45
40
35
30
Presentation 4 weeks 12 weeks 26 weeks
*All patients presented with an Anthonisen Type 1 exacerbation and were treated with an antibiotic. Exacerbators had a further
exacerbation during the follow-up period and non-exacerbators had none
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Spencer et al. Thorax 2003; 58: 589–93 L.SA.MKT.04.2017.0137

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AECBs impair patients’ quality of life
Frequent exacerbations significantly impair health-related quality

of life1,2
The effect of a single exacerbation on quality of life may persist
for months3
Exacerbations of COPD impact on the daily activities of patients4
• increased coughing (42% of patients), increased shortness of breath
(37%), increased fatigue (37%) and increased production of sputum
(35%) make life much more difficult
• only 41% of patients could continue with their normal life while
increasing their usual medication during an exacerbation
• 45% of patients with an exacerbation had to stay in bed or on the
couch all day
• 55% of those who worked had to stop working due
to the exacerbation
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1) Seemungal et al. Am J Respir Crit Care Med 1998; 157: 1418–22
2) Miravitlles et al. Thorax 2004; 59: 387–95
3) Spencer et al. Thorax 2003; 58: 589–93
4) Miravitlles et al. Respiratory Medicine 2007;101:453-60 L.SA.MKT.04.2017.0137
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Risk factors for chronic bronchitis
Smoking
Increasing age
Recurrent childhood respiratory infections
Atmospheric pollution
Occupational dust exposure
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Ball. CHEST 1995; 108: 43S–52S L.SA.MKT.04.2017.0137

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Smoking and chronic bronchitis
Main contributory factor

Smoking history in 90% of sufferers
Death from chronic bronchitis high in smokers
Stimulates bacterial colonization
Immune defence suppressed
Increased infection susceptibility
Stopping smoking slows disease progression
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US Surgeon General. The Health Consequences of Smoking: Chronic Obstructive Lung Disease. 1984 L.SA.MKT.04.2017.0137
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Lung function in COPD: effect of smoking
and smoking cessation
100
Never smoked and not
susceptible to smoke
80
Smoked regularly
and susceptible
FEV1 (%)
60 Stopped at
to its effects
age 45
40
Disability
20
Stopped at age
Death 65
0
20 30 40 60 70 80 90
Age (years)
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Fletcher & Peto. BMJ 1977; 1: 1645–8 L.SA.MKT.04.2017.0137

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Causal factors in chronic bronchitis
Cigarette smoking (predominant factor)

Long-term exposure to environmental pollution
Exposure to occupational dust and fumes
Recurrent chest infections
Inflammation of the bronchial mucosa

Airway changes (e.g. ciliary damage
and increase in number of mucus glands)
Impaired mucociliary clearance and hypersecretion of mucus
Inflammation and edema
Narrowing and obstruction of airflow
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Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press Communications, 2004 L.SA.MKT.04.2017.0137
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Role of bacterial infection in chronic
bronchitis
The Vicious Circle Hypothesis

Initiating factors
(e.g. viral infections, smoking, childhood respiratory disease)
Impaired
mucociliary
clearance
Damage to
Vicious Bacterial
airway
circle colonization
epithelium
Progression Inflammatory
of Bacterial response (cytokines,
COPD products enzymes etc.)
Alteration of elastase– Increased elastolytic

anti-elastase balance activity in lung
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Sethi & Murphy. Clin Microbiol Rev 2001; 14: 336–63 L.SA.MKT.04.2017.0137
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Definition of COPD
Chronic obstructive pulmonary disease (COPD) is a

progressive, preventable and treatable disease state
characterized by airflow limitation that is not fully reversible
The airflow limitation is usually both progressive
and associated with an abnormal inflammatory response
of the lungs to noxious particles or gases
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Global Initiative for Chronic Obstructive Lung Disease, 2011; http://www.goldcopd.com [Accessed March 2012] L.SA.MKT.04.2017.0137
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Prevalence, morbidity and mortality of COPD
USA1
• 12.1 million adults had COPD in 2000
– 24 million adults had evidence of impaired lung function, indicating underdiagnosis
• COPD caused 119,000 adult deaths in 2000
– 4th leading cause of death
• 1.5 million emergency department visits in 2000
– 726,000 hospitalizations
Worldwide2–4
• Worldwide prevalence of COPD in 1990 estimated at 9.34/1000 men
and 7.33/1000 women
– 15–25% of adults aged ≥40 years have airflow limitation defined as mild COPD or
higher
– Likely to be an underestimate
– Prevalence highest in countries where cigarette smoking has been/still is common
• COPD is the 4th leading cause of death in the world
– Morbidity increases with age and is greater in men than in women
– COPD is a significant part of physician visits, emergency department visits
and hospitalizations
Further increases in prevalence and mortality predicted1,2
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1) NIH/NHLBI 2003. Data Fact Sheet: Chronic Obstructive Pulmonary Disease
2) Global Initiative for Chronic Obstructive Lung Disease, 2011 http://www.goldcopd.com [Accessed March 2012]
3) World Health Organisation 1995; World Health Statistics Annual 1995. WHO, Geneva
4) Mathers et al. PLoS Med 2006; 3: e442 L.SA.MKT.04.2017.0137
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COPD mortality in the USA, 1980–2000
Male Female Total
120000
Number of deaths/year
100000
80000
60000
40000
20000
0
1980 1985 1990 1995 1996 1997 1998 1999 2000
Year
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Mannino et al. MMWR 2002; 51 (SS06): 1–16 L.SA.MKT.04.2017.0137

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COPD prevalence varies widely across
countries
25 Males Females
Number of cases per 100 population
20
15
10
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Mannino et al. Lancet 2007; 370: 765–773 L.SA.MKT.04.2017.0137

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COPD may be underdiagnosed: the role of
baselines and spirometry
Early detection of COPD and intervention is crucial

Definitions of ‘normal’ and its relation to obstruction can
lead to misdiagnosis
Several studies have compared the GOLD definition of
restriction (FEV1/FVC <70%) with FEV1/FVC < LLN* where
LLN is based on National Health and Nutrition Assessment
Survey (NHANES)
Using GOLD definition alone would result in a:
• False positive rate of 28% in patients >65 years of age
• False negative rate of 14% in patients <50 years of age
*LLN, lower limits of normal
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Brazzale et al. Respirology 2010; 15:1098–103 L.SA.MKT.04.2017.0137

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Treatment of AECB
Treatment of AECB requires symptomatic relief

and prevention of the transient loss of pulmonary function
that may lead to hospitalization
Patients require pharmacological therapy to:
• decrease the effort involved in breathing
• reduce airway inflammation
• reduce the bacterial burden in the lower airways
• treat any accompanying hypoxemia
Management of AECB involves several treatment modalities:
• bronchodilator therapy
• oxygen therapy
• mucous clearing strategies
• corticosteroid therapy
• antibiotic therapy
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Balter et al. Can Respir J 2003; 10 (Suppl B): 3B–32B L.SA.MKT.04.2017.0137

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Properties of an ideal antibiotic for AECB
Activity against the major respiratory pathogens

Resistant to inactivation by bacterial β-lactamases
High concentrations in respiratory mucosal secretion
Bacterial killing mechanism that does not increase
airway inflammation
Acceptable toxicity profile
Convenient dosage schedule
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Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press Communications 2004 L.SA.MKT.04.2017.0137
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Avalox® in AECB
PRECLINICAL ACTIVITY OF AVALOX®
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Faster eradication of S. pneumoniae with
moxifloxacin in vitro
(a) Strain 21, moxifloxacin MIC 0.25mg/L (b) Strain 25, moxifloxacin MIC 0.25mg/L
levofloxacin MIC 2mg/L levofloxacin MIC 4mg/L
10 10
Control Control
9 9
8 8 Eradication not
7 16 h difference 7 achieved
Log CFU/mL
Log CFU/mL
6 In time to 6 with levofloxacin
eradication 5
5
4 4
3 Levofloxacin
3 Levofloxacin
2 2
1 1
Moxifloxacin Moxifloxacin
0 0
0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40
Time (hours) Time (hours)
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Lister & Sanders. J Antimicrob Chemother 2001; 47: 811–8 L.SA.MKT.04.2017.0137

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Avalox® in AECB
EFFICACY OF AVALOX® AGAINST
RESISTANT BACTERIAL STRAINS
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Increasing prevalence of antibiotic
resistance
~25–45% of S. pneumoniae isolates are

penicillin-resistant1
Macrolide-resistant S. pneumoniae is increasing1
• 30–50% resistance to clarithromycin and azithromycin in
some areas
>98% of H. influenzae isolates have a macrolide efflux
mechanism due to one or several ribosomal mutations2
β-lactamase production in ~35% of H. influenzae isolates1
• Limited usefulness of amoxicillin and ampicillin
β-lactamase production in >90% of M. catarrhalis isolates1
• Limited usefulness of amoxicillin
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1) Miravitlles & Niederman. Lectures in Respiratory Tract Infections. Science Press Communications 2004
2) Peric et al. Antimicrob Agents Chemother 2003; 47: 1017–22 L.SA.MKT.04.2017.0137
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Worldwide rates of penicillin-non-
susceptible S. pneumoniae
Canada Europe
8.5% 6.5% 13.0% 11.1%
Asia
16.2% 44.1%
North America
(United States)
15.3% 20.2%
South America
(Brazil)
22.2% 7.9%
Africa
(South Africa) Middle East
27.4% 7.9% (Saudi Arabia)
35.7% 19.7%
Powis et al. Antimicrob Agents Chemother 2004; 48: 3305–3311
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Jones et al. Diagn Microbiol Infect Dis 2003; 47: 579–586 Penicillin-intermediate (MIC 0.12–1 µg/mL)
Fouda et al. J Chemother 2004; 16: 517–523 Penicillin-resistant (MIC ≥2 µg/mL)
Jenkins et al. J Infect 2005; 51: 355–363 L.SA.MKT.04.2017.0137
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Worldwide rates of macrolide-resistant
S. pneumoniae
Canada Europe
18% 29.4%
Asia
74.7%
United States
29.2%
South America
(Brazil)
9.5%
Africa
(South Africa) Middle East
13.6% (Saudi Arabia)
22.6%
Powis et al. Antimicrob Agents Chemother 2004; 48: 3305–3311
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Jones et al. Diagn Microbiol Infect Dis 2003; 47: 579–586 Azithromycin-resistant (MIC > 1 µg/mL)
Fouda et al. J Chemother 2004; 16: 517–523 Erythromycin-resistant (MIC > 0.5 µg/mL)
Jenkins et al. J Infect 2005; 51: 355–363 L.SA.MKT.04.2017.0137
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Worldwide rates of S. pneumoniae
non-susceptible to fluoroquinolones
Croatia Italy
Northern Ireland Ciprofloxacin 3.6% Levofloxacin 5.6%
Canada
Ciprofloxacin 15% Levofloxacin 3.4%
Levofloxacin 1.6%
Japan
Levofloxacin 1.3%
Hong Kong
Ciprofloxacin 17.8%
United States Levofloxacin 13.3%
Ciprofloxacin 2.3%
Singapore
Levofloxacin 1.6%
Spain
Ciprofloxacin 7%
South Africa
Levofloxacin 0.0% Saudi Arabia
Levofloxacin 0.0%
Deshpande et al. DMID 2000; 37: 139–142; Doern et al. Clin Infect Dis 2005; 45: 1721–29; Ho et al. J Antimicrob Chemother
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2001; 48: 659–665; Thornsberry et al. Clin Infect Dis 2002; 34(Suppl 1): S4–S16; Goldsmith et al. J Antimicrob Chemother
1998; 41: 420–421; Pankuch et al. Antimicrob Agents Chemother 2002; 46: 2671–2675; Perez-Trallero et al. Antimicrob Agents
Chemother 2001; 45: 3334–3340; Powis et al. Antimicrob Agents Chemother 2004; 48: 3305–3311 L.SA.MKT.04.2017.0137
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Moxifloxacin: fluoroquinolone with potential to
minimize selection of resistant S. pneumoniae
200 192
180 AUC/MIC >100 required to
minimize the potential for
160
resistance selection
140
AUC/MIC
120
100
80 68
60 48
40
20
0
Moxifloxacin (400mg) Gatifloxacin (400mg) Levofloxacin (500mg)
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Scheld. Emerg Infect Dis 2003; 9: 1–8
Blondeau. J Antimicrob Chemother 1999; 43 (Suppl B): 1–11 L.SA.MKT.04.2017.0137
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Moxifloxacin shows greater efficacy against
H. influenzae vs macrolides*
H. influenzae is the most common pathogen in AECB
Increasing H. influenzae resistance to macrolides is reflected in clinical
success and bacteriologic eradication rates**
Moxifloxacin † Macrolides † †
p<0.006
93
Success (%)
100 89.5 85.2

80 73.2
60
40
20
0
Clinical efficacy Bacteriological efficacy
*Pooled analysis of four studies with primary endpoint clinical efficacy; **Rates recorded at test of cure visit (7–37 days post-
therapy); †Moxifloxacin 400mg PO q.d. for 5 days; ††Azithromycin 500mg/ 250mg q.d. for 5 days or clarithromycin 500mg b.i.d.
for 7–10 days
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Niederman et al. Respir Med 2006; 100: 1781–90 L.SA.MKT.04.2017.0137

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Avalox® in AECB
SAFETY AND TOLERABILITY OF
AVALOX®
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Adverse events in Phase II/III studies with
oral moxifloxacin
Patients (%)
Moxifloxacin* (n=7,368) Comparators** (n=5,687)
Adverse events 43.3 43.0
Adverse drug reactions 25.1 23.4
Serious adverse drug reactions 3.3 3.8
Discontinuations due to ADR 2.7 3.0
Deaths 0.3 0.3
Adverse events (>1% of patients)
Nausea 7.1 5.2
Diarrhea 5.2 4.5
Dizziness 2.6 2.3
Abdominal pain 1.8 1.4
Headache 1.6 2.0
Vomiting 1.6 1.5
Dyspepsia 1.2 1.1
Abnormal liver function test result 0.9 1.1
*Moxifloxacin 400mg/day PO for 5–14 days depending on the indication.
**Comparators include cefuroxime axetil and trovafloxacin for ABS, azithromycin, cefixime, clarithromycin and
amoxicillin/clavulanate for AECB, amoxicillin and clarithromycin for CAP and cephalexin,
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ciprofloxacin/doxycycline/metronidazole, ofloxacin and trimethoprim/sulfamethoxazole for other indications
Ball et al. Clin Ther 2004; 26: 940–9 L.SA.MKT.04.2017.0137

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Cardiac adverse event profile in Phase II/III
studies with oral moxifloxacin
Patients (%)
Adverse event
(≥2% of patients) Moxifloxacin* (n=5,407) Comparators** (n=5,097)
Chest pain 0.8 0.7

Tachycardia 0.4 0.4
Hypotension 0.4 0.4
Atrial fibrillation 0.2 <0.1
Congestive heart failure 0.2 0.2
Angina pectoris 0.2 <0.1
Syncope 0.2 0.2
Arrhythmia <0.1 <0.1
QT-interval prolongation <0.1 <0.1
Shock <0.1 <0.1
Myocardial infarction <0.1 0.1
Abnormal electrocardiogram – –
Ventricular tachycardia – –
*Moxifloxacin 400mg/day PO for 5 to 14 days depending on the indication.
**Comparators include cefuroxime axetil and trovafloxacin for ABS, azithromycin, cefixime, clarithromycin and
amoxicillin/clavulanate for AECB, amoxicillin and clarithromycin for CAP and cephalexin,
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ciprofloxacin/doxycycline/metronidazole, ofloxacin and trimethoprim/sulfamethoxazole for other indications
Ball et al. Clin Ther 2004; 26: 940–9 L.SA.MKT.04.2017.0137

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Pooled safety data for moxifloxacin: double
blind studies
The safety profile of moxifloxacin was investigated via in-depth analysis of the complete
moxifloxacin clinical trials database
Treatment route
PO (n=17465) IV/PO (n=3745) IV (n=1159)
Moxifloxaci Comparator Moxifloxacin Comparator Moxifloxacin Comparator

n (n=8,822) (n=8,643) (n=1,889) (n=1,856) (n=588) (n=571)
Adverse events 3782 3711 1202 1138 305 253
Adverse drug
2211 2026 455 439 85 83
reactions
Serious adverse
318 316 315 282 74 54
events
Serious adverse
47 48 53 46 9 7
drug reactions
Discontinuation
366 337 144 131 16 9
s due to AE
Discontinuation
261 251 74 63 4 4
s due to ADR
Deaths due to
28 36 66 54 21 13
AE
Deaths due to
3 4 3 3 0 1
ADR
*PO: *
Moxifloxacin: pneumonia = 2, Clostridium difficile colitis and GI haemorrhage = 1; Comparator: acute renal failure, septicaemia and respiratory arrest, viral
pneumonia, confusional state.
IV/PO: Moxifloxacin: acute renal failure and coagulopathy, multi-organ failure, ventricular tachycardia; Comparator: cardio-respiratory arrest = 2, acute myocardial
infarction and respiratory failure.
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IV: Comparator: multi-organ failure
Tulkens et al. ECCMID 2012 [Poster P2210] L.SA.MKT.04.2017.0137

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Avalox® in AECB
AVALOX® KEY CLINICAL TRIALS IN
AECB
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Moxifloxacin clinical trials in AECB
EFEMAP
IMPAC
MOSAIC study
MOSAIC study post hoc analysis (MOSAIC II)
GIANT
Moxifloxacin vs macrolides
MAESTRAL
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EFEMAP study
Estudio FarmacoEconómico de Moxifloxicino en Atención Primaria
Objectives
• To define the effect of three antimicrobial regimens on the
clinical course of COPD and AECB in primary care,
principally related to the speed of onset of action
Design
• Observational, non-randomized, open-label 30 day study
carried out in 252 primary care practices in Spain
• Patients diagnosed with COPD or AECB received one of the
following regimens:
– Moxifloxacin 400mg PO q.d. for 5 days (n=575)
– Amoxicillin/clavulanate 500mg/125mg t.i.d. for 10 days (n=460)
– Clarithromycin 500mg b.i.d. for 10 days (n=421)
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Miravitlles et al. Clin Drug Invest 2004; 24: 63–72 L.SA.MKT.04.2017.0137

53
Proportion of patients achieving
clinical cure*
Moxifloxacin (n=575) Amoxicillin/clavulanate (n=460) Clarithromycin (n=421)
p<0.001
Patients with clinical cure (%)
80 p<0.001
70 68 69 68
p<0.001 66 65
60
50
p<0.001
40
27 30
20
20
10
6
0
3 5 10 30
Day of treatment
*Clinical cure=remission of the three cardinal symptoms of exacerbation (increased expectoration, change in sputum purulence,
increase dyspnoea)
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54
Days to resolution of clinical
signs/symptoms
Moxifloxacin (n=575) Amoxicillin/clavulanate (n=460) Clarithromycin (n=421)

p<0.05
p<0.05
Mean no. of days to symptom resolution (%)
p<0.05
p<0.05
6
4.6 4.4 4.6 4.6 4.8 4.9
5 4.2
4.1
3.8 3.8 3.8
4 3.4
3 2.3 2.4
2
2
1
0
o
Volume of Purulence of Dyspnea Fever (>38 C) Cough
expectoration expectoration
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55
EFEMAP study: summary
The time-course of recovery was faster with moxifloxacin

• Cure rates were significantly higher at 3 and 5 days in
moxifloxacin vs amoxicillin/clavulanate and clarithromycin
Moxifloxacin provided rapid resolution of symptoms
• The number of days to reduction in volume of expectoration
and purulence of expectoration was significantly faster than
with amoxicillin/clavulanate or clarithromycin
Clinical cure rates achieved with the three antimicrobial
regimens for COPD and AECB were similar at 10 days
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IMPAC study
Influencia de Moxifloxacino sobre la calidad de vida de los Pacientes
con Agudizaciones de la EPOC
Objectives
• To assess the time to recovery from acute exacerbation of
COPD in patients receiving moxifloxacin and comparators
Design
• Multicenter, 2-year observational study carried out on 441
outpatients with moderate or severe COPD* recruited from
respiratory clinics in Spain
• Year 1: comparators, including amoxicillin/clavulanate
500/125mg/8h, cefuroxime 500mg/12h, clarithromycin
500mg/12h
• Year 2: 1:1 non-randomized allocation of patients
to moxifloxacin 400mg PO for 5 days
or comparator antimicrobials
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*American Thoracic Society stage II or stage III COPD
57
Time to recovery† of acute exacerbations of
COPD with moxifloxacin vs comparators
Moxifloxacin Comparators
p=0.006 p=0.027 p=0.006
6
Mean number of days
with symptoms
5
4
3
2
1
0
All exacerbations Years 1+2 First exacerbation Year 2 All exacerbations Year 2
†
Time to recovery=the number of days required for patients to return to baseline after initiation of antibiotic therapy (secondary
endpoint of the study)
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58
Longitudinal analysis of mean time to
recovery† from acute exacerbation of COPD
p=0.01
Year 1 Year 2
p=0.76
8
Mean number of days
7 ∆–1.9
6 p=0.24
∆–3.1
5
p=0.02
4
3
2
1
0
Year 1: comparator Year 1: comparator
Year 2: moxifloxacin (n=27) Year 2: comparator (n=66)
†
Time to recovery=the number of days required for patients to return to baseline after initiation of antibiotic therapy (secondary
endpoint of the study)
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59
IMPAC study: summary
Moxifloxacin provided significantly faster recovery from

acute exacerbation of COPD in patients with moderate-to-
severe disease acute exacerbations of COPD vs
comparator agents
• ~20% reduction in time to recovery (>1 day)
Faster recovery should result in earlier return to work or
normal activities, as well as social and economic savings
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60
MOSAIC study
Moxifloxacin Oral tablets to Standard oral antibiotics given as first-
line therapy in outpatients with Acute Infective exacerbations of
Chronic bronchitis
Objectives
• To assess the short- and long-term outcomes of oral moxifloxacin
vs comparators in AECB
Design
• Multicenter, multinational, randomized, double-blind study
of 2 treatment arms
Inclusion criteria
• Outpatients 45 years with a history of chronic bronchitis
• Smoking exposure ≥20 packs/year
• History of ≥2 clinician-documented AECB episodes in the last 12 months
• FEV1 <85% of predicted value
Outcomes
• Primary – Clinical success 7–10 days after treatment end
• Secondary – Clinical success rate at the end of treatment, bacteriologic
success 7–10 days after the end of treatment, need for additional antibiotic
therapy and time to next exacerbation
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61
MOSAIC study: trial design
Moxifloxacin 400mg q.d. 5 days (n=354)
ARM 1
Monthly contact Next AECB

STRATIFICATION Phone contact 7–10 days from Month 1 episode
Day 7
Enrolment and after end (after end or
End of of treatment of treatment) Month 9
RANDOMIZATION treatment up to Month 9 (at a maximum)
ARM 2
Screening Post-treatment and follow-up
Treatment
(up to 12 months) (up to 9 months)
Choice of comparator (n=376) STRATIFICATION
left to investigator*
1. No steroids
Amoxicillin 500mg t.i.d. 7 days
or 2. Systemic steroids
Clarithromycin 500mg b.i.d. 7 days 3. Long-term inhaled steroids
or
4. Both systemic and inhaled steroid
Cefuroxime 250mg b.i.d. 7 days
*Cefuroxime axetil, 174 patients; clarithromycin, 114 patients; amoxicillin, 88 patients
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62
Important features of the MOSAIC study
Investigated a cohort of well characterized patients, many with one
or more risk factors predisposing to a poor outcome
Studied patients with chronic bronchitis enrolled when stable
• allowed a baseline to be established from which clinical improvement
and resolution of exacerbation could be determined
Stratified patients before treatment randomization according to their
corticosteroid use
• an important influence on outcome in an inflammatory condition
Compared moxifloxacin with three well-established first-line treatments
(two different drug classes)
• allowed investigators to choose comparator therapy according to medical
practice in their country
Collected data during long-term follow-up up to 9 months
Included assessments of clinical cure (not just clinical success)
and time to next exacerbation
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Wilson et al. CHEST 2004; 125: 953–64
Wilson et al. Thorax 2006; 61: 337–42 L.SA.MKT.04.2017.0137
63
Patient characteristics for prognostic factor
analysis (ITT population)
Comparator
Moxifloxacin
(n=376)
(n=354)
Male gender 68.6% 67.3%
Age, mean (years) 63.8% 62.6%
Years since chronic bronchitis diagnosis, mean 12.2 12.8
FEV1, % predicted
<50 42.1% 42.3%
≥50 57.9% 57.7%
No. AECB in previous year

<4 72.6% 71.8%
≥4 27.4% 28.2%
Smoking history, mean (years) 37.5 37.7
Cardiopulmonary disease Not

present 85.0% 86.2%
Present 15.0% 13.8%
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64
MOSAIC study: clinical efficacy at 7–10 days
post-therapy (ITT population)
Moxifloxacin treatment resulted in superior clinical cure rates

vs comparators
95% CI; –0.7, 9.5 95% CI; –1.4,17.9

95% CI; 1.4,14.9
Patients (%)
† ††
†††
†
Clinical success=clinical cure and improvement combined; sufficient improvement, no alternative antimicrobial therapy required
††
Clinical cure=return to pre-exacerbation status
†††
Clinical success (clinical cure and improvement combined) in patients with bacteriologically confirmed AECB
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65
post-therapy (PP population)
Moxifloxacin (5 days q.d.) resulted in superior clinical cure rates

vs comparators (7 days b.i.d or t.i.d.)
Moxifloxacin (n=274) Comparators (n=298)

95% CI; –3.0, 8.5 95% CI; –7.2,15.4
95% CI; 0.3,15.6
100 87.2 87.3
84.2 83.5
80 69.7
Patients (%)
62.1
60
40
20
0
Clinical success† Clinical cure† † Clinical success in
microbiologically-valid
population†††
†
Clinical success=clinical cure and improvement combined; sufficient improvement, no alternative antimicrobial therapy required
††
†††
Clinical success (clinical cure and improvement combined) in patients with bacteriologically confirmed AECB
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66
post-therapy by degree of airway obstruction
Moxifloxacin (5 days q.d.) provided superior clinical cure rates vs comparators

(7 days b.i.d or t.i.d.) in patients with FEV1 ≥50% (ITT population)
p=0.11
p=0.37 p=0.03
p=0.27
Patients (%)
1 1 –– 1 1 ––
† ††
Clinical success Clinical cure
†
Clinical success=sufficient improvement, no alternative antimicrobial therapy required
††
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67
MOSAIC study: bacteriologic efficacy at
7–10 days post-therapy
In the microbiologically-valid population, bacterial eradication with moxifloxacin (5
days q.d.) was superior to comparator (7 days b.i.d or t.i.d.) (91.5% vs 81.0%,
95% CI: 0.4, 22.1)
Moxifloxacin Comparators
95% CI; 0.4,22.1
95% CI; –1.8,20.4
100 91.5
76.8 81
80
Patients (%)
67.5
60
40
20
0
Bacteriologic success (ITT Bacteriologic success
population) (microbiologically-valid population)
Bacteriologic success=eradication or presumed eradication
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68
MOSAIC: requirement for additional
antibiotic therapy (PP population)
In both the PP population (p=0.045) and the ITT population (p=0.006) there was a
significantly lower frequency of additional antibiotic therapy with moxifloxacin
(5 days q.d.) than with comparator (7 days b.i.d or t.i.d.)
p=0.045
20
Percent of patients
15.1
15
9.5
10
0
Requirement for additional antibiotic
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69
Longer time to next exacerbation with
moxifloxacin vs standard therapy
During follow-up of the ITT population (excluding patients receiving further antibiotic for the
current exacerbation) moxifloxacin (5 days q.d.) significantly increased the time to next
AECB vs comparator (7 days b.i.d or t.i.d.) – 132.8 days vs 118.0 days, p=0.03

p=0.03
140 132.8
118
120
100
Days
80
60
40
20
0
Mean number of days to new AECB*
Reporting period=from randomization up to new AECB occurring within the 9-month follow-up (ITT population)
*
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70
MOSAIC: moxifloxacin significantly
increases time to composite event*
Overall: moxifloxacin, 5 days q.d., was significantly superior to

comparator, 7 days b.i.d or t.i.d., (p=0.03 for up to 5 months of
follow-up‡
)
Stratification: exacerbation 6 months prior to randomization
Moxifloxacin
100
90 Comparator
Patients not experiencing
composite event (%)
80
70
60
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10
Reporting period: from randomization up to 9 months post-study therapy

‡
Log rank test showed statistically significant superiority of moxifloxacin for up to 5 months post-treatment
*Composite event: treatment failure and/or new exacerbation and/or any further antibiotic treatment
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71
MOSAIC: moxifloxacin significantly increases time
to treatment failure composite event*
Stratification – patients with an exacerbation 6 months prior to

randomization (n=320): moxifloxacin is superior (p=0.01) to
comparator
Stratification: exacerbation 6 months prior to randomization

Moxifloxacin
100
90 Comparator
composite event (%)
80
70
60
50
40 p=0.01
30
20
10
0
1 2 3 4 5 6 7 8 9 10
Time since randomization (months)

*Composite event: treatment failure and/or new exacerbation and/or any further antibiotic
treatment
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Adapted from: Wilson R et al. CHEST 2004; 125: 953-964 L.SA.MKT.04.2017.0137

72
MOSAIC study: most common
drug-related adverse events (≥2 patient)
Moxifloxacin (N=354) Comparators (N=376)
n (%) n (%)
Any drug-related adverse
25 (7.1) 18 (4.8)
event
Abdominal pain 3 (0.8) 2 (0.5)
Headache 4 (1.1) 3 (0.8)
Diarrhea 9 (2.5) 3 (0.8)
Gastritis 2 (0.6) –
Nausea 3 (0.8) 2 (0.5)
Dizziness 3 (0.8) –
Nervousness 2 (0.6) –
Taste perversion – 3 (0.8)
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73
MOSAIC study: summary
Moxifloxacin 5 day q.d. treatment was:
• Equivalent to 7 day b.i.d or t.i.d. treatment with standard comparators for
clinical success at 7–10 days post-therapy (primary endpoint)
• Superior to standard therapy for:
– clinical cure (ITT population, PP population and patients with
FEV1 ≥50%)
– bacteriologic eradication
– requirement for additional antibiotic therapy
– time to next exacerbation
Long-term follow-up showed that moxifloxacin treatment

significantly delayed the onset of a composite failure event
vs comparators
• For the first 5 months of follow-up in the ITT population
• For the complete 9 months of follow-up for patients who had experienced an
exacerbation 6 months prior to randomization
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74
MOSAIC study post hoc analysis: objectives
To identify prognostic factors for short- and long-term

treatment outcomes in AECB and their value for clinical
research
To evaluate:
• whether moxifloxacin has a positive effect on the short-
and long-term endpoints relative to the comparator treatment
• which other demographic variables related to AECB have
an effect on these endpoints (univariate analysis)
• whether the beneficial effect of moxifloxacin is still evident
after the possible influence of other factors has been taken
into account (multivariate analysis)
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75
MOSAIC post hoc analysis: short-term
endpoints
Clinical response 7–10 days after the end of treatment

• Clinical cure: complete return to pre-exacerbation status
• Clinical success: sufficient improvement in signs and
symptoms so that no further antimicrobial therapy is required
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76
MOSAIC post hoc analysis: factors selected
for exploratory analyses
Age
Chronic bronchitis severity
• <65
AECBor ≥65
number
years
in previous year: 2–3 or ≥4
• FEV
Body 1 – <50%
mass indexor ≥50% of predicted at enrolment
• ≤30 kg/m
Duration of 2chronic bronchitis
or >30 kg/m 2
• <10 or ≥10 years

Sex
• male
Time or female
since previous AECB
• <6 orsmoking
Current ≥6 monthsstatus
• smoker
Use or not smoker
of concomitant medications (yes or no)
• steroids
Alcohol consumption
• bronchodilators
• yes or no
Presence or absence of comorbidities
• diabetes mellitus
• cardiopulmonary disease
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77
MOSAIC II analysis: significant prognostic
factors for clinical cure in AECB
Univariate analysis
Clinical cure
Factor A vs Factor B
Factor A Factor B p value*
Moxifloxacin vs comparator treatment 71% 63% p=0.020
No steroid use vs steroid use 72% 63% p=0.014
No cardiopulmonary disease vs
69% 52% p≤0.001
cardiopulmonary disease
FEV1 ≥50% vs <50% at enrolment 74% 56% p≤0.001
2–3 AECBs vs ≥4 AECBs in previous year 69% 60% p=0.019
>6 months vs ≤6 months since previous

70% 63% p=0.035
AECB
*2 test
The prognostic factors BMI at enrolment, age, sex, smoking status, alcohol intake, duration of chronic bronchitis, diabetes,
and acute bronchodilator use showed no statistical difference for clinical cure
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78
Prognostic factors for clinical cure
Univariate analysis identified several factors that

individually were significant predictors of clinical cure
evaluated 7–10 days after the end of treatment:
• treatment with moxifloxacin
• steroid use
• presence of cardiopulmonary disease
• FEV1 <50% at enrolment
• 4 AECBs in the previous year
• >6 months since previous AECB
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79
MOSAIC post hoc analysis: moxifloxacin is
associated with superior clinical cure in AECB
Multivariate analysis
• Treatment with moxifloxacin was independently associated with
a higher clinical cure rate than comparator treatments
Comparator vs moxifloxacin
≥50% vs <50%
1.5
NO vs YES
2–3 vs ≥4
Odds ratio
0.5
0
Treatment Cardiopulmonary FEV1 Previous AECBs
disease
Cox regression model

Concurrent cardiopulmonary disease, FEV1 <50% of predicted and 4 AECBs in the previous year had a detrimental effect on
this short-term outcome
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80
MOSAIC post hoc analysis: prognostic
factors for clinical success in AECB
Univariate analysis
Clinical cure
No steroid use vs steroid use 88% 83% p=0.043
No cardiopulmonary disease vs
87% 75% p=0.002
cardiopulmonary disease
FEV1 ≥50% vs <50% at enrolment 88% 81% p=0.006
No acute use of bronchodilators vs acute

87% 79% p=0.028
use of bronchodilators
Moxifloxacin vs comparator treatment 88% 83% p=0.063
2–3 AECBs vs ≥4 AECBs in previous year 87% 81% p=0.054
*2 test
The prognostic factors time elapsed from previous AECB, BMI at enrolment, age, sex, smoking status, alcohol intake, duration
of chronic bronchitis and diabetes showed no statistical difference for clinical success.
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81
MOSAIC post hoc analysis: moxifloxacin is
associated with superior clinical success in AECB
Moxifloxacin was independently associated with a significantly
higher clinical success rate than comparator treatments
2.5
NO vs YES
NO vs YES
Odds ratio
1.5
0.5
0
Treatment Cardiopulmonary Bronchodilator use
disease
Concurrent cardiopulmonary disease (odds ratio 0.41, 95% CI 0.246–0.683, p<0.001) and use of acute bronchodilators (odds
ratio 0.497, 95% CI 0.296–0.835, p=0.008) had a negative effect on this short-term outcome
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82
Short-term outcomes from MOSAIC post hoc
analysis
Moxifloxacin is significantly more effective than the three

first-line treatments in terms of:
• clinical cure (univariate and multivariate analyses)
• clinical success (multivariate analyses)
Clinical cure rate was negatively influenced by:
• comorbid cardiopulmonary disease
• FEV1 <50% at enrolment
• a history of 4 AECBs in the previous year
Poorer clinical success was predicted by:
• comorbid cardiopulmonary disease
• use of acute bronchodilators
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83
MOSAIC post hoc analysis: long-term
outcome
Composite event
• Time to treatment failure, occurrence of new AECB
or need for antibiotic use for new AECB during up to 9
months of follow-up
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84
MOSAIC post hoc analysis: significant
prognostic factors for a composite event
Univariate analysis
Factors that had a significant influence on the occurrence of the
composite event were 4 AECB in the previous year and use of
acute bronchodilators
Occurrence of composite
event
<65 years vs ≥65 years 60% 71% p=0.072
2–3 AECBs vs ≥4 AECBs in previous year 58% 75% p≤0.001
No bronchodilator use vs bronchodilator

60% 79% p≤0.001
use
*2 test
The prognostic factors treatment, steroid use, cardiopulmonary disease, FEV1 at enrolment, time elapsed from previous AECB,
BMI at enrolment, age, sex, smoking status, alcohol intake, duration of chronic bronchitis, and diabetes showed no statistical
L.EG.MKT.06.2017.0095
difference for occurrence of composite event.

85
MOSAIC post hoc analysis: factors predicting an
early composite event occurrence
Moxifloxacin was significantly more effective long-term than comparator treatments, in terms
of occurrence of the composite event (p=0.031)
Significant factors with a detrimental effect were age 65 years (p=0.039), FEV1 <50% of
predicted at enrolment (p=0.014), 4 AECBs in previous year (p<0.001) and acute
bronchodilator use (p=0.001)
2
<65 years vs ≥65 years
≥50% vs <50%
1.5
NO vs YES
2–3 vs ≥4
Hazard ratio
0.5
0
Treatment Age FEV1 at enrolment Previous AECBs Bronchodilator
use
There was no interaction between treatment and any of the individual factors (age, p=0.080; FEV1, p=0.505; number of previous
AECBs, p=0.247; acute bronchodilators, p=0.752)
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86
MOSAIC post hoc analysis: time to first
composite event in patients ≥65 years
During the 9 month follow up, moxifloxacin treated patients

experienced significantly fewer composite events (p=0.015)
Moxifloxacin
100
90 Comparator
composite event (%)
80
70 n=344
60
50
40 p=0.015
30
20
10
0
1 2 3 4 5 6 7 8 9 10
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87
MOSAIC post hoc analysis: time to first
composite event in patients with ≥4 AECBs
Moxifloxacin was significantly more effective than comparator in

extending the time to occurrence of the composite event in
patients with 4 AECBs in the previous year (p=0.047)
Moxifloxacin
100
90 Comparator
composite event (%)
80
70 n=203
60
50
40 p=0.047
30
20
10
0
1 2 3 4 5 6 7 8 9 10
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88
Long-term outcomes MOSAIC post hoc
analysis
Moxifloxacin is significantly more effective than

comparators in terms of the long-term outcome of AECB
• The beneficial effect was primarily seen in patients ≥65 years
• Moxifloxacin also had a significant effect in patients with ≥4
AECBs in previous year
Factors having a detrimental effect on long-term outcome
of AECB:
• Age ≥65 years
• FEV1 <50% predicted
• ≥4 AECBs in previous year
• Acute bronchodilator use
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89
MOSAIC post hoc analysis: overall summary
The overall beneficial effect of moxifloxacin on clinical

resolution in MOSAIC was confirmed in the MOSAIC post
hoc analysis when prognostic factors were taken into
account
Number of AECBs in the past 12 months and baseline
FEV1 level were confirmed to be potent prognostic factors
in short and long-term treatment outcomes of AECB
Comorbid cardiopulmonary disease negatively affected
short-term outcome
Acute use of bronchodilators flagged a population at higher
risk for early next composite event
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90
MOSAIC post hoc analysis: conclusions
Despite selection of a homogeneous population of chronic

bronchitis patients, between-group differences can still be
confounded by underlying factors related to medical
history, severity of disease and use of concomitant
medication
Design of future clinical trials should take these factors into
account to increase the sensitivity of studies to detect
differences between antibiotic regimens
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91
MOSAIC: overall summary
Moxifloxacin 5 day q.d. treatment was:
• Equivalent to 7 day b.i.d or t.i.d. treatment with standard
comparators for clinical success at 7–10 days post-therapy (primary
endpoint)
• Superior to standard therapy for:
– clinical cure (ITT population, PP population and patients with
FEV1 ≥50%)
– bacteriologic eradication
– requirement for additional antibiotic therapy
– time to next exacerbation
Long-term follow-up showed that moxifloxacin treatment
significantly delayed the onset of a composite failure event vs
comparators
• For the first 5 months of follow-up in the ITT population
• For the complete 9 months of follow-up for patients who had
experienced an exacerbation 6 months prior to randomization
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92
Targeting patients at risk of treatment failure
Moxifloxacin in AECBs Trial (MAESTRAL)
There is a clear unmet need to establish antibiotic

superiority in AECB
• Particularly for commonly used antibiotics
• In patients at high risk of treatment failure
MOSAIC demonstrated moxifloxacin was superior to
comparator antibiotics for:
• Clinical cure
• Bacterial eradication
MAESTRAL builds on MOSAIC but it…
• Is powered to demonstrate antibiotic superiority
• Selects chronic bronchitis patients with moderate-to-severe
COPD
• Assesses clinical failure at 8 weeks post-treatment
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Wilson et al. Int J COPD 2011; 6:373-383 93
MAESTRAL: Objectives and design
Objective
• To compare the efficacy of a 5-day course of moxifloxacin
with that of a 7-day course of amoxicillin/clavulanic acid in
treating outpatients with AECOPD who are at high risk of
treatment failure
Study design
• MAESTRAL is a prospective, multinational, multicentre,
randomised, double blind, double dummy controlled study in
30 countries and 150 sites
• Patients received moxifloxacin 400 mg o.d. for 5 days or
amoxicillin/clavulanic acid 825 mg/125 mg for 7 days
• Patients were stratified according to steroid dosing for the
current exacerbation (short course or systemic)
• Analysis population = 1056
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Wilson et al. Int J COPD 2011; 6:373-383
Wilson R et al., Eur Resp J 2012; 40: 17-27 L.SA.MKT.04.2017.0137
94
MAESTRAL: design
Enrolled
n=1492
Not randomised n=120
Stratified by steroid use
Oral corticosteroid use No oral corticosteroid use
Moxifloxaci Randomised Randomised

Amoxicillin/
n n=686 n=686 clavulanic acid
400 mg 825 mg / 125 mg
5 days End of Treatment 7 days
Day 13 ± 1
4 weeks post-therapy
Day 35 ± 3
PRIMARY ENDPOINT
8 weeks post-therapy
Day 63 ± 3
L.EG.MKT.06.2017.0095 Primary endpoint: clinical failure at 8 weeks post-therapy - patient’s symptoms have
not improved or have worsened such that additional or alternate systemic
Wilson et al. Int J COPD 2011; 6:373-383 antimicrobial and/or corticosteroid therapy is required any time up to EOT
Wilson R et al., Eur Resp J 2012; 40: 17-27 L.SA.MKT.04.2017.0137
95
Demographics: patients at high risk recruited
(ITT population)
Avelox Amoxicillin/ clavulanic acid
(N=538) (N=518)
Male sex, n (%) 425 (79) 408 (79)
Age (years), mean ± SD 69.6 ± 6.8 69.3 ± 6.3

Range 59 – 93 60 – 88
≥65 years, n (%) 389 (72) 378 (73)
Systemic corticosteroid use, n (%) 182 (34) 189 (36)
FEV1 (mL), mean ± SD 982 ± 370 970 ± 352
FEV1, % predicted, mean ± SD 39.28 ± 11.62 39.18 ± 11.36

FEV1<30%, n (%) 139 (26) 129 (25)
All comorbidities 417 (78) 419 (81)
Exacerbations in previous year

Mean ± SD 2.5 ± 1.1 2.5 ± 1.1
≥3 exacerbations 165 (31) 152 (29)
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Wilson R et al., Eur Resp J 2012; 40: 17-27 96
Moxifloxacin was superior with confirmed
bacterial exacerbations
Populations Avelox Amoxicillin/clavulanic acid P value
n/N (%) n/N (%)
ITT with pathogens 62/327 (19.0) 85/335 (25.3) 0.016
PP with pathogens 50/260 (19.2) 68/261 (26.1) 0.030
ITT with pathogens PP with pathogens
Moxifloxacin Amoxicillin/clavulanate Moxifloxacin Amoxicillin/clavulanate

30 30
25 25
Clinical failure (% patients)

20 20
15 15
10 10
P=0.016 P=0.030
5 5
0 0
During treatment EOT 4 weeks 8 weeks During EOT 4 weeks 8 weeks
post-therapy post-therapy treatment post-therapy post-therapy
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Wilson R et al., Eur Resp J 2012; 40: 17-27
Wilson et al. ERS 2011. Oral presentation 195 L.SA.MKT.04.2017.0137
97
Time to clinical failure/relapse was significantly longer for
AECOPD patients with confirmed bacterial exacerbations
treated with moxifloxacin vs amoxicillin/clavulanic acid
ailure (valid for safety / ITT) Figure: Time to clinical failure (valid for safety / ITT)
ITT population ITT with pathogens population
cal Failure Probability of Clinical Failure
Accumulating probability of clinical failure

Accumulating probability of clinical failure
0.40
0.40 0.40
0.40
0.35
0.35 0.35
0.35
0.30
0.30 0.30
0.30
0.25
0.25 P=0.688 0.25
0.25 P=0.015
0.20
0.20 0.20
0.20
0.15
0.15 0.15
0.15
0.10
0.10 0.10
0.10
Avelox Avelox
0.05
0.05 Amoxicillin/clavulanic acid
0.05
0.05 Amoxicillin/clavulanic acid
0.00
0.00 0.00
0.00
00 10
10 20
20 30
30 40
40 50
50 60
60 70 00 10
10 20
20 30
30 40
40 50
50 60
60 70
4 weeks post
8 weeks post
End of therapy
Start of therapy
therapy
therapy
Start of therapy
End of therapy
4 weeks post
therapy
8 weeks post
therapy
Study days Study days
Study Day Study Day
atment group Moxifloxacin Co-Amoxiclav Treatment group Moxifloxacin Co-Amoxiclav
Length of therapy
/patdb/projects /128039/11980/stat/prod/pgms/tf-pubs-newtimetofail.s as mobcv 24MAY2012 13:11 Global Biostatistics: /by-sasp/patdb/projects /128039/11980/stat/prod/pgms/tf-pubs-newtimetofail-sforg.sas mobcv 24MAY2012 13:11
1
Time to clinical failure or relapse defined as the relative day (relative to start of
Avelox® study drug treatment) at which the first antibiotic or steroid is given to treat a
clinical failure or relapse
Amoxicillin/clavulanic acid Patients who are not clinical failures or relapses treated as censored observations
at their last visit
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Anzueto A et al. ALAT 2012 Poster ID 71 L.SA.MKT.04.2017.0137

98
Clinical failure rates1 at 8 weeks post-
therapy by systemic corticosteroid use
Moxifloxacin is superior to amoxicillin/clavulanic acid in bacteriologically

positive patients
95% CI 95% CI
–20.8, 2.1 –25.8, 0.21
P=0.110 P=0.055 Moxifloxacin
40 Amoxicillin/clavulanic acid
33.6 34.4
35
95% CI 95% CI
30 –13.9, 0.54 –13.6, 3.2

27.0
P=0.072 P=0.266
24.5
25 21.4
20.8
20 16.3
13.9
15
10
5
34/126 40/119 23/94 32/93 28/201 45/216 27/166 36/168
0
ITT PP ITT PP
With corticosteroid use Without corticosteroid use
1
Failures and relapses are included in the failure rate calculation
95% CI stratified by region
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Characteristics of microbiologically positive
patients
Patients who were microbiologically positive were significantly more likely to have
an FEV1 ≥30%, be ≥75 years of age, not have received antibiotics in the previous 3
months and have cardiopulmonary disease
Percentage of patients (%)
90
P=0.021
80
P=0.021 ITT with pathogens
70
(n=662)
60 ITT no pathogens
50 (n=690)
40
30 P=0.0003
20 P=0.011
10
0
FEV ₁≥30% No previous Age Cardiopulmonary
antibiotic use ≥75 years disease
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Eradication rates – bacteriological efficacy
Moxifloxacin has significantly superior bacteriological efficacy to

amoxicillin/clavulanic acid (p=0.0004). ITT with pathogens group.
80 P=0.0004
70 P=0.088
N.S.
60
Eradication rates (%)
50
Moxifloxacin
40
Amoxicillin/
30 clavulanic acid
20
10
0
Overall 4 weeks 8 weeks
post therapy post therapy
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Moxifloxacin showed a sustained advantage against
H. influenzae vs amoxicillin/clavulanic acid
100
92.3
89.2
Bacteriological success (% patients)
80.0
80 85.3 72.3
60 66.7 65.3
56.0
40
Avelox
Amoxicillin/clavulanic acid
20
0
During therapy End of therapy 4 weeks 8 weeks
post-therapy post-therapy
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Eradication rates1,2 at EOT by most common
organisms
Moxifloxacin shows an advantage over amoxicillin/clavulanic

acid for H. influenzae
Organism Avelox Amoxicillin/clavulanic acid

n/N (%) n/N (%)
H. influenzae 58/65 (89.2) 50/75 (66.7)
P. aeruginosa 31/57 (54.5) 32/54 (59.3)
S. pneumoniae 44/49 (89.8) 33/38 (86.8)
M. catarrhalis 30/36 (83.3) 37/43 (86.0)
S. aureus 20/23 (87.0) 16/20 (80.0)
ITT with pathogens
1
Include eradication and presumed eradication
2
Indeterminates counted as non-successes
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Bacteriological response1 at EOT correlated to
clinical cure2 at week 8 post-therapy
(ITT with pathogens population)
Patients treated with moxifloxacin demonstrated a higher clinical
cure rate than those treated with amoxicillin/clavulanic acid
Confirmed eradication at EOT
100 P=0.0014 P=0.003

Confirmed persistence/superinfection at EOT
Clinical cure at 8 weeks post -therapy
P=0.150
80.4
80 76.8
72.4
62.1 61.1 63.0
60
40
20
149/194 123/198 86/107 55/90 63/87 68/108

0
Overall Moxifloxacin Amoxicillin/clavulanic acid
1
Confirmed eradication vs confirmed persistence/ superinfection;
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2
Clinical cure or continued clinical cure
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Overview of treatment-emergent adverse
events through week 8 post-therapy
(ITT/safety population)
Event Avelox Amoxicillin/clavulanic acid

MedDRA Preferred Term (version 13.1) N=677 N=675
n (%) n (%)
Any adverse event (AE) 220 (32.5) 218 (32.3)
Drug-related AE 53 (7.8) 41 (6.1)
Serious AE (SAE) 46 (6.8) 51 (7.6)
Serious drug-related AE 4 (0.6) 2 (0.3)
Premature discontinuation due to drug- 12 (1.8) 9 (1.3)

related AE
Premature discontinuation due to SAE 7 (1.0) 3 (0.4)
AE-related deaths 3 (0.4) 3 (0.4)
P>0.05 for all categories
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MAESTRAL Study Results Summary – 1/2
Avelox was equivalent to amoxicillin/clavulanic acid in the treatment of

acute exacerbations in outpatients with moderate-to-severe COPD.
Avelox was superior to amoxicillin/clavulanic acid in terms of clinical

cure at 8 weeks post-therapy for patients with confirmed bacterial
exacerbations at baseline.
Patients with confirmed bacterial exacerbations who received

concomitant steroids generally had more severe disease and had a
higher clinical failure rate than those who were not on steroids.
In this sicker population of patients with confirmed bacterial

exacerbations who received steroids, there was a trend for lower clinical
failure rates with Avelox vs amoxicillin/clavulanic acid.
L.EG.MKT.06.2017.0095
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MAESTRAL Study Results Summary – 2/2
The overall eradication rate at end-of-therapy was higher with Avelox

than with amoxicillin/clavulanic acid, mainly explained by a better
efficacy against H. influenzae.
There was a clear correlation between bacteriological response at end-

of-therapy and clinical cure at 8 weeks post-therapy – overall and for the
Avelox group.
Both treatments were well-tolerated and had similar safety profiles.
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GIANT study
Greatest International ANti-infective Trial
Objective
• To evaluate the impact of AECB on the patient and the
community as well as the effect and safety of treatment with
moxifloxacin tablets in clinical practice
Study design
• Prospective, open-label, non-interventional, non-controlled
multicenter study in 35 countries in outpatients with AECB*
receiving oral moxifloxacin 400mg
– Analysis population 43,435 patients (9225 in Europe)
– Therapy duration at the treating physician’s discretion
– Documentation comprised epidemiologic data and the clinical
course of the current AECB treated with moxifloxacin
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*Diagnosis of AECB was independent of duration and severity of underlying chronic bronchitis
Miravitlles et al. Ther Adv Respir Dis 2009; 3: 267-277 L.SA.MKT.04.2017.0137

109
GIANT study: aims
Provide a global perspective on the epidemiology

of chronic bronchitis
Create a therapeutic profile of the AECB patient across
a wide range of populations and situations
Evaluate the impact and effectiveness of antibiotics
in providing AECB patients with rapid symptom relief
and overall effective management of the condition
Give patients and physicians greater insight into
how antibiotics can best be used to treat AECB
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110
GIANT trial design
Presentation of
Initial examination,
AECB Moxifloxacin prescribed
diagnosis
symptoms
Enrolment
Patient case report
Patient questionnaire
Observation period
Patient follow up
assessment
(1 / 2nd follow up)
st
Long-term follow up
(6, 12 months)
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111
Duration of chronic bronchitis
Final analysis of European Data n=9225

<10 years
80
>10 years
70
60
50
40
30
20
10
0
e ria tia y ry s d ia d
rop s t a an g a nd lan e n la
n
u u ro m
un
lr a o ov
r
E A C er H h e P
S l itz
e
G
et Sw
N
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112
FEV1 values of the patients enrolled
Only 35% (n=3242) had an FEV1 measurement at enrollment.

Patients with FEV1 measurements typically had chronic bronchitis
for >10 years (39.0% vs 25.1%, p<0.001
2.5
1.5
Mean FEV1
0.5
0
All patients ≥35 years to ≤65 ≥65 years
years
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113
Concomitant diseases by system organ
classes (categories with >5 of patients)
Final analysis of European patients (n=9225)
100
90
80
70
60
50
40
30
20
10
0
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114
AECB number, physician visits and hospitalizations
due to AECB/patient in the past 12 months

No. of exacerbations
6 No. physician visits
No. hospitalisations
5
3
Mean
0
e ria tia y ry s d ia d
rop s t a an g a nd lan e n la
n
u u ro m
un
lr a o ov
r
E A C er H h e P
S l itz
e
G
et Sw
N
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115
AECB number, physician visits and hospitalizations
due to AECB/patient in the past 12 months by
Anthonisen criteria
Anthonisen criteria 1 and 2 exacerbations were associated with
significantly greater impact than Anthonisen 3 exacerbations
(p<0.001)
5
4.5
4
3.5 AECB
3 Physician visits
Mean
2.5 Hospitalisation
2
1.5
1
0.5
0
Anthonisen 1+2 Anthonisen 3

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116
Prior AECB vs current AECB treated
with moxifloxacin
Prior AECB AECB treated with moxifloxacin
8.3
Mean number of days/nights
6
5.4 5.2
5
4
3.3
3
0
Series1
Days with impact Nights with sleep
on daily life disturbance
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117
Physicians’ final assessment of moxifloxacin
efficacy and tolerability
Patients (%)
0.6
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118
GIANT study: data summary
GIANT results confirm the good efficacy and safety of

moxifloxacin therapy in AECB
The overall safety profile of moxifloxacin was good,
as already shown in previous post-marketing
surveillance studies
The current AECB episode had less impact on the daily
life activities of moxifloxacin-treated patients than the
last episode
• Number of nights with sleep disturbance was also reduced
More than 94% of physicians rated moxifloxacin as ‘very
good’ or ‘good’ with respect to efficacy and tolerability and
98% were ‘satisfied’ or ‘very satisfied’ with the
effectiveness of moxifloxacin
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119
Moxifloxacin vs macrolides: current
treatment of AECB in general practice
Objective
• To compare current treatment of AECB using moxifloxacin or
macrolides in normal clinical practice in terms of symptom
relief, time to improvement/cure and overall efficacy and
tolerability
Study design
• Prospective, open-label, non-interventional, multicenter study
in outpatients with AECB receiving macrolide therapy for their

last episode
• The current AECB was treated with oral moxifloxacin or oral
macrolide (azithromycin, clarithromycin or roxithromycin)
– Therapy dose and duration at the treating physician’s discretion
– Documentation comprized epidemiologic data, time until
improvement and recovery, global efficacy, tolerability
and patient satisfaction
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120
Moxifloxacin treatment gave better symptom
relief vs macrolides
Percentages of moxifloxacin- and macrolide-treated patients in good condition or without
symptoms at last follow-up. Data are presented as percentages of the whole population
(moxifloxacin n=904; macrolides n=846)
Moxifloxacin (n=904) Macrolides (n=846)

p<0.0001
p<0.0001
96.6 98.9 97.9 p<0.0002
100 91.2
81.4
80 69
67.6 p<0.0001
Patients (%)
60.2
60
42.5
40 33.1
20
0
Patient No fever No purulent No dyspnea No cough
condition sputum
good
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121
Moxifloxacin showed superior overall
treatment efficacy vs macrolides
Moxifloxacin (n=904) Macrolides (n=846)
100 96.1
80
67.5
Patients (%)
60
40
25.3
20
6.9
2.5 0.9
0
Very good/good Sufficient Insufficient
Mean time to improvement/cure: moxifloxacin 3.2 days/6.2 days vs macrolides 4.4 days/7.5
days (p<0.0001)
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Schaberg et al. Clin Drug Invest 2006; 26: 733–44 122
Moxifloxacin vs macrolides: summary
Comparison of moxifloxacin and macrolide therapy

for AECB for the first time in real-life treatment conditions
showed:
• Superior efficacy of moxifloxacin vs macrolides
– Faster symptom relief
– Higher recovery rates
• Moxifloxacin and macrolides had comparable safety profiles
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123
Avalox® in AECB
AVALOX® HEALTH ECONOMICS DATA
IN AECB
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Distribution of costs of AECB
Emergency
Clinic visit New clinic
7%
5% Failure visit 1%
63%
Initial drugs
14% Failure
costs
Add-on drugs
Hospitalization
18%
92%
Average Cost to treat AECB without relapse = $58.70

Average cost to treat AECB with initial treatment failure = $477.50
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125
AECB: cost of treatment failure
Cost of treating AECB is markedly increased by treatment

failures particularly when patients are hospitalized
following relapse
• Average cost of treating AECB in patients with chronic
bronchitis in Spain = $159
• Average cost of treating AECB in those patients who did not
relapse = $58
• Hospitalization of the 3.4% of patients with treatment failure
accounted for 58% of the total cost of AECB
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126
Association between exacerbations
frequency and risk of treatment failure
n=107
Patients with at least one failure (%)
100 100 100 100

100
80
60
44
38
40
24
20
6
0
1 2 3 4 5 6 7 8
Number of exacerbations in a 24-month period
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127
AECB causes absenteeism and decreases
productivity
AECB causes considerable levels of absenteeism and decreased work
productivity
Patients receiving moxifloxacin reported significantly higher productivity
at work than those taking levofloxacin (70% vs 50%, p=0.03)
Moxifloxacin Levofloxacin
Hours missed from work due to illness (mean ± SD):

Between visits 1 and 2
5.2 ± 9.8 7.6 ± 12.9
Between visits 2 and 3
5.2 ± 10.2 5.6 ± 12.9
Median lost productivity while at work:

Between visits 1 and 2 3.0 5.0
Mean total work hours available:

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128
Effective AECB therapy reduces
healthcare costs
Exacerbations of chronic bronchitis and COPD are costly:1

• Costs derive primarily from therapeutic failures, particularly
those that result in hospitalization
– 58% of total costs
Direct plus indirect health-care costs expended on COPD
have been reported as follows:2
• European Union – €38.6 billion2
• USA (2002) – US$ 32.1 billion3
• Sweden (1999) – US$ 871 million ($1,284 per capita)4
• Netherlands (1993) – US$ 876 per patient with COPD5
Minimizing treatment failures and subsequent
hospitalizations can:6
• Reduce costs
• Contain the spread of antimicrobial resistance
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1) Miravitlles et al. CHEST 2002; 121: 1449–55; 2) Global Initiative for Chronic Obstructive Lung Disease, 2011; http://www.goldcopd.com
3) NIH/NHLBI 2002. Morbidity and mortality: 2002 Chart book on cardiovascular, lung, and blood diseases.
http://www.nhlbi.nih.gov/resources/docs/02_chtbk.pdf ; 4) Jansson et al. CHEST 2002; 122: 1994–2002
5) Rutten-Van Mölken et al. Respir Med 1999; 93: 779–87; 6) Destache. Pharmacotherapy 2002; 22: 12S–17S L.SA.MKT.04.2017.0137
129
Cost savings for oral moxifloxacin vs
intramuscular ceftriaxone
Oral moxifloxacin 400mg q.d. for 5 days (n=241) was

compared with intramuscular ceftriaxone 1g q.d. for 7 days
(n=235) for AECB
Moxifloxacin was associated with:
• Cost savings of 226.57 Euros/patient/episode (INHS) and
448.23 Euros/patient/episode (total cost to society)
• Reduction of 137 days in hospital
• Fewer working days lost
– 90 vs 156 days for ceftriaxone
• Lower costs of tests/procedures
– 149.96 vs 201.62 Euros for ceftriaxone
• Lower drug acquisition costs
– 25.82 vs 104.84 Euros for ceftriaxone
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INHS, Italian National Health Service
Grassi et al. J Chemother 2002; 14: 597–608 L.SA.MKT.04.2017.0137
130
Lower cost of relapse in AECB in
moxifloxacin patients vs comparators
Moxifloxacin 400mg/day PO for 5 days (n=450)
Amoxicillin/clavulanate 500mg/8h PO for 7–10 days (n=338)
Clarithromycin 500mg/12h PO for 7–10 days (n=309)
100
80
Cost (Euros)
60 54.76 57.82
47.01
40
20
0
Series1
Mean cost per patient incurred by treatment failures in the group
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131
Avalox® in AECB
CURRENT AECB GUIDELINES
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Current guidelines for AECB (1)
Australia Australian Lung Foundation and the Thoracic Society of
Australia and New Zealand (2003,2010)1,2
Canada Canadian Thoracic Society and the Canadian Infectious
Disease Society (2004)3
Europe European Respiratory Society and the European Society
for Clinical Microbiology and Infectious Diseases (2011)4
Finland Finnish Medical Society Duodecim (2007)5
France Agence Française de Sécurité Sanitaire des Produits de
Santé (AFSSaPS) (2005)6 and Société de Pathologie Infectieuse
de Langue Française (2006)7
Germany Deutschen Atemwegsliga in der Deutschen
Gesellschaft für Pneumologie (2007)8
Latin America Latin American Thoracic Society (2004)9
1) McKenzie et al. MJA 2003; 178 (Suppl 6): S1–S40; 2) McKenzie D et al. http://www.copdx.org.au/images/stories/about/
The_COPD-X_Plan_Version_2.26_August_2011_2.pdf; [Accessed Jan 2012] 3) Balter et al. Can Respir J 2003; 10 (Suppl B):
3B–32B; 4) Woodhead M et al. Clin Microbiol Infect 2011; 17 (Suppl 6): E1-E59; 5) Finnish Medical Society Evidence Based
L.EG.MKT.06.2017.0095
Medicine, Wiley & Sons 2007; 6) Agence Française de Sécuritié Sanitaire des Produits de Santé,2005; 7) Société de
Pathologie Infectieuse de Langue Française, 2006; 8) Vogelmeier et al. Pneumologie 2007; 61: e1-e40; 9) Miravitlles et al. Arch
Bronchoneumol 2004; 40: 315–25 L.SA.MKT.04.2017.0137
133
Current guidelines for AECB (2)
Scotland Scottish Intercollegiate Guidelines

Network (2002)1
Spain Spanish Society of Respiratory Medicine
and Thoracic Surgery (SEPAR), the Spanish Society
of Chemotherapy (SEQ) and the Spanish Society
of Family and Community Medicine (SEMFyC) (2003)2
Switzerland Swiss Respiratory Society (2002)3
USA American College of Physicians–American Society
of Internal Medicine (ACP–ASIM) and the American
College of Chest Physicians (2001)4
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1) SIGN, 2002
2) Álvarez et al. Rev Esp Quimioterap 2002; 15: 375–85
3) Russi et al. Swiss Med Wkly 2002; 132: 67–78
4) Snow et al. Ann Intern Med 2001; 134: 595–9 L.SA.MKT.04.2017.0137
134
European guidelines
Country Recommendation
For patients Preferred: amoxicillin or tetracycline

treated outside Alternative: macrolide (where macrolide resistance
hospital is low) or levofloxacin or moxifloxacin
For patients
admitted to
Preferred: amoxicillin/clavulanate
hospital without
Alternative: levofloxacin or moxifloxacin
risk factors for P.
aerugiunosa
Europe1
For patients
admitted to
Preferred: ciprofloxacin
hospital with risk
Alternative: piperacillin/tazobactam i.v
factors for P.
aeruginosa
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Woodhead et al. Clin Microbiol Infect 2011; 17(Suppl 6): E1–E59 L.SA.MKT.04.2017.0137
135
Summary of current AECB guidelines (1)
Amoxicillin 500mg t.i.d. for 10 days or doxycycline 150mg q.d. for 10
Finland1
days or co-trimoxazole (dose of trimethoprim 160mg b.i.d. for 10 days)
Stage 0 (simple chronic bronchitis): no antibiotic treatment

Stages I (mild) & II (moderate) without risk factors*: amoxicillin or
macrolide or pristinamycin or telithromycin
Stage III (severe) or with risk factors*: amoxicillin/clavulanate or
France2
second generation cephalosporin (cefuroxime-axetil) or third
generation cephalosporin (cefpodoxime-proxetil, cefotiam,
ceftriaxone), antipneumococcal fluoroquinolone (levofloxacin or
moxifloxacin)
Absence of dyspnea: no antibiotic

Effort-induced dyspnea: if sputum purulent – amoxicillin or second
generation cephalosporin (cefuroxime-axetil) or third generation
cephalosporin (cefpodoxime-proxetil, cefotiam) or macrolide or
France3
pristinamycin or telithromycin
Dyspnea on mild effort or at rest: amoxicillin/clavulanate, injectable
third generation cephalosporin or antipneumococcal fluoroquinolone
(levofloxacin or moxifloxacin)
*Risk factors: >4 exacerbations/year, systemic corticosteroid therapy, comorbidities, symptoms of pneumonia
L.EG.MKT.06.2017.0095
1) Finnish Medical Society Evidence Based Medicine, Wiley & Sons 2007
2) Agence Française de Sécuritié Sanitaire des Produits de Santé, 2005
3) Société de Pathologie Infectieuse de Langue Française, 2006 L.SA.MKT.04.2017.0137
136
Summary of current AECB guidelines (2)
First line: doxycycline or amoxicillin (alternatively, erythromycin or

Australia 1
roxithromycin)
Second line: amoxicillin/clavulanate
First line: aminopenicillin (plus β-lactamase inhibitor),

oral cephalosporin, macrolides, tetracycline
Germany2
(uncomplicated illness)
Second line: fluoroquinolones with pneumococcal activity, ketolide
Scotland3 Aminopenicillin, macrolides, tetracyclines
Group IIa:† levofloxacin, moxifloxacin, telithromycin,

Spain 4
amoxicillin/clavulanate
Group IIb:†† ciprofloxacin, levofloxacin
Switzerland5 Amoxicillin/clavulanate, co-trimoxazole, macrolides, fluoroquinolones
First line: narrow-spectrum antibiotics (superiority

USA6
of newer, broad-spectrum antibiotics has not been established)
Moderate COPD; ††Moderate COPD with risk of P. aeruginosa infection
†
L.EG.MKT.06.2017.0095
1 ) McKenzie D et al. http://www.copdx.org.au/images/stories/about/ The_COPD-X_Plan_Version_2.26_August_2011_2.pdf;
[Accessed Jan 2012] 2) Worth et al. Pneumologie 2002; 56: 704–38; 3) SIGN, 2002; 4) Álvarez et al. Rev Esp Quimioterap
L.SA.MKT.04.2017.0137
2002; 15: 375–85; 5) Russi et al. Swiss Med Wkly 2002; 132: 67–78; 6) Snow et al. Ann Intern Med 2001; 134: 595–9 137
Latin American guidelines for AECB
Group FEV1 Recommendation treatment
Amoxicillin/clavulanate, cefuroxime,
Slight COPD without risk factors >50%
azithromycin/ clarithromycin
As above plus moxifloxacin/

Slight COPD with risk factors* >50% gatifloxacin/levofloxacin,
telithromycin
Moxifloxacin/gatifloxacin/
Moderate COPD 35–50% levofloxacin, telithromycin,
amoxicillin/clavulanate
Moxifloxacin/gatifloxacin/levofloxacin,
Ciprofloxacin if Pseudomonas is
Severe COPD <35%
suspected Amoxicillin/clavulanate (if
allergic to fluoroquinolones)
*Age >65 years, severe dyspnea, significant comorbidity, >4 exacerbations within previous 12 months,
hospitalization due to exacerbation during previous 12 months, use of systemic corticosteroids in last 3 months,
use of antibiotics in last 15 days, malnutrition
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138
Canadian guidelines for AECB: risk groups
Group Clinical state/symptoms
Acute tracheobronchitis: cough and sputum without previous pulmonary

0
disease
Chronic bronchitis without risk factors (simple):

I
increased cough and sputum, sputum purulence and increase dyspnea
Chronic bronchitis with risk factors (complicated): as

for I but with one of FEV1 <50% predicted, >4 exacerbations / year, cardiac
II
disease, use of home oxygen, chronic oral steroid use, antimicrobial use in
the last 3 months
Chronic suppurative bronchitis: as for II but with constant purulent sputum,

III possibly bronchiectasis, FEV1 usually <35% predicted, or multiple risk
factors
L.EG.MKT.06.2017.0095

139
Canadian guidelines for AECB:
recommended antimicrobial therapy
Group Recommended therapy
First line Second line

0 None Macrolide or tetracycline
2nd generation macrolide,

2nd or 3rd generation cephalosporin, Fluoroquinolone, β-lactam/β-
I
amoxicillin, doxycycline, lactamase inhibitor
co-trimoxazole
May require parenteral β-lactamase

II Fluoroquinolone, β-lactam
inhibitor therapy
Ambulatory patients:
Tailor therapy to airway pathogen
III
Hospitalized patients:
Parenteral therapy usually required
L.EG.MKT.06.2017.0095

140
Avalox® in AECB
OTHER ANTIBIOTICS IN AECB
L.SA.MKT.04.2017.0137
Other antibiotics in AECB
Amoxicillin/clavulanate
Azithromycin
Clarithromycin
Telithromycin
Levofloxacin
Gemifloxacin
Efficacy of competitors in AECB
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142
Amoxicillin/clavulanate
Indication in prescribing information

• Lower respiratory tract infections caused by β-lactamase-
producing strains of H. influenzae, and M. catarrhalis – this
includes AECB
Dosage
• 500mg q12h or 250mg q8h
• Serious infections: 875mg q12h or 500mg q8h
Disadvantages
• Twice or three times daily therapy
Amoxicillin/clavulanate XR is not indicated for AECB
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AUGMENTIN® Prescribing Information, 2006 L.SA.MKT.04.2017.0137

143
Clarithromycin XL
Indication*
• AECB due to H. influenzae, H. parainfluenzae, M. catarrhalis
or S. pneumoniae
Dosage*
• 2 x 500mg q24h for 7 days
• Equivalent to standard clarithromycin based on AUC PK studies
Advantages over standard clarithromycin:
• Equivalent to standard clarithromycin in clinical efficacy and bacterial
eradication, with improved GI tolerability
• Improved compliance/convenience (q.d. vs b.i.d. dosing)
Disadvantages
• Increasing resistance of H. influenzae and S. pneumoniae
to macrolides
• Reduced killing rate against H. influenzae vs moxifloxacin
L.EG.MKT.06.2017.0095
*Only AECB indication and dosage shown
BIAXIN® Prescribing Information, 2011; Gotfried. Expert Rev Anti-infec Ther 2003; 1: 9–20 L.SA.MKT.04.2017.0137
144
Gemifloxacin
Indication*
• AECB due to H. influenzae, H. parainfluenzae, M. catarrhalis
or S. pneumoniae
Dosage*
• 320mg once daily for 5 days
Advantages
• Once-daily therapy
• Short duration of treatment
• High levels of fluoroquinolone susceptibility among
Gram-negative, Gram-positive, and atypical pathogens
Disadvantages
• Poor side-effect profile
L.EG.MKT.06.2017.0095
*Only AECB indication and dosage shown
FACTIVE® Prescribing Information, 2008 L.SA.MKT.04.2017.0137
145
Efficacy of gemifloxacin vs clarithromycin
in AECB
Gemifloxacin 320mg PO q.d. for 5 days (n=351)

Clarithromycin 500mg PO b.i.d. for 7 days (n=358)
100
Success at 2–3 week follow-up (%)
85.4 84.6 86.7

80 73.1
60
40
20
0
Clinical success Bacteriologic success
Significantly more patients receiving gemifloxacin than clarithromycin remained free of AECB
recurrences; 71% vs 59%, p=0.016
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Wilson et al. Clin Ther 2002; 4: 639–52 L.SA.MKT.04.2017.0137

146
Efficacy of levofloxacin vs clarithromycin
in AECB
Levofloxacin 500mg PO q.d. for 7 days (n=250)

Clarithromycin 250mg PO b.i.d. for 10 days (n=254)
Response at the end of treatment (%)
p<0.0001
100 96
82.8 79.8 81.7
80
60
40
20
0
Clinical response Bacterial response
No significant differences were observed in the exacerbation-free interval between

levofloxacin and clarithromycin treatment groups
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Lode et al. Eur Respir J 2004; 24: 947–53 L.SA.MKT.04.2017.0137

147
Efficacy of levofloxacin vs azithromycin in
uncomplicated AECB

Azithromycin 750mg PO q.d. for 5 days (n=202)
96.3 93.8
Success at post-therapy visit (%)
100 93 90.1 87.4

82.8
80
60
40
20
0
CE ME ME
Microbiological
Clinical success
eradication
L.EG.MKT.06.2017.0095
CE, clinically evaluable patients; ME, microbiologically evaluable patients
Martinez et al. Eur Respir J 2005; 25: 1001–10 L.SA.MKT.04.2017.0137
148
Efficacy of levofloxacin vs
amoxicillin/clavulanate in complicated AECB

Amoxicillin/clavulanate 875mg/125mg PO b.i.d. for 10 days (n=182)
Success at post-therapy visit (%)
100
79.2 81.7 81.4 80.9 81.4 79.8
80
60
40
20
0
CE ME ME
Microbiological
Clinical success
eradication
CE, clinically evaluable patients; ME, microbiologically evaluable patients
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Martinez et al. Eur Respir J 2005; 25: 1001–10 L.SA.MKT.04.2017.0137

149
Comparable efficacy of telithromycin and
amoxicillin/clavulanate in AECB
Telithromycin 800mg PO q.d. for 5 days

Amoxicillin/clavulanate 500mg/125mg PO t.i.d. for 10 days
100
Test of cure success (%)
86.1 82.1
80 69.2 70
60
40
20
0
Clinical cure Bacteriologic eradication
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Aubier et al. Respir Med 2002; 96: 862–71 L.SA.MKT.04.2017.0137

150
Comparable efficacy of telithromycin and
clarithromycin in AECB
Telithromycin 800mg PO q.d. for 5 days

Clarithromycin 500mg PO b.i.d. for 10 days
100 89.2
85.8
Test of cure success (%)
81.9 82.9
80
60
40
20
0
Clinical cure Bacteriologic eradication
L.EG.MKT.06.2017.0095
Fogarty et al. CHEST 2005; 128: 1980–1988 L.SA.MKT.04.2017.0137

151
Telithromycin: lower health-care resource
utilization vs clarithromycin
p<0.03
p<0.04
Number of patients
p<0.37
*AECB-related hospitalizations and all other respiratory-related hospitalizations
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Fogarty et al. CHEST 2005; 128: 1980–8 L.SA.MKT.04.2017.0137

152
Clinical efficacy of oral moxifloxacin vs
comparators in AECB
Moxifloxacin 400mg PO q.d. for 5 days
Amoxicillin/clavulanate 625mg PO t.i.d. for 7 days
Clarithromycin 500mg PO b.i.d. for 7* or 10** days
Azithromycin 500mg PO q.d. 1 day then 250mg PO q.d. 4 days
Test of cure clinical success (%)
100 96 92 89 88 89 91 88 88
80
60
40
20
n=261 n=251 n=287 n=289 n=135 n=127 n=221 n=243
0
Schaberg Wilson Chodosh DeAbate
et al.1 et al. 2 et al.3 et al.4
L.EG.MKT.06.2017.0095
1) Schaberg et al. J Int Med Res 2001; 29: 314–28
2) Wilson et al. J Antimicrob Chemother 1999; 44: 501–13
3) Chodosh et al. Respir Med 2000; 94: 8–27
4) DeAbate et al. Respir Med 2000; 94: 1029–37 L.SA.MKT.04.2017.0137
153
Oral moxifloxacin bacteriologic efficacy vs
comparators in AECB
Moxifloxacin 400mg PO q.d. for 5 days
Amoxicillin/clavulanate 625mg PO t.i.d. for 7 days
Clarithromycin 500mg PO b.i.d. for 7* or 10** days
Test of cure bacteriologic success (%)
Azithromycin 500mg PO q.d. 1 day then 250mg PO q.d. 4 days
100 94 91
87.7 89.6 89 86
77
80
62
60
40
20
n=73 n=67 n=115 n=114 n=135 n=91 n=89 n=86
0
Schaberg Wilson Chodosh DeAbate

et al.1 et al.2* et al.3** et al.4
L.EG.MKT.06.2017.0095
1) Schaberg et al. J Int Med Res 2001; 29: 314–28
2) Wilson et al. J Antimicrob Chemother 1999; 44: 501–13
3) Chodosh et al. Respir Med 2000; 94: 8–27
4) DeAbate et al. Respir Med 2000; 94: 1029–37 L.SA.MKT.04.2017.0137
154
Avalox® in AECB
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the Swiss guidelines. Swiss Med Wkly 2002; 132: 67–78
Rutten-Van Mölken MPMH, Postma MJ, Joore MA, et al.Current and future medical cost of asthma and chronic
obstructive pulmonary disease in the Netherlands. Respir Med 1999; 93: 779–87
Schaberg T, Ballin I, Huchon H et al. A multinational, multicentre, non-blinded, randomized study of
moxifloxacin oral tablets compared with co-amoxiclav oral tablets in the treatment
of acute exacerbations of chronic bronchitis. J Int Med Res 2001; 29: 314–28
Schaberg T, Möller M, File T et al. Real-life treatment of acute exacerbations of chronic bronchitis with
moxifloxacin or macrolides – a comparative post-marketing surveillance study in general practice. Clin Drug
Invest 2006; 26: 733–44
Scheld WM. Maintaining fluoroquinolone class efficacy: review of influencing factors.
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Scottish Intercollegiate Guidelines Network (SIGN), 2002. Community management of lower respiratory tract
infection in adults. SIGN publication no. 59. Available at: http://www.sign.ac.uk/pdf/sign59.pdf
Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality
of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 1418–
22
Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. CHEST 2000;
117: 380S–385S
Sethi S. Moxifloxacin for the treatment of acute exacerbations of chronic obstructive pulmonary disease. Clin
Infect Dis 2005; 40: S489–97
Sethi S, Muscarella K, Evans N et al. Airway inflammation and etiology of acute exacerbations of chronic
bronchitis. CHEST 2000; 118: 1557–65
Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art
review. Clin Microbiol Rev 2001; 14: 336–63
Sethi S, Evans N, Grant BJB et al. New strains of bacteria and exacerbations of chronic obstructive pulmonary
disease. N Engl J Med 2002; 347: 465–71
Sethi S, File TM. Managing patients with recurrent acute exacerbations of chronic bronchitis: a common clinical
problem. Curr Med Res Opin 2004; 20: 1511–21
Snow V, Lascher S, Mottur-Pilson C et al. Evidence base for management of acute exacerbations of chronic
obstructive pulmonary disease. Ann Intern Med 2001; 134: 595–9
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Société de Pathologie Infectieuse de Langue Française. Prise en charge des infections des voies respiratoires
basses de l’adulte immunocompetent, 15 e Conference de Consensus en Therapeutique Anti-infectieuse,
March 2006. http://www.infectiologie.com/site/congres.php
Spencer S, PW Jones for the GLOBE Study Group. Time course of recovery of health status following an
infective exacerbation of chronic bronchitis. Thorax 2003; 58: 589–93
Stass H. Evaluation of the antibacterial activity of moxifloxacin vs. gatifloxacin vs. levofloxacin in serum and
target tissues in vitro and in silico PK/PD modelling. 14th European Congress of ESCMID, Prague, Czech
Republic, May 1–4, 2004; Abstract 902-p1815
Tulkens P, Arvis P, Kruesman F. Clinical Safety of Moxifloxacin (MXF): an analysis of “valid for safety” data from
controlled Phase II to Phase IV studies between 1996 and 2010. ECCMID 2012 (P2210)
US Surgeon General. The Health Consequences of Smoking: Chronic Obstructive Lung Disease. Washington,
DC: DHHS, 1984; Publication No. 84-50205
Vogelmeier , Buhl R, Criée A et al. Guidelines for the Diagnosis and Therapy of COPD issued by Deutsche
Atemwegsliga and Deutsche Geselleschaft für Pneumologie und Beatmungsmedizin. Pneumologie 2007;
61:e1-e40
Wilson R, Allegra L, Huchon G et al. Short-term and long-term outcomes of moxifloxacin compared to standard
antibiotic treatment of acute exacerbations of chronic bronchitis. CHEST 2004; 125: 953–64
Wilson R, Anzueto A, Miravitlles M et al. A novel study design for antibiotic trials in acute exacerbations of
COPD: MAESTRAL methodology. Int J COPD 2011; 6: 373–383
Wilson R, Anzueto A, Miravitlles M et al.Moxifloxacin vs amoxicillin/clavulanic acid in outpatients AECOPD:
MAESTRAL results. Eur Respir J 2012; 40: 17-27
Wilson R, Jones P, Schaberg T et al. Antibiotic treatment and factors influencing short and
long-term outcomes of acute exacerbations of chronic bronchitis.
Thorax 2006; 61: 337–42
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References (Wilson–ZITHROMAX®)
Wilson R, Kubin R, Ballin I et al. Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for
the treatment of acute exacerbations of chronic bronchitis.
J Antimicrob Chemother 1999; 44: 501–13
Wilson R, Schentag JJ, Ball P et al. A comparison of gemifloxacin and clarithromycin in acute exacerbations of
chronic bronchitis and long-term clinical outcomes.
Clin Ther 2002; 4: 639–52
Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections –
full version. Clin Microbiol Infect 2011; 17(Suppl 6): E1–E59
Worth H, Buhl R, Cegla U et al. Guidelines for the diagnosis and treatment of chronic obstructive bronchitis and
pulmonary emphysema. Pneumologie 2002; 56: 704–38
ZITHROMAX® Prescribing information, Pfizer Laboratories, 2003
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Bayer Middle East 24/7 PV contacts
Tel: +20225980666 +20225980664 +201093334440
E-mail: pv.me@bayer.com
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Avalox 400 mg film-coated tablets for use in adults. Composition: The active substance is moxifloxacin. Each film coated tablet contains 400 milligram moxifloxacin as hydrochloride. The other ingredients
are: Tablet core: Microcrystalline cellulose, Croscarmellose sodium, Lactose monohydrate (see section Avalox contains lactose) and Magnesium stearate. Film coating: Hypromellose, Macrogol 4000, Ferric
oxide (E172) and Titanium dioxide (E171). What Avalox is and what it is used for. Indications: Avalox contains the active substance moxifloxacin which belongs to a group of antibiotics called
fluoroquinolones. Avalox works by killing bacteria that cause infections. Avalox is used in patients of 18 years and older for treating the following bacterial infections when caused by bacteria against which
Moxifloxacin is active. Avalox should only be used to treat these infections when usual antibiotics cannot be used or have not worked: Infection of the sinuses, sudden worsening of long term inflammation of
the airways or infection of the lungs (pneumonia) acquired outside the hospital (except severe cases). Mild to moderate infections of the female upper genital tract (pelvic inflammatory disease), including
infections of the fallopian tubes and infections of the uterus mucous membrane. Avalox tablets are not sufficient for sole therapy of this kind of infections and therefore another antibiotic in addition to Avalox
tablets should be prescribed by the doctor for the treatment of infections of the female upper genital tract (see section. What you need to know before you take Avalox, Warnings and precautions, Patient has
to talk to the doctor before taking Avalox). If the following bacterial infections have shown improvement during initial treatment with Avalox solution for infusion, Avalox tablets may also be prescribed by the
doctor to complete the course of therapy: Infection of the lungs (pneumonia) acquired outside the hospital, infections of the skin and soft tissue. Avalox tablets should not be used to initiate therapy for any
type of infections of the skin and soft tissue or in severe infections of the lungs. What patient needs to know before taking Avalox. Contraindications: Avalox should not be taken: If patient is allergic to
the active substance moxifloxacin, any other quinolone antibiotics or any of the other ingredients of this medicine (listed above). If patient is pregnant or breast-feeding. If patient is less than 18 years of age.
If patient has a history of tendon disease or disorder which was related to treatment with quinolone antibiotics (see sections Warnings and precautions and Possible side effects). If patient was born with or
have had any condition with abnormal heart rhythm (seen on ECG, electrical recording of the heart), has salt imbalance in the blood (especially low level of potassium or magnesium in the blood), has a very
slow heart rhythm (called ‘bradycardia’), has a weak heart (heart failure), has a history of abnormal heart rhythms, or is taking other medicines that result in abnormal ECG changes (see section Other
medicines and Avalox). This is because Avalox can cause changes on the ECG, which is a prolongation of the QT-interval i.e. delayed conduction of electrical signals. If patient has a severe liver disease or
increased liver enzymes (transaminases) higher than 5 times the upper normal limit. Warnings and precautions. Patient has to talk to the doctor before taking Avalox. Avalox can change the heart’s
ECG, especially if patient is female, or if patient is elderly. If patient is currently taking any medicine that decreases the blood potassium levels, patient has to consult the doctor before taking Avalox (see also
sections Contraindications and Other medicines and Avalox). If patient suffers from epilepsy or a condition which makes him/her likely to have convulsions, patient should consult the doctor before taking
Avalox. If patient has or have ever had any mental health problems, patient should consult the doctor before taking Avalox. If patient suffers from myasthenia gravis taking Avalox may worsen the symptoms
of his/her disease. If patient thinks he/she is affected, patient must consult the doctor immediately. If patient or any member of his/her family have glucose-6-phosphate dehydrogenase deficiency (a rare
hereditary disease), patient then has to inform the doctor, who will advise whether Avalox is suitable for the patient. If patient has a complicated infection of the female upper genital tract (e.g. associated with
an abscess of the fallopian tubes and ovaries or of the pelvis), for which her doctor considers an intravenous treatment necessary, treatment with Avalox tablets is not appropriate. For the treatment of mild to
moderate infections of the female upper genital tract, the doctor should prescribe another antibiotic in addition to Avalox. If there is no improvement in symptoms after 3 days of treatment, patient should
consult her doctor. When taking Avalox: If patient experiences palpitations or irregular heart beat during the period of treatment, patient should inform the doctor immediately. Doctor may wish to perform an
ECG to measure the patient’s heart rhythm. The risk of heart problems may increase with increase of the dose. Therefore, the recommended dosage should be followed. There is a rare chance that patient
may experience a severe, sudden allergic reaction (an anaphylactic reaction/shock) even with the first dose, with the following symptoms: tightness in the chest, feeling dizzy, feeling sick or faint, or
experiences dizziness on standing. If so, patient should stop taking Avalox and seek medical advice immediately. Avalox may cause a rapid and severe inflammation of the liver which could lead to life-
threatening liver failure (including fatal cases, see section Possible side effects). Patient should contact the doctor before continuing the treatment if patient develops signs such as rapidly feeling unwell
and/or being sick associated with yellowing of the whites of the eyes, dark urine, itching of the skin, a tendency to bleed or liver induced disease of the brain (symptoms of a reduced liver function or a rapid
and severe inflammation of the liver). If patient develops a skin reaction or blistering and/or peeling of the skin and/or mucosal reactions (see section Possible side effects), patient should contact the doctor
immediately before he/she continues the treatment. Quinolone antibiotics, including Avalox, may cause convulsions. If this happens, patient should stop taking Avalox and contact the doctor immediately.
Patient may experience symptoms of neuropathy such as pain, burning, tingling, numbness and/or weakness. If this happens, he/she should inform the doctor immediately prior to continuing treatment with
Avalox. Patient may experience mental health problems even when taking quinolone antibiotics, including Avalox, for the first time. In very rare cases depression or mental health problems have led to
suicidal thoughts and self-injurious behavior such as suicide attempts (see section Possible side effects). If patient develops such reactions, he/she should stop taking Avalox and inform the doctor
immediately. Patient may develop diarrhoea whilst taking, or after taking, antibiotics including Avalox. If this becomes severe or persistent or the patient notices that the stool contains blood or mucus he/she
should stop taking Avalox immediately and consult the doctor. In this situation, patient should not take medicines that stop or slow down bowel movement. Avalox may cause pain and inflammation of the
tendons, even within 48 hours of starting treatment and up to several months after discontinuing Avalox therapy. The risk of inflammation and rupture of tendons is increased if patient is elderly or if patient is
currently being treated with corticosteroids. At the first sign of any pain or inflammation he/she should stop taking Avalox, rest the affected limb(s) and should consult the doctor immediately. Patient has to
avoid any unnecessary exercise, as this might increase the risk of a tendon rupture (see sections Contraindications and Possible side effects). If patient is elderly with existing kidney problems, patient has to
take care that his/her fluid intake is sufficient because dehydration may increase the risk of kidney failure. If patient’s eyesight becomes impaired or if his/her eyes seem to be otherwise affected, patient
should consult an eye specialist immediately (see sections Driving and using machines and Possible side effects). Fluoroquinolone antibiotics may cause disturbances in blood sugar, including both a
decrease in blood sugar below normal levels (hypoglycemia) and an increase in blood sugar above normal levels (hyperglycemia). In patients treated with Avelox, disturbances in blood sugar occurred
predominantly in elderly patients receiving concomitant treatment with oral antidiabetic medicines that lower blood sugar (e. g. sulfonylurea) or with insulin. If patient suffers from diabetes, his/her blood sugar
should be carefully monitored (see section Possible side effects). Quinolone antibiotics may make patient’s skin become more sensitive to sunlight or UV light. Patient should avoid prolonged exposure to
sunlight or strong sunlight and should not use a sunbed or any other UV lamp while taking Avalox. The efficacy of moxifloxacin solution for infusion in the treatment of severe burns, infections of deep tissue
and diabetic foot infections with osteomyelitis (infections of the bone marrow) has not been established. Children and adolescents: this medicine should not be given to children and adolescents under the
age of 18 because efficacy and safety have not been established for this age group (see section Contraindications). Other medicines and Avalox: doctor or pharmacist should be told if patient is taking,
have recently taken or might take any other medicines besides Avalox. For Avalox, patient should be aware of the following: If he/she is taking Avalox and other medicines that affect his/her heart there is an
increased risk for altering his/her heart rhythm. Therefore, Avalox should not be taken together with the following medicines: Medicines that belong to the group of anti-arrhythmics (e.g. quinidine,
hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), antipsychotics (e.g. phenothiazines, pimozide, sertindole, haloperidol, sultopride), tricyclic antidepressants, some antimicrobials (e.g.
saquinavir, sparfloxacin, intravenous erythromycin, pentamidine, antimalarials particularly halofantrine), some antihistamines (e.g. terfenadine, astemizole, mizolastine), and other medicines (e.g. cisapride,
intravenous vincamine, bepridil and diphemanil). Patient must tell the doctor if he/she is taking other medicines that can lower his/her blood potassium levels (e.g. some diuretics, some laxatives and enemas
[high doses] or corticosteroids [anti-inflammatory drugs], amphotericin B) or cause a slow heart rate because these can also increase the risk of serious heart rhythm disturbances while taking Avalox. Any
medicine containing magnesium or aluminium such as antacids for indigestion, or any medicine containing iron or zinc, medicine containing didanosine or medicine containing sucralfate to treat
gastrointestinal disorders can reduce the action of Avalox tablets. Therefore, Avalox tablet is taken 6 hours before or after taking the other medicine. Taking oral medicinal charcoal at the same time as Avalox
tablets reduces the action of Avalox. Therefore it is recommended that these medicines are not used together. If patient is currently taking oral anti-coagulants (e.g. warfarin), it may be necessary for his/her
L.EG.MKT.06.2017.0095
doctor to monitor his/her blood clotting times. Avalox with food and drink The effect of Avalox is not influenced by food including dairy products
L.SA.MKT.04.2017.0137
169
Pregnancy, breast-feeding and fertility. Avalox should not be taken if patient is pregnant or breast-feeding. If patient is pregnant or breast-feeding, she should think she may be
pregnant or are planning to have a baby, she should ask her doctor or pharmacist for advice before taking this medicine. Animal studies do not indicate that fertility will be
impaired by taking this medicine. Driving and using machines: Avalox may make patient feel dizzy or light-headed, patient also may experience a sudden, transient loss of
vision, or might faint for a short period. If patient is affected in this way, he/she must not drive or operate machinery. Avalox contains lactose. If patient has been told by the doctor
that he/she has intolerance to some sugars, he/she should contact the doctor before taking Avalox. Possible side effects: Like all medicines, this medicine can cause side
effects, although not everybody gets them. The most serious side effects observed during the treatment with Avalox are listed below: If patient notices an abnormal fast heart
rhythm (rare side effect) that he/she suddenly starts feeling unwell or notice yellowing of the whites of the eyes, dark urine, itching of the skin, a tendency to bleed or disturbances
of thought or wakefulness (these can be signs and symptoms of fulminant inflammation of the liver potentially leading to life-threating liver failure (very rare side effect, fatal cases
have been observed)) alterations of the skin and mucous membranes like painful blisters in the mouth/nose or at the penis/vagina (Stevens-Johnson syndrome or toxic epidermal
necrolysis) (very rare side effects, potentially life threatening) a severe, sudden generalised allergic reaction incl. very rarely a lifethreatening shock (e.g. difficulty in breathing,
drop of blood pressure, fast pulse) (rare side effect) swelling incl. swelling of the airway (rare side effect, potentially lifethreatening) convulsions (rare side effect) troubles
associated with the nervous system such as pain, burning, tingling, numbness and/or weakness in extremities (rare side effect) depression (in very rare cases leading to self-
harm, such as suicidal ideations/thoughts, or suicide attempts) (rare side effect) insanity (potentially leading to self-harm, such as suicidal ideations/ thoughts, or suicide
attempts) (very rare side effect) severe diarrhoea containing blood and/or mucus (antibiotic associated colitis incl. pseudomembranous colitis), which in very rare circumstances,
may develop into complications that are life threatening (rare side effects) pain and swelling of the tendons (tendonitis) (rare side effect) or a tendon rupture (very rare side effect).
Patient must stop taking Avalox and tell the doctor immediately as he/she may need urgent medical advice. In addition, if he/she notices transient loss of vision (very rare
side effect), an eye specialist must be contacted immediately. If patient has experienced life-threatening irregular heart beat (Torsade de Pointes) or stopping of heart beat while
taking Avelox (very rare side effects), he/she must tell the treating doctor immediately that he/she has taken Avelox and does not restart the treatment. A worsening of the
symptoms of myasthenia gravis has been observed in very rare cases. If this happens, doctor must be consulted immediately. If patient suffers from diabetes and notices that
his/her blood sugar is increased or decreased (rare or very rare side effect), he/she should inform the doctor immediately. If patient is elderly with existing kidney problems and
notices decrease in urine output, swelling in his/her legs, ankles or feet, fatigue, nausea, drowsiness, shortness of breath or confusion (these can be signs and symptoms of
kidney failure, a rare side effect), doctor must be consulted immediately. Other side effects which have been observed during treatment with Avelox are listed below by how likely
they are: Common (may affect up to 1 in 10 people) nausea, diarrhoea, dizziness, stomach and abdominal ache, vomiting, headache, increase of a special liver enzyme in the
blood (transaminases), infections caused by resistant bacteria or fungi e.g. oral and vaginal infections caused by Candida, change of the heart rhythm (ECG) in patients with low
blood potassium level. Uncommon (may affect up to 1 in 100 people): rash, stomach upset (indigestion/heartburn), changes in taste (in very rare cases loss of taste), sleep
problems (predominantly sleeplessness), increase of a special liver enzyme in the blood (gamma-glutamyltransferase and/or alkaline phosphatase), low number of special white
blood cells (leukocytes, neutrophils), constipation, itching, sensation of dizziness (spinning or falling over), sleepiness, wind, change of the heart rhythm (ECG), impaired liver
function (incl. increase of a special liver enzyme in the blood (LDH)), decreased appetite and food intake, low white blood cells count, aches and pains such as back, chest,
pelvic and extremities pains, increase of special blood cells necessary for blood clotting, sweating, increased specialised white blood cells (eosinophils), anxiety, feeling unwell
(predominantly weakness or tiredness), shaking, joint pain, palpitations, irregular and fast heart beat, difficulty in breathing incl. asthmatic conditions, increase of a special
digestive enzyme in the blood (amylase), restlessness / agitation, tingling sensation (pins and needles) and/or numbness, skin hives, widening of blood vessels, confusion and
disorientation, decrease of special blood cells necessary for blood clotting, visual disturbances incl. double and blurred vision, decreased blood clotting, increased blood lipids
(fats), low red blood cell count, muscle pain, allergic reaction, increase of bilirubin in the blood, inflammation of the stomach, dehydration, severe heart rhythm abnormalities, dry
skin, angina pectoris. Rare (may affect up to 1 in 1,000 people), muscle twitching, muscle cramp, hallucination, high blood pressure, swelling (of the hands, feet, ankles, lips,
mouth, throat), low blood pressure, kidney impairment (incl. increase in special kidney laboratory test results like urea and creatinine), inflammation of the liver, inflammation of
the mouth, ringing/noise in the ears, jaundice (yellowing of the whites of the eyes or skin), impairment of skin sensation, abnormal dreams, disturbed concentration, difficulty in
swallowing, changes in smell (incl. loss of smell), balance disorder and poor co-ordination (due to dizziness), partial or total loss of memory, hearing impairment including
deafness (usually reversible), increased blood uric acid, emotional instability, impaired speech, fainting, muscle weakness. Very rare (may affect up to 1 in 10,000 people)
inflammation of joints, abnormal heart rhythms, increase of skin sensitivity, a feeling of self-detachment (not being yourself), increased blood clotting, muscle rigidity, significant
decrease of special white blood cells (agranulocytosis). Furthermore, there have been very rare cases of the following side effects reported following treatment with other
quinolone antibiotics, which might possibly also occur during treatment with Avalox: increased blood sodium levels, increased blood calcium levels, a special type of reduced red
blood cell count (haemolytic anaemia), muscle reactions with muscle cell damage, increased sensitivity of the skin to sunlight or UV light. Reporting of side effects: If the
patient gets any side effects, he/she should talk to the doctor or pharmacist. This includes any side effects not listed in this leaflet. Reporting side effects can help provide more
information on the safety of this medicine. Manufacturer Bayer Pharma AG Site: 51368 Leverkusen, Germany. Marketing authorization holder Bayer Pharma AG 13342 Berlin,
Germany.
This leaflet was last revised in June 2015.
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Thank you for your attention!
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Avalox in Aecb: PP-AVE-JO-0006-1

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Avalox® in AECB

TYPE I TYPE II TYPE III

Data are mean (range) percentage of total bacterial isolates

Sethi. Clin Infect Dis 2005; 40: S489–97 L.SA.MKT.04.2017.0137

Pseudomonas spp., Serratia

Eller et al. CHEST 1998; 113: 1542–8 L.SA.MKT.04.2017.0137

Percent of clinic visits when an Percent of clinic visits for

Pathogen No pathogen New strain No new strain

Sethi et al. N Engl J Med 2002; 347: 465–71 L.SA.MKT.04.2017.0137

COPD patients with significant levels of obstruction

Infrequent exacerbators (3.59% decline in FEV /year)

Frequent exacerbators (4.22% decline in FEV /year)

Donaldson et al. Thorax 2002; 57: 847–52 L.SA.MKT.04.2017.0137

Spencer et al. Thorax 2003; 58: 589–93 L.SA.MKT.04.2017.0137

Frequent exacerbations significantly impair health-related quality

Ball. CHEST 1995; 108: 43S–52S L.SA.MKT.04.2017.0137

Main contributory factor

Fletcher & Peto. BMJ 1977; 1: 1645–8 L.SA.MKT.04.2017.0137

Cigarette smoking (predominant factor)

Inflammation of the bronchial mucosa

Impaired mucociliary clearance and hypersecretion of mucus

Inflammation and edema

Narrowing and obstruction of airflow

The Vicious Circle Hypothesis

Alteration of elastase– Increased elastolytic

Chronic obstructive pulmonary disease (COPD) is a

Male Female Total

Mannino et al. MMWR 2002; 51 (SS06): 1–16 L.SA.MKT.04.2017.0137

Mannino et al. Lancet 2007; 370: 765–773 L.SA.MKT.04.2017.0137

Early detection of COPD and intervention is crucial

*LLN, lower limits of normal

Brazzale et al. Respirology 2010; 15:1098–103 L.SA.MKT.04.2017.0137

Treatment of AECB requires symptomatic relief

Balter et al. Can Respir J 2003; 10 (Suppl B): 3B–32B L.SA.MKT.04.2017.0137

Activity against the major respiratory pathogens

Time (hours) Time (hours)

Lister & Sanders. J Antimicrob Chemother 2001; 47: 811–8 L.SA.MKT.04.2017.0137

~25–45% of S. pneumoniae isolates are

100 89.5 85.2

Niederman et al. Respir Med 2006; 100: 1781–90 L.SA.MKT.04.2017.0137

Ball et al. Clin Ther 2004; 26: 940–9 L.SA.MKT.04.2017.0137

Chest pain 0.8 0.7

Ball et al. Clin Ther 2004; 26: 940–9 L.SA.MKT.04.2017.0137

PO (n=17465) IV/PO (n=3745) IV (n=1159)

Moxifloxaci Comparator Moxifloxacin Comparator Moxifloxacin Comparator

Tulkens et al. ECCMID 2012 [Poster P2210] L.SA.MKT.04.2017.0137

Miravitlles et al. Clin Drug Invest 2004; 24: 63–72 L.SA.MKT.04.2017.0137

Moxifloxacin (n=575) Amoxicillin/clavulanate (n=460) Clarithromycin (n=421)

Miravitlles et al. Clin Drug Invest 2004; 24: 63–72 L.SA.MKT.04.2017.0137

Moxifloxacin (n=575) Amoxicillin/clavulanate (n=460) Clarithromycin (n=421)

Miravitlles et al. Clin Drug Invest 2004; 24: 63–72 L.SA.MKT.04.2017.0137

The time-course of recovery was faster with moxifloxacin

Miravitlles et al. Clin Drug Invest 2004; 24: 63–72 L.SA.MKT.04.2017.0137

p=0.006 p=0.027 p=0.006

Miravitlles et al. Clin Drug Invest 2003; 23: 439–50 L.SA.MKT.04.2017.0137

Miravitlles et al. Clin Drug Invest 2003; 23: 439–50 L.SA.MKT.04.2017.0137

Moxifloxacin provided significantly faster recovery from

Miravitlles et al. Clin Drug Invest 2003; 23: 439–50 L.SA.MKT.04.2017.0137

Wilson et al. CHEST 2004; 125: 953–64 L.SA.MKT.04.2017.0137

Moxifloxacin 400mg q.d. 5 days (n=354)

Monthly contact Next AECB

*Cefuroxime axetil, 174 patients; clarithromycin, 114 patients; amoxicillin, 88 patients

Wilson et al. CHEST 2004; 125: 953–64 L.SA.MKT.04.2017.0137