Transcript Document 7348441

5/23/2016
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AVELOX (moxifloxacin HCl)
NDA # 21-085
Introduction
Carl E. Calcagni, R.Ph.
Vice President, Regulatory Affairs
Bayer Corporation, Pharmaceutical Division
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AVELOX (moxifloxacin HCl)
NDA # 21-085
Bayer Corporation - a global leader in the development
of quinolones and anti-infectives
 Cipro Tablets approved in 1987
 12 years of marketed clinical experience in the USA
 Over 200 million patients treated worldwide
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AVELOX (moxifloxacin HCl)
NDA # 21-085
Advanced generation quinolone (1994 Bayer AG,
Leverkusen, Germany)
Synthesized and developed:
 to cover respiratory tract pathogens by enhancing
Gram positive and atypical activity
 to provide longer half-life to ensure QD dosing
 to improve compliance by shorter course of therapy
and good tolerability
 to potentially minimize antibiotic resistance
 to provide new alternative for community RTI
treatment
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AVELOX (moxifloxacin HCl)
NDA # 21-085
 Current Approval Status
 Mexico
(December 1998)
 Germany
(July 1999)
 Argentina
(August 1999)
 Switzerland
(August 1999)
 Vietnam
(August 1999)
 Colombia
(September 1999)
 EU Mutual Recognition Procedure in Final Stages
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AVELOX (moxifloxacin HCl)
NDA # 21-085
Objectives
 To demonstrate that moxifloxacin is safe and effective for:
 Acute Bacterial Exacerbations of Chronic Bronchitis
 Acute Sinusitis
 Community Acquired Pneumonia
 Uncomplicated Skin/Skin Structure Infections
 To review the observation of QTc prolongation with
moxifloxacin, assess relative risk factors and present
submitted labeling that is appropriate and responsible
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AVELOX (moxifloxacin HCl)
NDA # 21-085
Dosage Administration and Proposed Indications
Indication
Acute Bacterial Exacerbation of Chronic
Duration
5 Days
Bronchitis
Uncomplicated Skin and Skin Structure
7 Days
Infections
Acute Sinusitis
10 Days
Community Acquired Pneumonia
10 Days
One 400 mg tablet taken once daily
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Agenda
Introduction:
Carl E. Calcagni, R.Ph.
Vice President, Regulatory Affairs, Bayer
Efficacy/Safety:
Deborah Church, M.D.
QTc Background:
Director Anti-Infectives, Medical, Bayer
Joel Morganroth, M.D.
Clinical Professor of Medicine, University of
Pennsylvania
QTc Data:
Alan Hollister, M.D., Ph.D., FACP
Deputy Director, Clinical Pharmacology, Bayer
Risk/Benefit &
Stephen H. Zinner, M.D.
Conclusion:
Charles S. Davidson Professor of Medicine,
Harvard Medical School
Chair, Department of Medicine, Mount Auburn
Hospital
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Experts
John DiMarco, M.D., Ph.D.
Director, Clinical Electrophysiology Laboratory
Associate Division Head, Cardivascular Division
University of Virginia
Gerald Faich, M.D., M.Ph.
President
Pharmaceutical Safety Assessments, Inc.
Lance Peterson, M.D.
Professor of Pathology and Medicine
Director, Clinical Microbiology Laboratory
Northwestern University
David Talan, M.D., F.A.C.E.P., Professor of Medicine, UCLA
F.I.D.S.A
Chair, Faculty of Infectious Diseases
Olive View-UCLA Medical Center
Lowell Young, M.D.
Clinical Professor of Medicine
University of California, San Francisco
Chief, Division of Infectious Diseases
California Pacific Medical Center
FDA Advisory
Committee
Moxifloxacin
Efficacy & Safety
Deborah A. Church, M.D.
Director, Anti-Infectives Medical Department
Bayer Corporation
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Overview
 Efficacy
 Safety
 Rationale for
Development
 Dosing and Metabolism
 Microbiology
 Extent of Exposure
 Drug resistance
 Adverse Events
 PK/PD
 Clinical / bacteriologic
results for AS, AECB,
CAP and SSSI
 Outcomes Analysis
 Drug Interactions
Premature
Discontinuations
Serious Adverse
Events
 Deaths
 Selected quinolonerelated events
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Moxifloxacin:
Rationale for
Development
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Rationale for Development
 Respiratory tract infections still account for
significant morbidity and mortality
 Drug resistance has increased over time,
underscoring evolutionary adaptiveness
of microorganisms
 New antibiotics and a change in selection/use
may be needed to alter these trends
 Potent, new fluoroquinolones should have an
important place in the management of
infectious diseases
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Decreasing Penicillin/Macrolide
Susceptibility of S. pneumoniae in the US
100
80
60
40
20
0
Pen S
Pen I
1979-1987
Pen R
1994-1995
Ery S
1997-1998
Spika et al.
Doern et al.
MRL RTI Surveillance Study, 1997-1998,
Data on File
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Rationale for the Design
of Moxifloxacin
Increased knowledge of quinolone structureactivity relationship facilitates rational design,
providing for:
 Excellent Gram-negative coverage plus
enhanced Gram-positive, atypical and
anaerobe activity
 Innovative approach to resistance in terms
of efflux and mechanisms of action
 Optimal pharmacokinetics and
pharmacodynamics (i.e., selection of
appropriate dose)
 Favorable safety profile
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Chemical Structure of Moxifloxacin
• Minimizes efflux (S. pneumoniae, S. aureus)
• Enhances gram-positive activity
OH
O
F
H
N
5
4
6
3
7
2
8
1
N
NH
O
*HCI
O
H3C
H
• Minimizes development of resistance
• Enhances anaerobic activity
Petersen et al 1996
Domagala, JM 1994
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Microbiology of
Moxifloxacin
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In Vitro Activity of Moxifloxacin
Against Key RTI Pathogens
Pathogen (# of isolates)
Strain
MIC90 (g/mL)
S. pneumoniae
(6636)
Penicillin-Susceptible
Penicillin-Intermediate
Penicillin-Resistant
0.25
0.25
0.25
H. influenzae
(1892)
 -Lactamase negative
 -Lactamase positive
0.06
0.06
M. catarrhalis
(1203)
 -Lactamase negative
 -Lactamase positive
0.06
0.06
Legionella spp. (149)
Chlamydia pneumoniae (19)
Mycoplasma pneumoniae (131)
0.125
1
0.06
Atypicals
NDA Data on File
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In Vitro Activity of Moxifloxacin
Against Other RTI Pathogens
Pathogen (# of isolates)
MIC90 (g/mL)
H. parainfluenzae
(81)
0.25
K. pneumoniae
(138)
1
S. aureus
(835)
0.125 (MS*)
4 (MR*)
S. pyogenes
(1607)
0.25
MS* = Methicillin Susceptible, MR* = Methicillin Resistant
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In Vitro Activity of Moxifloxacin
Against Other Pathogens
Moxifloxacin is active against:
 A wide variety of clinically important anaerobic species
Bacteroides
(MIC90 2 g/mL)
Peptostreptococcus
(MIC90 0.25 g/mL)
MIC90 value is less than 2 g/mL for the majority of anaerobes
 Active against M. tuberculosis (MIC90 0.5 g/mL)
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Moxifloxacin MIC90 for S. pneumoniae is
Unaffected by Resistance to Penicillin
MXF LEV CIP CLR AZM AMC CXM
MIC: g/mL
S. pneumoniae
Pen-S (n=3603)
0.25
1.0
1.0
0.03
0.06
0.03
<0.12
Pen-I (n=1267)
0.25
1.0
1.0
32
>4.0
1.0
4.0
Pen-R (n=770)
0.25
1.0
1.0
>32
>4.0
4.0
8.0
MRL RTI Surveillance Study, 1997-1998. MRL Pharmaceutical Services
MXF, moxifloxacin; LEV, levofloxacin; CIP, ciprofloxacin; CLR, clarithromycin;
AZM, azithromycin; AMC, amox/clav; CXM cefuroxime.
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Moxifloxacin
and
Drug Resistance
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Mechanisms of Resistance and
Quinolones
Mutations in the norA gene that upregulate
membrane-associated drug efflux pump
 Despite increased antibiotic efflux from
norA-containing S. pneumoniae and
S. aureus, moxifloxacin MICs remain
identical to wild type
Mutations in topoisomerase IV (grlA and grlB) and
DNA gyrase (gyrA and gyrB)
 Simultaneous independent mutations in both
grlA and gyrA are required to increase
moxifloxacin MICs; even when this occurs,
MICs are still near clinically observed Cmin
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Differential Emergence of Resistance
Between Levofloxacin and Moxifloxacin
(S. pneumoniae 4241)
MIC: g/mL
100
10
Slow
development
of resistance
to MXF and to
a lesser extent
than LEV.
1.0
0.1
100
0
2
4
6
8
Number of Passages from serial exposure at 0.5 x MIC
= LEV
= MXF
Data on File
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Differential Emergence of Resistance
Between Levofloxacin and Moxifloxacin
(S. aureus 133)
MIC: g/mL
100
10
Slow
development
of resistance
to MXF and to
a lesser extent
than LEV.
1.0
0.1
100
0
2
4
6
8
Number of Passages from serial exposure at 0.5 x MIC
= LEV
= MXF
Data on File
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No Development of Moxifloxacin
Resistance in Rat Granuloma Pouch Model
Infecting
Organism
Type of
Mutant
Created
MXF MIC
(g/ml)
Day 0
MXF MIC
(g/ml)
Day 8
S. aureus
Wild Type
0.06
0.06
133
1st Step
0.12
0.12
Multi-Step
2
2
Wild Type
0.12
0.12
1st Step
0.25
0.25
Multi-Step
1
1
S. pneumoniae
4241
Dalhoff. Moxifloxacin in Practice. P 81, 1999.
Dosing regimens: 100 mg/kg/day starting 1 h postinfect; 100 mg/kg/day, starting 24 h
postinfection; 50 mg/kg/day, starting 24 h postinfection. MICs for each dosing regimen
were the same.
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Moxifloxacin: Minimization of the
Emergence of Resistance
Summary
 Targeting of both DNA gyrase and
topoisomerase IV has been achieved
 Minimization of resistance has been
demonstrated in:
 in vitro: minimal changes in MIC under selective
pressure, in contrast to levofloxacin.
 animal studies: no emergence of resistance in rat
granuloma pouch model.
 These important results are achieved via the
methoxy at C-8 (significantly delays the
selection of resistance), and the bicyclic amine
at C-7 (minimizes drug efflux)
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Moxifloxacin
Pharmacokinetics and
Pharmacodynamics
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Pharmacokinetics of Moxifloxacin Support
Once Daily Oral Dosing of 400 mg
Plasma Concentration (mg/L)
Steady-State Plasma Concentrations of
Moxifloxacin Obtained With Once Daily
Dosing of 400 mg (mean;SD) (n=10)
6
5
4
Variable
Day 1
Day 10
AUC (mg·h/L)
30.2
48
Cmax (mg/L)
3.36
4.52
Cmin (mg/L)
0.52
0.94
T1/2 (h)
9.3
12
Sullivan et al. ECCMID, 1997
3
2
1
0
0
4
8
12
16
20
24
28
MIC90
0.25 (S. pneumoniae)
0.125 (S. aureus)
0.06 (H. influenzae)
(M. catarrhalis)
Time (hours)
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Moxifloxacin and Levofloxacin
Concentrations in Plasma and Respiratory
Tissue
Tissue or Fluid
Plasma
Concentration*
(g/ml)
Tissue or Fluid
Concentration*
(g/ml or g/g)
MXF
Tissue:
Plasma
Ratio*
LEV
Tissue:
Plasma
Ratio**
Respiratory
•Alveolar Macrophages
•Bronchial Mucosa
•Epithelial Lining Fluid
3.3 + 0.7
3.3 + 0.7
3.3 + 0.7
61.8 + 27.3
5.5 + 1.3
24.4 + 14.7
21.2 + 10.0
1.7 + 0.3
8.7 + 6.1
7.3 / 6.8
1.3 / 1.8
0.8 / 3.0
Sinus
•Maxillary Sinus Mucosa
3.7 + 1.1
7.6 + 1.7
2.0 + 0.3
ND
NDA Data on File
*Mean ± SD measured 3H after dosing with 400 mg Andrews, et al. JAC 40:573-577, 1997
**Measured 2 and 4H after dosing with 500 mg
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Moxifloxacin
Pharmacokinetics/Pharmacodynamics
PK/PD Parameters that best correlate with
Quinolone Efficacy*
 Cmax / MIC90 > 8-10
 AUC / MIC90 > 100
*for review, see Craig, 1998
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Cmax/MIC90* Data for Selected Quinolones^
MXF
LEV
CIP
SPFX GREP
S. pneumoniae
18
5.7
4.3
2.2
5.4
H. influenzae
150
190
143
37
90
M. catarrhalis
75
95
72
37
90
* For optimal antibiotic effect and to minimize development of
resistance, the Cmax/MIC90 ratio should be at least 8-10 (for review, see
Craig 1998)
^ Clinical correlation not confirmed
MXF PK data based on NDA Data on File; Levofloxacin, Ciprofloxacin (750 mg),
Sparfloxacin, Grepafloxacin Data from PDR. RTI isolates from 1997-1998
Surveillance Study, MRL Pharmaceutical Sciences
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AUC/MIC90* Data for Selected
Quinolones^
MXF
LEV
CIP
SPFX GREP
S. pneumoniae
192
47.5
20.2
37
56.4
H. influenzae
1600
1583
673
940
623
M. catarrhalis
800
792
337
623
940
* For optimal antimicrobial effect and to minimize resistance, AUC/MIC90
should be > 100 (for review, see Craig 1998)
^ Clinical correlation not confirmed
MXF PK data based on NDA Data on File; Levofloxacin, Ciprofloxacin
(750 mg), Sparfloxacin, Grepafloxacin Data from PDR. RTI isolates
from 1997-1998 Surveillance Study, MRL Pharmaceutical Sciences.
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Summary of Moxifloxacin
PK/PD Attributes
 Moxifloxacin PK supports qd dosing and
provides plasma and tissue levels above the
MIC90 for relevant respiratory pathogens for the
entire 24 hour dosing interval
 A 400 mg qd dose of moxifloxacin provides
optimal PK/PD
 Moxifloxacin PK results in optimal overall PD
characteristics (Cmax/MIC;AUC/MIC) compared
with other fluoroquinolones
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Moxifloxacin
Clinical Development
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Phase II/Phase III
Clinical Development Program
 Phase II/III studies were performed in acute
sinusitis, AECB, CAP and SSSI indications
 FDA/IDSA guidelines were implemented
 Primary efficacy variable was clinical outcome
assessed at the test-of-cure
 Secondary variables included bacteriological
response and safety
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Phase II/Phase III
Clinical Development Program (continued)
 Treatment groups were tested for equivalence
Definition: Lower limits of the two-sided
95% CI for the difference between groups
[moxifloxacin - control] greater
than - 10%
 ITT safety population included all patients who
took at least one documented dose of
study drug
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Phase II/III Studies* of Moxifloxacin in
Patients with Infectious Diseases
Indication
No. of
Studies
No. of
Patients
No. of Pts.
Receiving
Comparator
No. of Pts.
Receiving
Moxifloxacin
(400 mg)
Acute
Sinusitis
6
2807
1030
1380
AECB
4
2381
924
1224
CAP
5
2182
705
955
Total RTI
15
7370
2659
3559
SSSI
3
936
450
456
Total All
Requested
Indications
18
8306
3109
4015
*NDA Data - # Valid for Safety (Intent-to-treat)
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Moxifloxacin
NDA Phase III
Acute Sinusitis
Clinical Program
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Acute Sinusitis (North America)
Clinical Resolution at Test-of-Cure
Study #
Study Design
Moxifloxacin
400 mg qd
7 Days
Cefuroxime
250 mg BID
10 Days
10 Days
Total #
Pts.
% Cure
Total #
Pts.
% Cure
Total #
Pts.
% Cure
100107
Double-Blind
Prospective
Multi-center
-
-
223
90
234
89
D96-024
Double-Blind
Prospective
Multi-center
191
81
-
-
193
91
D96-023
Open Noncomparative
336
80
-
-
-
-
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Acute Sinusitis (Ex-North America)
Clinical Response at Test-of-Cure
Study # Study Design
Moxifloxacin
400 mg qd
7 Days
Cefuroxime
250 mg BID
10 Days
10 Days
Total #
Pts.
% Cure
Total #
Pts.
% Cure
Total #
Pts.
% Cure
116
Double-Blind
Prospective
Multi-center
195
90
-
-
212
84
161
Double-Blind
Prospective
Multi-center
-
-
217
94
222
95
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Acute Sinusitis: Pathogen Eradication
Rates at Test-of-Cure Visit*
Moxifloxacin 400 mg
7 Days
Cefuroxime 250 mg BID
10 Days
#isolates
%erad
#isolates
%erad
S. pneumoniae
46
98
20
95
H. influenzae
42
86
13
85
M. catarrhalis
25
88
3
67
* Eradication + presumed eradication, Pathogens isolated by needle aspiration
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Conclusions for Acute Sinusitis
 Both North American and Ex-North American
studies demonstrate equivalence between 10
days of moxifloxacin and 10 days of cefuroxime
 Microbiologic efficacy of 7 day moxifloxacin was
demonstrated against the 3 target pathogens
 Moxifloxacin given for 10 days is clinically and
bacteriologically effective for the treatment of
acute maxillary sinusitis
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Moxifloxacin NDA
Phase III
Acute Exacerbation of
Chronic Bronchitis (AECB)
Clinical Program
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AECB:
(North America and Ex-North America)
Clinical Resolution at Test-of-Cure
Study# Study Design
Moxifloxacin
Control*
(Location)
400 mg x 10
days
D96-027 Double-Blind
(NA)
Prospective
Multi-center
124
(Ex-NA)
Double-Blind
Prospective
Multi-national
400 mg x 5
days
# pts
% cure
# pts
% cure
# pts
% cure
256
91
250
89
251
89
-
-
322
89
327
88
*D96-027 – Clarithromycin 500 mg BID x 10 days
124 – Clarithromycin 500 mg BID x 7 days
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AECB: Overall Pathogen Eradication Rates*
at Test-of-Cure (All studies pooled)
Moxifloxacin
400 mg x 5 Days
Clarithromycin
500 mg BID**
#isolates
%erad
#isolates
%erad
H. influenzae
81
90
84
64
S. pneumoniae
54
89
59
95
M. catarrhalis
50
86
48
98
S. aureus
17
94
19
84
K. pneumoniae
20
85
11
91
H. parainfluenzae
25
84
18
100
Pathogen
*includes eradication + presumed eradication
**10 day regimen for D96-027, 7 day regimen for 124
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Conclusions for Acute Exacerbation
of Chronic Bronchitis
 Moxifloxacin consistently demonstrated
equivalence to comparator
 Moxifloxacin is effective against the major
pathogens associated with AECB
 A five day treatment course is recommended
based on the favorable clinical and
bacteriologic results; the shorter duration may
increase compliance and facilitate
patient convenience
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Moxifloxacin
NDA Phase III
in
Community-Acquired
Pneumonia (CAP)
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CAP:
(North America and Ex-North America)
Clinical Resolution at Test-of-Cure
Study Study Design
(Location)
Moxifloxacin
Comparator*
400 mg x 10 days
# pts
% cure
# pts
% cure
D96-026
(NA)
Double-Blind
Prospective
Multi-center
194
95
188
95
D96-025
(NA)
Open, Noncomparative
196
93
-
-
119
(Ex-NA)
Double-Blind
Prospective
Multinational
152
93
153
92
0140
(Ex-NA)
Double-Blind
Prospective
Multinational
160
89
178
89
*119 and D96-026 – Clarithromycin 500 mg bid x 10 days
0140 - Amoxicillin 1 gm tid x 10 days
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Community-Acquired Pneumonia: Pathogen
Eradication Rates* by Culture at Test-of-Cure
Moxifloxacin
400 mg x 10 day
Pathogen
Control**
# isolates
% erad
# isolates
% erad
S. pneumoniae
88
89
74
88
H. influenzae
52
90
43
74
M. catarrhalis
14
86
7
86
K. pneumoniae
15
87
10
80
S. aureus
18
94
10
90
M. pneumoniae
83^
94
64
95
C. pneumoniae
132^
92
68
96
* Eradication + presumed eradication
** Clarithromycin 500 mg BID X 10 days or
Amoxicillin 1 gm tid X 10 days
^by culture and/or serology
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Summary and Conclusions for CAP
 Moxifloxacin is clinically and microbiologically
effective in CAP
 Moxifloxacin shows favorable activity against
typical and atypical target pathogens
associated with CAP
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Moxifloxacin
NDA Phase III
Clinical Program
Skin and Skin
Structure Infections
(SSSI)
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Uncomplicated Skin and Skin
Structure Infections
Clinical Response Rate (%) at Test-of-Cure
Study Number
97-005
0131
Design
Double-Blind
Prospective, Multicenter
Double-Blind
Prospective, Multinational
Moxifloxacin** 400 mg
Control**
# pts. % cure
# pts. % cure
145
89
136
90
132
95
150
93
**For study D97-005, moxifloxacin or cephalexin were administered for 7 days; for study 0131, moxifloxacin
was administered alone, while cephalexin was administered with/without metronidazole for 5-14 days
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Uncomplicated SSSI: Pathogen Eradication Rates*
in Microbiologically Evaluable Patients:
Moxifloxacin** 400 mg
Control**
Pathogen
# isolates
% erad
# isolates
% erad
S. aureus
50
92
45
93
S. pyogenes
1
100
3
67
S. agalactiae
5
80
5
80
S. aureus
50
92
42
88
S. pyogenes
9
89
12
92
S. agalactiae
1
100
0
0
D97-005
0131
* Eradication + presumed eradication
** For study D97-005, moxifloxacin or cephalexin were administered for 7 days; for study
0131, moxifloxacin was administered alone, while cephalexin was administered
with/without metronidazole for 5 - 14 days.
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Summary and Conclusions for
Skin and Skin Structure Infections
 Moxifloxacin is clinically effective and
microbiologically active for uncomplicated
SSSI infections
 A 400 mg dose once a day for 7 days is
recommended for optimal patient
compliance and convenience
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Proposed Indications and Durations
Dose: Moxifloxacin 400 Mg QD
Indication
Duration
(days)
Pathogens
Acute
Sinusitis
10
H. influenzae
S. pneumoniae*
M. catarrhalis
Bronchitis
(AECB)
5
H. influenzae
S. pneumoniae
M. catarrhalis
H. parainfluenzae
K. pneumoniae
S. aureus
CAP
10
H. influenzae
S. pneumoniae*
M. catarrhalis
K. pneumoniae
S. aureus
C. pneumoniae
M. pneumoniae
Skin/Skin
Structure
Infection
7
S. aureus
S. agalactiae
S. pyogenes
*Including penicillin-intermediate and – resistant S. pneumoniae
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Additional
Analyses
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Penicillin intermediate and resistant isolates of
S. pneumoniae from pivotal trials
(400 mg moxifloxacin and control)
Overall, 146 of 207 isolates (71%) of S. pneumoniae were penicillin susceptible
Moxifloxacin
Indication
Control
Penicillin
Susceptibility*
# isolates
% eradication**
(% Cure)
Sinusitis
I
R
8
6
88
100
(88)
(100)
-
-
-
CAP
I
R
19
8
89
75
(89)
(75)
10
3
80
100
(80)
(100)
AECB
I
R
4
1
75
100
(75)
(100)
1
4
100
75
(100)
(75)
All Studies
I
R
31
15
87
87
(87)
(87)
11
5
82
80
(82)
(80)
# isolates
% eradication**
(% Cure)
Susceptibility testing was done by standard microdilution technique or E-test method
*I = (Intermediate) - MIC range >0.1 - <2.0 g/mL, R (Resistant) - MIC range >2.0 g/mL
**eradication = eradication + presumed eradication
5/23/2016
58
Activity of Moxifloxacin Against DrugResistant S. pneumoniae
 Forty-six (37%) of the S. pneumoniae isolates
recovered from patients treated with
moxifloxacin had MICs in the penicillinintermediate/resistant range
 The high clinical success rate observed in
patients with penicillin-intermediate/resistant
S. pneumoniae suggests that these infections
respond to moxifloxacin 400 mg
 These clinical and eradication success rates
were either comparable or higher than those
observed for comparator
5/23/2016
59
Outcome Analysis: Acute Exacerbation
Chronic Bronchitis/Community Acquired
Pneumonia
Goal: To examine additional benefits of
moxifloxacin treatment
Methods:
 Retrospective analysis of data* from acute exacerbations of
chronic bronchitis and community-acquired pneumonia
indications
 Data analyzed for overall hospitalization rates
 Rates pooled across US and International studies vs
comparators
*all 400 mg moxifloxacin comparative NDA trials
5/23/2016
60
Outcome Analysis: Worsening of Respiratory
Conditions Resulting In Hospitalization (AECB
and CAP Studies)
Moxifloxacin
400 mg
(N=1925)
Control*
(N=1629)
Bronchitis
1 (0.05%)
4 (0.25%)
Pneumonia
13 (0.68%)
13 (0.80%)
Lung Disorder
4 (0.21%)
15 (0.92%)
Any of the Above
18 (0.94%)
30 (1.84%)
Adverse Events*
*worsening of respiratory conditions resulting in hospitalization, as
presented in COSTART terms
Conclusion: Hospitalization rates were significantly lower in
AECB and CAP patients treated with moxifloxacin than with
control (p=0.020)
5/23/2016
61
Efficacy Conclusions
 Moxifloxacin is microbiologically and clinically effective in
the treatment of acute sinusitis, AECB, CAP and skin and
skin-structure infections
 Clinical and eradication success rates for penicillinintermediate/resistant S. pneumoniae were either
comparable or higher than those observed for comparator
 Data from additional morbidity analysis demonstrate
favorable results for moxifloxacin vs comparator with
respect to hospitalization rates in CAP and AECB patients
5/23/2016
62
Review of
Moxifloxacin
Safety Profile
5/23/2016
63
Moxifloxacin Safety and Tolerability:
Dosing and Metabolism
 Moxifloxacin dosage adjustment is not
necessary for:
 age (pediatric population not studied)
 gender
 race
 renal or hepatic impairment
 Moxifloxacin is not metabolized by cytochrome
P450 enzyme system
 Moxifloxacin has no apparent clinical effects on
cytochrome P450 enzyme system
 Moxifloxacin exhibits balanced excretion by
both renal and biliary (fecal) route
5/23/2016
64
Moxifloxacin Safety and Tolerability:
Drug Interactions
 No clinically significant drug-drug interactions
 theophylline
 warfarin
 digoxin
 probenecid
 ranitidine
 glyburide
 Reduced moxifloxacin bioavailability with:
 antacids and iron (class interaction)
5/23/2016
65
Moxifloxacin Safety Profile
 Worldwide 5233 patients were enrolled in either 200
mg or 400 mg moxifloxacin treatment groups
 5189 (99.2%)* patients were evaluated for safety;
89% were treated with 400 mg moxifloxacin
 Of the 400 mg moxifloxacin-treated patients valid
for safety:
 4008 patients (87%) were enrolled in controlled trials
 625 patients (13%) were enrolled in uncontrolled trials
* 0.8% patients enrolled did not receive or have documentation of being given at least
one dose of study drug.
5/23/2016
66
Safety Procedures
Visit 1
(Baseline
Pre-therapy)
Visit 2
(During)
Visit 3
(End-ofTherapy)
Visit 4(1)
(Follow-up)
X
X
Patient Eligibility
X
Monitor Clinical
Evaluation
X
X
Labs:
Chemistries
Hematology
Electrolytes
Urinalyses
PT/PTT
Additional eg.
Theophylline
X
X
(3)
X
X
(4)
X
X
12 –Lead ECG’s
Monitoring AE’s
(2)
X
X
1 Follow-up usually 4 weeks after last dose of study drug.
2 Abnormal results repeated at appropriate intervals to assess reversibility.
3 ECG monitoring done at Cmax.
4 SAE monitored throughout follow-up.
X
5/23/2016
67
Moxifloxacin
Safety Profile
Extent of
Moxifloxacin Exposure
5/23/2016
68
Patient Exposure to Moxifloxacin
and Comparators
Number of Patients
Indication
(# Trials)
200 mg MXF
All
MXF
400 mg MXF
Uncontrolled
400 mg MXF
Controlled
Comparator
AECB (4)
233
1457
0
1224
924
AS (6)
26
1406
371
1009
1030
CAP (5)
267
1222
254
701
705
SSSI (3)
30
486
0
456
450
Others (3)
NA
618
0
618
580
Total (21)
556
5189
625
4008
3689
5/23/2016
69
Incidence of Adverse Events of Body System: Controlled
Studies with 400 mg Moxifloxacin and Control:
All Indications (Worldwide)*
MXF
Adverse
Event
Any Event
Nausea
Diarrhea
Headache
Dizziness
Abdominal Pain
Vomiting
Asthenia
Liver Functions
Abnormal
Dyspepsia
Rhinitis
Rash
Taste Perversion
GGTP
Amoxicillin
400 mg Control
(n=4008) (n=3689)
1 gm
(n=208)
Cefuroxime
Clarithromycin Cephalexin
250 mg 500 mg
500 mg
500 mg
(n=1005) (n=234)
(n=1166)
(n=266)
46%
9%
7%
5%
4%
3%
3%
2%
2%
45%
7%
6%
4%
2%
3%
2%
2%
2%
49%
<1%
6%
2%
<1%
1%
<1%
0%
11%
38%
4%
6%
4%
2%
2%
<1%
2%
<1%
47%
6%
6%
7%
1%
3%
<1%
1%
<1%
47%
7%
7%
4%
2%
2%
2%
1%
1%
36%
4%
4%
7%
1%
2%
<1%
<1%
<1%
2%
2%
2%
1%
<1%
2%
1%
2%
3%
<1%
<1%
<1%
2%
0%
5%
2%
3%
1%
1%
<1%
<1%
<1%
2%
0%
5%
2%
1%
1%
6%
0%
<1%
1%
2%
0%
0%
5/23/2016
70
Premature Discontinuations Due to Adverse
Events: Moxifloxacin 400 mg and Controlled
Studies (Worldwide)*
Moxifloxacin 400 mg
(n=4008)
# of events (%)
Control
(n=3689)
# of events (%)
Any Event
190 (5)
160 (4)
Nausea
Dizziness
Diarrhea
Vomiting
Rash
Headache
Abdominal Pain
Pruritus
Dyspepsia
Dyspnea
Nausea & Vomiting
Chest Pain
Insomnia
36 (0.9)
26 (0.6)
24 (0.6)
19 (0.5)
16 (0.4)
13 (0.3)
10 (0.2)
8 (0.2)
7 (0.2)
6 (0.1)
6 (0.1)
3 (0.07)
2 (0.05)
30 (0.8)
9 (0.2)
20 (0.5)
14 (0.4)
13 (0.4)
11 (0.3)
17 (0.5)
9 (0.2)
0
3 (0.08)
7 (0.2)
6 (0.2)
6 (0.2)
Adverse
Event
*Occurring in 5 or more patients in the 400 mg Moxifloxacin and/or Control groups. Most
common reasons for premature discontinuation were GI in nature and dizziness.
5/23/2016
71
Incidence of Serious Adverse Events
in Patients Valid for Safety Analysis*
Moxifloxacin 400 mg
(n=4008)
# of events (%)
Control
(n=3689)
# of events (%)
Any Event
158 (4)
167 (5)
Pneumonia
Chest Pain
Dyspnea
Atrial Fibrillation
Infection
Asthma
Carcinoma of Lung
Pleural Effusion
Apnea
Lung Disorder
Abdominal Pain
GU Surgery
16 (0.4)
10 (0.2)
9 (0.2)
6 (0.1)
5 (0.1)
5 (0.1)
5 (0.1)
5 (0.1)
4 (0.09)
4 (0.09)
3 (0.07)
3 (0.07)
14 (0.4)
3 (0.08)
5 (0.1)
0
6 (0.2)
4 (0.1)
5 (0.1)
1 (0.02)
6 (0.2)
16 (0.4)
6 (0.2)
8 (0.2)
Adverse
Event
*Occurring in 5 or more patients in the 400 mg Moxifloxacin or Control group
5/23/2016
72
Adverse Event Profile:
Controlled Trials
Moxifloxacin
400 mg (N=4008)
# patients; (%)
Comparator
(N=3689)
# patients; (%)
Incidence of Adverse Events
1856 (46%)
1654 (45%)
Incidence of Serious Adverse
Events
158 (4%)
167 (5%)
Premature Discontinuations
(Due to Adverse Events)
190 (5%)
160 (4%)
Conclusion:
Moxifloxacin was comparable to well-established
control drugs.
Most adverse events reported were mild to moderate
in severity and required no therapy
5/23/2016
73
Mortality Rates* Moxifloxacin 400 mg
Controlled Studies (Worldwide)
CAP + AECB
RTI + Skin
Moxifloxacin
400 mg
(N = 3390)
Control
(N = 3109)
Moxifloxacin
400 mg
(N = 1925)
CAP
Control
(N = 1629)
Moxifloxacin
400 mg
(N = 701)
Control
(N = 705)
#
Deaths
%
#
Deaths
%
#
Deaths
%
#
Deaths
%
#
Deaths
%
#
Deaths
%
7
0.21
15
0.48
5
0.26
15
0.92
4
0.57
12
1.70
P = 0.056
P = 0.009
P = 0.045
Conclusion:
Mortality rates were significantly lower in CAP and CAP/AECB
patients treated with moxifloxacin than with control.
*Deaths recorded through 30 days post study drug administration.
5/23/2016
74
Selected Events Associated with
Some Quinolones
Adverse Event
Moxifloxacin 400mg
(n=4008)
Comparators
(n=3689)
Seizures
Pain in Achilles tendon
Tendon Rupture
Phototoxicity
Elevated LFTs
1 (<0.1%)
2 (<0.1%)
0
2 (<0.1%)
63 (1.6%)
2 (<0.1%)
0
0
3 (<0.1%)
70 (1.9%)



In vitro and in vivo studies did not show evidence of phototoxicity
Double-blind, placebo controlled, clinical phototoxicity study
showed MED (Minimal Erythema Dose) at 7 days comparable
to placebo
No action taken for phototoxicity and pain in Achilles
tendon events
5/23/2016
75
Preclinical/Phase I Hepatic Safety
 Morphological liver alterations were seen in
monkeys only at lethal doses and were not seen in
dogs
 Elevations of liver enzymes were slight and
transient in nature
 Liver impairment did not influence the
pharmacology of moxifloxacin in Phase I trials
 Moxifloxacin is excreted via multiple routes (20%
renal, 51% hepatic and 25% trans-intestinal)
5/23/2016
76
Incidence Rates of Lab Abnormalities: (LFTs)
400mg Moxifloxacin vs Control Pool: Controlled
Studies (Worldwide)
Lab Variable
Criterion
400 mg MXF
Control
SGPT
>ULN
>1.8 x ULN
>3 x ULN
202/3482 (6%)
105/3730 (3%)
38/3788 (1%)
247/3183 (8%)
122/3394 (4%)
34/3474 (<1%)
SGOT
>ULN
>1.8 x ULN
>3 x ULN
268/3489 (8%)
70/3717 (2%)
28/3738 (<1%)
285/3173 (9%)
73/3397 (2%)
31/3461 (<1%)
Bilirubin
>ULN
>1.8 x ULN
>3 x ULN
108/3566 (3%)
13/3723 (<1%)
5/3755 (<1%)
70/3228 (2%)
13/3404 (<1%)
5/3424 (<1%)
Elevated LFT were observed similarly in the MXF and control
treated patients. No difference noted when comparing by gender,
race or age group. Premature discontinuations due to elevated
LFTs >3 x ULN were noted in equal numbers in MXF and
control patients.
5/23/2016
77
Moxifloxacin: Summary of Safety
 The only adverse events occurring in
> 5% of patients were nausea and diarrhea
 Premature discontinuation was <1% for any single
adverse event
 The mortality rates in CAP and CAP/AECB for
moxifloxacin-treated patients were lower than those
observed for the comparators
 Selected events associated with quinolones, ie
phototoxicity, LFT abnormalities and seizures were rare
with rates comparable to comparator agents
5/23/2016
78
Moxifloxacin: Summary of Attributes
 Pneumococcus activity
(including pen-resistant)
 H. flu and M. cat activity
(including -lactamase +)
 Activity against atypicals
 Optimal PK/PD for major
RTI organisms
 Once daily dosing for a short
duration (5-10 days)
 Minimization of resistance
 No dose adjustments in
special populations
 No interaction with the
cytochrome P450 system
 No significant drug-drug
interactions
 Favorable morbidity and
mortality trends
 Favorable safety profile,
including hepatic safety and
phototoxicity
5/23/2016
79
Conclusions
 Moxifloxacin is safe and effective in the
treatment of respiratory and skin infections
 The favorable PK/PD profile of moxifloxacin
enhances efficacy and safety
 Once daily, short (5-10D) courses of therapy
offer patients convenience, compliance and
safety advantages
5/23/2016
80
5/23/2016
81
QTc Background
Joel Morganroth, M.D.
Clinical Professor of Medicine
University of Pennsylvania
and
CEO, Premier Research
ECG Grid Paper
5 mm
1 mm
0.04 sec = 40 msec
0.20 sec = 200 msec
1.0 sec
How to Measure QTc
• Difficulties to Measure
 Noisy Baseline, Low Amplitude Signals
 Low T Wave Morphology
 Presence of U Waves
• Marked Variability: Normals = 15-70 msec
 Multiple Measures: + 75 msec, 5% > 500 msec
 Cardiac Patients More Variable, 20-90 msec
 Heart Rate is Major Influence: Bazett’s,
Fredericia’s, etc. correction
QTc Prolongation and
Arrhythmias
• Most investigators consider QTc interval
duration as a risk for Torsade de Pointes
when the absolute QTc > 500 msec.
• Epidemiologic data needed to link QTc
and Torsade due to rarity of this endpoint
Committee for Proprietary Medicinal
Products (CPMP) Criteria
QTc (msec)
Normal
Borderline
Prolonged
Risk of Arrhythmia
Male
<430
431-450
>450
>500
Change in QTc, msec
<30
31-60
>60
Female
<450
451-470
>470
>500
Implications
No concern
Possible drug effect
Arrhythmia concern
QTc dispersion: > 100 msec or increase > 100%
What Causes the QTc to
Lengthen?
•
•
•
•
•
•
•
Electrolyte Abnormalities
Bradycardia/ SA Blocks
Myocardial Ischemia/Infarction
Mitral Valve Prolapse
CNS Disorders
Endocrinopathy: Hypothyroidism
Congenital Long QT Syndrome
What Causes the QTc to
Lengthen?
• Drugs
 Antiarrhythmics (IA, III)
 Psychotropics (tricyclics,phenothiazines)
 Antibiotics (macrolides, sparfloxacin)
 Antihistamines (terfenadine, astemizole)
 Others (bepridil, ketanserin, probucol,
lidoflazine, cisapride…)
Drugs Listed in PDR with QT
Prolongation and/or Torsade de Pointes
erythromycin
clarithromycin
dirithromycin
azithromycin
itraconazole
fluconazole
ketoconazole
sparfloxacin
grepafloxacin
ganciclovir
foscarnet
saquinavir
amiodarone
procainamide
astemizole
flecainide
disopyramide
cisapride
sotalol
ibutilide
quinidine
omeprazole
risperidone
haloperidol
pimozide
mesoridazine
quietiapine
fluoxetine
desipramine
protriptyline
venlafaxine
nefazodone
bepridil
isradipine
nicardipine
penbutolol
salmeterol
albuterol
dolasetron
citalopram
tamoxifen
tolterodine
zolmitriptan
fluvoxamine
moexipril
LAAM
felbamate
fosphenytoin
octreotide
KCl
Kcitrate
Kayexelate
tizanidine
naratriptan
moricizine
Approved Drugs Not Listed in PDR as QT
Prolonging, but Listed in Literature, in Other
Drug Labels, or by Other Regulatory Agencies
amitriptyline
amoxapine
bupropion
clomipramine
doxepin
lithium
nortriptyline
maprotiline
imipramine
sertraline
tranylcypromine
trazodone
trimipramine
clozapine
chlorpromazine
droperidol
fluphenazine
loxapine
molindone
perphenazine
thioridazine
trifluoperazine
promethazine
prochlorperazine
thiethylperazine
thioridazine
bretylium
quinine
chloroquine
pentamidine
indinavir
ritonavir
troleandomycin
cimetidine
bumetanide
chlorothiazide
chlorthalidone
ethacrynic acid
furosemide
hydrochlorothiazide
indapamide
metolazone
polythiazide
methyclothiazide
torsemide
hydroxyzine
diphenhydramine hydroflumethiazide
amantadine
ampicillin
amiloride
aminophylline
atropine
bromocriptine
chloral hydrate
cyclobenzaprine
cyclosporine
diethylpropion
doxorubicin
epoprostenol
glyburide
tacrolimus
QT Interval Prolongation
• Clinical Symptoms
 None
 Torsade de Pointes
• Dizziness
• Syncope
• Death
Drugs That Prolong the QTc
Antiarrhythmics IA and III Increase QTc by 20-60
msec at Therapeutic Doses
Drug
%TdP/Yr
Reference
Ibutilide
Quinidine
8.3
1.5
12
Stambler, Circ ‘96
Roden, AHJ ‘86
Hohnloser, JACC ‘95
Sotalol
Amiodarone
2.4
1.0
MacNeil, AJC ‘95
Scheinman, Circ ‘95
Drugs That Affect QTc
• Terfenadine Story
 200M Patients - 83+ Cardiac ADRs
 5 cases TdP/million pt-mo
 At 60 mg b.i.d. - QTc Increases 6 msec
 QTc effect due solely to parent,
not metabolite
 Metabolized by CYP450 3A4 - blocked by
macrolides, ketoconazole, alcohol, overdose
Moxifloxacin-Related QT
Prolongation
Assessment of Clinical Risk
• Small QT effect at therapeutic doses- 6 msec
 similar to or less than multiple antibiotics
• Short duration of therapy
 indication: bacterial infections
• No drug interactions or clearance problems
 major advantage over other drugs with QT issues
• QT issue can be handled with appropriate
cautionary labeling
MOXIFLOXACIN AND
THE QT INTERVAL
Alan S. Hollister, M.D., Ph.D.
Bayer Corporation
5/23/2016
95
Introduction
During pre-clinical and Phase I development
of moxifloxacin a 6 msec mean prolongation
of the corrected QT (QTc) interval was
observed
5/23/2016
96
Why is QTc Prolongation an Issue?
 A risk factor for ventricular arrhythmias,
including Torsade de Pointes.
 Magnitude of prolongation does not
predict risk (within limits).
 Risk is greater with drug accumulation,
and/or in specific subpopulations.
5/23/2016
97
Moxifloxacin and the QTc Interval:
Presentation
 QT Background
 Pre-clinical evaluation of moxifloxacin
effect on the QT interval
 Analyses of ECG and clinical risk
predictors
 Evaluation of outliers, adverse events,
and deaths
5/23/2016
98
ECG Complexes and Intervals
QRS
complexes
and waves
P
P R
T
intervals and
segments
S T
Q
U
T
5/23/2016
99
QT Interval and Heart Rate
Correction
 QT interval = Depolarization +
Repolarization time
 Normal Range ~ 300 - 450/470 msec (M/F)
 Spontaneous variation ~ 75 msec
 Corrected QT Interval: Correction for
Heart Rate
 Bazett’s correction: QTc = QT/pRR
5/23/2016
100
Action Potential and Potassium
Currents
time (msec)
0
100
200
300
400
0
-20
0
membrane
potential (mV)
membrane
potential (mV)
+20
-40
-60
-80
-100
2
1
-90
Ito
Early After Depolarization
IK1
potassium
current
(IK1)
IKr + IKs
0
5/23/2016
101
Moxifloxacin Preclinical Studies
 Blockade of repolarizing K+ channels (Ikr and Iks)
 Varies by tissue preparation
 Concentration dependent prolongation of action
potential duration in guinea pig myocardium:
Threshold: moxifloxacin = 50 M
sparfloxacin = 3 M
 No appearance of early after depolarizations
5/23/2016
102
Preclinical Studies
Arrhythmia Models
 Anesthetized, methoxamine-infused rabbit:
 Moxifloxacin
 PVC’s in 1/6 at 96 mg/kg
 No tachyarrhythmias to 120 mg/kg
 Sparfloxacin
 PVC’s in 3/6 at 62, 82, and 120 mg/kg
 Ventricular tachycardias, including Torsade de
Pointes, in 3/6 at 70, 118, and 120 mg/kg
 Overdose in anesthetized dog:
 Ventricular arrhythmias only at extreme overdoses (50
fold) and plasma concentrations > 200 mg/l
 Not possible in conscious dog: CNS toxicity limits dose
5/23/2016
103
Rabbit Arrhythmia Model
Sparfloxacin vs. Moxifloxacin
400
VT,
TdP
VT
VT
QT interval, msec
350
slope:
2.1
sparfloxacin
300
slope:
1.2
250
moxifloxacin
200
test drug (2 mg/kg/min)
150
methoxamine (10 µg/kg/min)
100
0
10
20
30
40
50
60
minutes
5/23/2016
104
Moxifloxacin Effects on QTc:
Clinical Studies
ECG risk factors for arrhythmias and adverse
cardiac events:
 Magnitude of QT prolongation
 Dose dependent, and concentration dependent QT
prolongation
 QTc limits, using CPMP criteria
 Increased QT dispersion > 100 msec
 Reverse rate dependency of QTc prolongation
 Others
5/23/2016
105
Mean + S.D. QTc Change from Baseline
(msec): All Comparative Studies
Data Pool
Worldwide
n
)QTc
Moxifloxacin 400 mg
787
6 ± 26
All Comparators
Clarithromycin
Cephalexin
Cefuroxime 250
Cefuroxime 500
Amoxicillin
759
136
167
266
47
110
1 ± 23
2 + 23
3 ± 16
2 ± 20
-8 ± 15
-4 ± 30
North America
n
)QTc
595 8 ± 20
562
104
167
244
47
2 ± 18
6 + 20
3 ± 16
2 ± 19
-8 ± 15
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Antibiotics with QTc Prolongation:
Clinical Studies
Drug
Interactions
Elimination
Issues
yes
Hepatic
clarithromycin
oral 13.8 msec1
i.v. 51 msec2
3 - 11 msec3-5
yes
Renal
grepafloxacin
10 msec6
yes
Hepatic
sparfloxacin
11 msec1,4,5,7
---
Renal
Drug
erythromycin
QTc Prolongation
1. Jaillon P, et al., J Antimicrob Chemother 1996; 37 (Suppl A): 161.
2. Oberg KC, Bauman JL, Pharmacother 1995; 15: 687.
3.
4.
5.
6.
7.
van Haarst AD, et al., Clin Pharmacol Ther 1998; 64: 542.
Henry DC, et al., Clin Ther 1999; 21: 340.
Ramirez J, et al., Clin Ther 1999; 21: 103.
Glaxo-Wellcome, data on file, 1997.
Lipsky BA, et al., Clin Ther 1999; 21: 675.
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QTc versus Moxifloxacin
Concentration Phase I Data at Cmax
n = 211
slope = 3.1 msec / mg/l
r = 0.16
p = 0.02
normal
limit
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Committee for Proprietary Medicinal
Products (CPMP) Criteria
QTc (msec)
Normal
Borderline
Prolonged
Risk of Arrhythmia
Change in QTc, msec
<30
31-60
>60
Male
<430
431-450
>450
>500
Female
<450
451-470
>470
>500
Implications
No concern
Possible drug effect
Concern for Arrhythmias
QTc dispersion > 100 msec, or increase > 100%
European Union Regulatory Authority
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Outlier Frequency by Drug Treatment:
Modified CPMP Criteria
n
Moxifloxacin
787
All Comparators 759
Clarithromycin 136
Cephalexin
167
250 CefuroximeAxetil b.i.d
266
500 CefuroximeAxetil b.i.d.
47
Amoxicillin
110
DoxycyclineMetronidazole 23
QTc ) >
Any QTc
)QTc
30 msec
> 500 msec > 60 msec to abnl
3 (0.4%)
1 (0.1%)
0
0
0
0
1 (0.9%)
0
10 (1.3%)
2 (0.3%)
0
0
0
0
1 (0.9%)
1 (4.3%)
%)QTc
> 15%
13 (1.7%) 13 (1.7%)
13 (1.7%) 4 (0.5%)
5 (3.7%)
0
0
0
Any QTc
Outlier
21 (2.7%)
17 (2.2%)
5 (3.7%)
0
4 (1.5%)
2 (0.8%)
0
4 (3.6%)
0
1 (0.9%)
0
5 (4.5%)
1 (4.3%)
1 (4.3%)
0
6 (2.3%)
All paired valid, Worldwide
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Effects of Moxifloxacin on QTc
Dispersion (Phase I)
QT and QTc Interval Dispersion (msec) at expected Cmax
(N=17)
Parameter
Placebo
Moxifloxacin
400mg p.o.
Moxifloxacin
800mg p.o.
QT dispersion
27.1/12.6*
25.2/11.0
27.7/11.0
QTcB **
dispersion
27.9/13.9
26.0/11.6
28.5/11.1
*arithmetic means/standard deviation
** QTcB: QT corrected by Bazett’s formula
Conclusion: Moxifloxacin does not increase QT dispersion
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Reverse Rate Dependency
Per Cent QT Changes Between
Oral Doses and Placebo
(n = 17)
QT Changes (%)
5
4
3
2
1
0
40
60
80
100
120
Heart Rate
400 mg
140
160
800 mg
Conclusion: No reverse-rate dependency was observed with moxifloxacin
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Change in QTc for Patients in Top
Quartile for Baseline QTc
Moxifloxacin 400 mg
All Comparators
Clarithromycin
n
Mean + SD
Change in
QTc, msec
312
273
-8 + 25
-12 + 26
58
-8 + 25
Conclusion: Patients with longer baseline QTc are
not at greater risk for QTc prolongation.
Expanded ITT, All Studies
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Summary of ECG Risk Factors for QT
Prolongation in Moxifloxacin Studies
 Magnitude
 Dose/Concentration
Dependence
 QT Outliers (CPMP
Criteria)
- mean 6 msec
- yes, shallow




-
QTc Dispersion
Reverse Rate Dependency
Long Baseline QTc
QRS Widening
 T Wave Abnormalities
 New U Waves
- no overall difference
no effect
none
QTc decreases
none
- unchanged
- no differences
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QT Prolongation-Associated Clinical
Risk Factors






Cardiovascular disease
Age
Gender
Electrolyte abnormalities, 9K+
Bradycardia
Drug interactions that increase the concentration of
relevant drug
 Reduced organ function that increases concentration of
relevant drug
 Concomitant drugs that increase the QTc interval
 Metabolites with increased risk or accumulate in organ
dysfunction
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Clinical Risk Factors
n
Mean + S.D. QTc
Change, msec
 Cardiovascular Disease
 Present
122
4 + 28
 Absent
665
7 + 25
 < 65 years
651
7 + 25
 > 65 years
136
2 + 28
 Male
353
5 + 26
 Female
434
7 + 25
 Age
 Gender
All Comparative Studies, Worldwide
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Clinical Risk Factors
Risk Factor
 Electrolyte Imbalance
 Normal
 K+ < 3.5
n
764
22^
Mean + S.D. QTc
Change, msec
6 + 24
5 + 26
 Heart Rate
 Normal
 Bradycardia*
707
6 + 23
80
0 + 24
^ excludes one patient with all intervals doubled
* < 60/min, absolute QT
All Comparative Studies, Worldwide
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Clinical Risk Factors:
Drug Interactions
 Moxifloxacin does not inhibit cytochrome
P450 enzymes.
 No Phase I drug-drug interactions
 Moxifloxacin is not metabolized by the
P450 system, including the 3A4
isoenzyme.
 No risk for accumulation with coadministration of inhibitors
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Moxifloxacin Drug Interaction Studies
Metabolizing CYP
Isoenzyme
Drug
Theophylline
Glyburide
Warfarin
Ranitidine
1A2
3A4
2C9
weak inhibitor
Results
No Change
Glyburide Sl. 9
No Change
No Change
Conclusion: No increase in moxifloxacin levels, nor
in those of concomitant drugs.
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Clinical Risk Factors
Risk Factor
 QT Prolonging Drugs*
 Present
n
Mean + SD QTc
Change, msec
61
6 + 44
1085
7 + 25
 Normal
8
5 + 14
 < 30 ml/min
8
6 + 14
8
7 + 18
10
4 + 26
 Absent
 Renal Function**
 Hepatic Function**
 Normal
 Reduced
*All Comparative Studies, Worldwide
**Phase I studies
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Summary: Clinical Risk Factors for QT
Prolongation in Moxifloxacin Studies




Cardiovascular disease
Age, gender
Drug Interactions
Concomitant “QT” drugs
 Organ Dysfunction
 Electrolyte imbalances
 Bradycardia
- no change in )QTc
- no change in )QTc
- no metabolic interactions
- no change in )QTc
- no drug accumulation,
no change in )QTc
- no change in )QTc
- no change in )QT
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Is There an Increased Risk for
Cardiovascular AEs in Patients Who Are
QTc Outliers?
Drug
Moxifloxacin
Comparators
n
4008
3689
DQTc
Outliers
n
38
28
CV Events*
1 [sinus tachycardia]
4 [2 sinus tachycardia,
1 atrial flutter, 1 vent.
arrhythmia]
Conclusion: No increased risk of CV AEs in moxifloxacin-treated
patients who exhibit CPMP criteria QTc prolongation.
*Includes cardiac arrest, sudden death, syncope, palpitations,
clinically diagnosed arrhythmias.
Phase III Comparative Studies, Worldwide
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Incidence of Treatment-Emergent Clinical
AEs Considered Surrogates for QTc
Prolongation
Worldwide, 400 mg, Controlled Trials
Clinical Event
Moxifloxacin- All ComparatorTreated
Treated
(n = 3689)
(n = 4008)
Tachycardia
Angina, Chest Pain, MI
Palpitation
CHF/LV Failure
Syncope
Arrhythmia
19 (0.5%)
11 (0.3%)
11 (0.3%)
10 (0.2%)
9 (0.2%)
3 (0.1%)
15 (0.4%)
10 (0.3%)
10 (0.3%)
8 (0.2%)
7 (0.2%)
3 (0.1%)
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Deaths in Moxifloxacin Clinical Development
Program in Relation to Therapy
1.0%
Comparator
Moxifloxacin 400 mg
0.5%
0.0%
*
s
py**
days
a
days
eat h
r
7
0
e
D
3
n
h
y
T
in
th i
An
s on
s wi
w i th
h
h
t
s
t
a
h
a
t
De
De
D ea
* Within 30 days of study drug discontinuation
** Within one day of last dose of study drug
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Moxifloxacin and the QTc Interval:
Conclusions
 Moxifloxacin produces a 6 msec mean
QTc prolongation
 No ECG or clinical predictors for
excessive QTc prolongation by
moxifloxacin
 Patients with the greatest changes in
QTc did not experience more
cardiovascular adverse events
 Deaths were less common in
moxifloxacin-treated patients
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Moxifloxacin
Benefit - Risk Evaluation
Benefit









Broader spectrum of coverage
Improved efficacy ratios
Superior resistance characteristics
Straightforward PK, elimination
Short duration, once daily therapy
No dose adjustments
No CYP 450 interactions
No liver, CNS, phototoxicity
Favorable morbidity and mortality
trends
Risk
-QTc prolongation
without other ECG,
subpopulation, or
clinical evidence
of risk.
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Proposed QT Labeling
Warnings
Moxifloxacin, as with some other quinolones and
macrolides, has been shown to prolong the QTc
interval of the electrocardiogram. The degree of
mean (+ standard deviation) QTc prolongation
with moxifloxacin in clinical trials was 6 (+ 26)
msec compared with 2 (+ 23) msec in patients
treated with clarithromycin. Consequently,
moxifloxacin should be used with caution in
patients with congenital or acquired syndromes of
QTc prolongation or in patients taking
concomitant medication known to prolong the
QTc interval (e.g. class Ia and Class III
antiarrhythmics).
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Moxifloxacin Summary
Stephen H. Zinner, MD
Charles S. Davidson Professor of
Medicine, Harvard Medical School
Chair, Department of Medicine
Mount Auburn Hospital
Cambridge, MA
Stephen H. Zinner, MD
Disclosures
Consultant:
Research Support:
Abbott Labs
Bayer Corp.
Bayer Corp*.
Bristol Myers Squibb
Bristol-Myers Squibb*
Glaxo-Wellcome
Glaxo-Wellcome
HMR
Hoechst Marion Roussel
Pfizer
Pfizer*
SKB
Pharmacia and Upjohn
Rhône-Poulenc Rorer*
SmithKline Beecham
Wyeth-Ayerst Labs*
Astra-Zeneca Pharmaceuticals
Moxifloxacin is safe and effective for
• Acute Exacerbations of Chronic Bronchitis
• Community Acquired Pneumonia
• Acute Sinusitis
• Skin and Skin Structure Infection
And, Moxifloxacin has:
• Excellent in vitro activity against common RTI organisms
• Pharmacokinetics that promote rapid killing
• Novel properties that might minimize antibiotic resistance
• Possible positive impact on mortality and hospitalization
in LRTI.
New antimicrobials are needed
in today’s clinical environment
• Resistance in respiratory tract pathogens is increasing
 High level penicillin resistance to S. pneumoniae up to 10-15%
 Beta-lactamase + strains of M. catarrhalis; H. influenzae
 Macrolides (20-40% PRSP)
• Respiratory infections continue to be associated with
significant morbidity and mortality
• New Pathogens (e.g. atypicals)
Therapy is usually empiric, directed against all of the
common causative organisms.
Moxifloxacin:In-vitro activity against
common RTI pathogens
MIC 90 (mg/l)
• S pneumoniae
0.25
• H influenzae
0.06
• H parainfluenzae
0.25
• M catarrhalis
0.06
• S aureus
0.12
• S pyogenes
0.25
• Legionella spp
0.12
• M pneumoniae
0.06
• C pneumoniae
1.0
Activity of moxifloxacin against RTI organisms is
not affected by B-lactam or macrolide resistance
Organism
S pneumoniae
pen-s
pen-r
MXF
LEV
CLR
AM/C
CXM
0.25
0.25
1.0
1.0
<0.03
>32
0.03
4.0
<0.12
8.0
H influenzae
B-lactamase B-lactamase +
0.06
0.06
0.03
0.03
8.0
8.0
2.0
2.0
1.0
2.0
M catarrhalis
B-lactamase B-lactamase +
0.06
0.06
0.06
0.06
0.12
0.12
0.06
0.06
0.05
2.0
- MXF = moxifloxacin
- CLR= Clarithromycin
- LEV= Levofloxacin
- AM/C- Amoxicillin Clavulante
- CXM = Cefuroxime
Antimicrobial Resistance
Common properties for fluoroquinolones
• Not affected by B-lactamases or other mechanisms
including those that affect macrolides or aminoglycosides
Differences do exist among fluoroquinolones with
respect to resistance mechanisms
• Nor A mutations - efflux pump
• Topoisomerase mutations-gyrase II and topo IV
Moxifloxacin: Resistance Perspectives
• Efflux pump mechanism virtually no effect
on MXF
• Needs 2 mutations to cause resistance in vitro
• In-vitro passage studies show a low
propensity for resistance
• No in vivo resistance development in rat
granuloma model
Moxifloxacin:
Pharmacokinetics/Pharmacodynamics
• >90% Bioavailable; Cmax = 4.5 mg/l
• Long T1/2 - 12 hours
• High serum and tissue levels
– >MIC90 for most RTI pathogens over entire dosing
interval
• Cmax/MIC90 (S. pneumoniae) -- 18
• AUC/MIC90 (S. pneumoniae) -- 192
• Rapidly bactericidal
Moxifloxacin: Clinical Profile
• Development focused on Acute Sinusitis,
AECB, CAP, SSSI
• 400 mg p.o. QD: 5-10 days
• Studies designed to show equivalence with FDA
approved comparators:
 AECB - Clarithromycin
 CAP - Clarithromycin, Amoxicillin
 Sinusitis - Cefuroxime axetil
 Skin/Skin Structure - Cephalexin
Moxifloxacin: Safety Profile
• Over 5,000 patients received 400mg QD
 ~39,000 exposure days
• Adverse events - most events <5%, except
nausea 9%, diarrhea 7%; no surprises
• Discontinuations MXF = comparators
• Serious AE’s MXF = comparators
Moxifloxacin: Safety Profile
•
•
•
•
No hepatotoxicity
No nephrotoxicity
No phototoxicity
QTc prolongation comparable to
commonly used antimicrobials
 no cardiac events related to QTc
Moxifloxacin: Clinical Pharmacology
Supports Complete Safety Profile
• Balanced metabolism and elimination
• Not metabolized by P450 system
• No drug-drug interactions

No dosage adjustments needed in renal or
hepatic insufficiencies

No risk for serious adverse events due to
interactions with other agents

Minimizes risk associated with slight
QTc prolongation
Unanticipated Outcomes
• Lower overall mortality rate in
RTI studies
• Lower rates of hospitalization than
comparators in RTI treated patients
Summary
• Moxifloxacin demonstrates safety and efficacy for its
proposed indications: treatment of AS, AECB, CAP
and SSSI
• Moxifloxacin’s benefits balance any theoretical risk
attributed to a small prolongation in the QTc interval,
especially given its metabolism and excretion
• Any potential risk attributed to QTc prolongation is
appropriately addressed in proposed labeling
Summary (2)
• Despite limited clinical data, moxifloxacin is
effective in infections caused by PRSP
• Moxifloxacin is a useful addition to the
antibiotic armamentarium: In addition to its
clinical success, it might also provide a
beneficial effect on hospitalizations, mortality
and antibacterial resistance