# Presentation: 659769

## Slide 1

## AVELOX (moxifloxacin HCl)NDA # 21-085

**Introduction**
*Carl E. Calcagni, R.Ph.*
*Vice President, Regulatory Affairs*
*Bayer Corporation, Pharmaceutical Division*

## 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**

## 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**
**  ****	****  **

## 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**

## 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**

## AVELOX (moxifloxacin HCl)NDA # 21-085

**Dosage Administration and Proposed Indications**
**	****	****	**_**Indication**__**	**__**	**__**	**__**	**__**Duration**_
**	****Acute Bacterial Exacerbation of Chronic****	****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***

## Agenda

**Introduction:****	****	****Carl E. Calcagni, R.Ph.**
**	****	****	***Vice President, Regulatory Affairs, Bayer*
**Efficacy/Safety:****	****	****Deborah Church, M.D.**
**	****	****	***Director Anti-Infectives, Medical, Bayer*
**QTc Background:****	****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*
*	**	**	**	*

## 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***

## Overview

**Efficacy**
**Rationale for Development**
**Microbiology**
**Drug resistance**
**PK/PD**
**Clinical / bacteriologic results for AS, AECB, CAP and SSSI**
**Outcomes Analysis**

**Safety**
**Dosing and Metabolism**
**Drug Interactions**
**Extent of Exposure**
**Adverse Events**
**Premature Discontinuations**
**Serious Adverse Events**
**Deaths**
**Selected quinolone-related events**

## Moxifloxacin:
Rationale for
Development

**Rationale for**
**Development**

## Rationale for Development

**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**

## Decreasing Penicillin/Macrolide Susceptibility of S. pneumoniae in the US

**Spika et al.**
**Doern et al.**
**MRL RTI Surveillance Study, 1997-1998, Data on File**

**% Susceptible**

## Rationale for the Design of Moxifloxacin

**Increased knowledge of quinolone structure-activity 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**

## Chemical Structure of Moxifloxacin

**Minimizes development of resistance **
**Enhances anaerobic activity**

**Minimizes efflux (*****S. pneumoniae, S. aureus*****) **
**Enhances gram-positive activity**

**Petersen *****et al***** 1996****	****Domagala, JM 1994**

**Chemical Structure of Moxifloxacin**

**F**

**O**

**OH**

**O**

**H**

**H**

***HCI**

**NH**

**N**

**N**

**O**

***6***

***5***

***7***

***8***

***4***

***1***

***2***

***3***

## Microbiology of

**Moxifloxacin**

## In Vitro Activity of Moxifloxacin Against Key RTI Pathogens

***Pathogen****** ******(# of isolates)***

***                     ******Strain***
**Penicillin-Susceptible****Penicillin-Intermediate****Penicillin-Resistant**
****** ****-Lactamase negative******** -Lactamase positive**
****** ****-Lactamase negative******** -Lactamase positive**
***Legionella spp*****. (149)*****Chlamydia pneumoniae***** (19)*****Mycoplasma pneumoniae***** (131)**

***S. pneumoniae*****(6636)**

***H. influenzae*****(1892)**

***M. catarrhalis*****(1203)**

**Atypicals**

***MIC******90****** (************g/mL)***
**0.25****0.25****0.25**
**0.06****0.06**
**0.06****0.06**
**0.125****1****0.06**

**NDA Data on File**

## In Vitro Activity of Moxifloxacin Against Other RTI Pathogens

***Pathogen (# of isolates)***

***H. parainfluenzae*****(81)**

***K. pneumoniae*****(138)**

***S. aureus*****(835)**

***S. pyogenes*****(1607)**

***MIC******90****** (************g/mL)***
**0.25**
**1**
**0.125 (MS*)****4 (MR*)**
**0.25**

**MS* = Methicillin Susceptible, MR* = Methicillin Resistant**

## In Vitro Activity of Moxifloxacin Against Other Pathogens

**Moxifloxacin is active against:**
**A wide variety of clinically important anaerobic species**
***	******	******	******Bacteroides*****                 *****Peptostreptococcus***
**	****	****           ****(MIC****90**** 2 ********g/mL)****	****           (MIC****90**** 0.25 ********g/mL)**
**	****MIC****90**** value is less than 2  ********g/mL for the majority of anaerobes**
**Active against *****M. tuberculosis***** (MIC****90**** 0.5 ********g/mL)**

## Moxifloxacin MIC90 for S. pneumoniae is Unaffected by Resistance to Penicillin

**Moxifloxacin MIC****90**** for *****S. pneumoniae***** is Unaffected by Resistance to Penicillin**

|  |
| --- |
| S. pneumoniae
  Pen-S (n=3603) |
| Pen-I (n=1267) |
| Pen-R (n=770) |

| MXF |
| --- |
| 
0.25 |
| 0.25 |
| 0.25 |

| LEV |
| --- |
| 
1.0 |
| 1.0 |
| 1.0 |

| CIP |
| --- |
| 
1.0 |
| 1.0 |
| 1.0 |

| CLR |
| --- |
| 
0.03 |
| 32 |
| >32 |

| AZM |
| --- |
| 
0.06 |
| >4.0 |
| >4.0 |

| AMC |
| --- |
| 
0.03 |
| 1.0 |
| 4.0 |

| CXM |
| --- |
| 
<0.12 |
| 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.**

**MIC: ********g/mL**

## Moxifloxacin

**and**
**Drug Resistance**

## 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 C****min**

## Differential Emergence of Resistance Between Levofloxacin and Moxifloxacin (S. pneumoniae 4241)

- = LEV 	= MXF

**Differential Emergence of Resistance Between Levofloxacin and Moxifloxacin ****(*****S. pneumoniae***** 4241)**

**100**

**MIC: ********g/mL**

**Data on File**

**Slow development of resistance to MXF and to a lesser extent than LEV.**

**10**

**0.1**

**1.0**

**100**

## Differential Emergence of Resistance Between Levofloxacin and Moxifloxacin(S. aureus 133) 

**Number of Passages from serial exposure at 0.5 x MIC**

- = LEV 	= MXF

**MIC: ********g/mL**

**Data on File**

**Slow development of resistance to MXF and to a lesser extent than LEV.**

**100**

**10**

**0.1**

**1.0**

**100**

## No Development of Moxifloxacin Resistance in Rat Granuloma Pouch Model

**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.**

| Infecting Organism | Type of Mutant
Created | MXF MIC
(g/ml)
Day 0 | MXF MIC
(g/ml)
Day 8 |
| --- | --- | --- | --- |
| S. aureus
133

S. pneumoniae 4241 | Wild Type
1st Step
Multi-Step
Wild Type
1st Step
Multi-Step | 0.06
0.12
2
0.12
0.25
1 | 0.06
0.12
2
0.12
0.25
1 |

## 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)**

## Moxifloxacin

**Pharmacokinetics and**
**Pharmacodynamics**

## Pharmacokinetics of Moxifloxacin Support Once Daily Oral Dosing of 400 mg 

**Plasma Concentration (mg/L)**

**Time (hours)**

**Steady-State Plasma Concentrations of Moxifloxacin Obtained With Once Daily Dosing of 400 mg (mean;SD) (n=10)**

- 0.25 (*S. pneumoniae*)

- 0.125 (*S. aureus*)

- 0.06 (*H. influenzae*)
- 	(*M. catarrhalis*)

**Pharmacokinetics of Moxifloxacin Support Once Daily Oral Dosing of 400 mg **

**MIC****90**

## Moxifloxacin and Levofloxacin Concentrations in Plasma and Respiratory Tissue

**7.6 **_**+**_** 1.7**

**3.7 **_**+**_** 1.1**

_***Sinus***_
**Maxillary Sinus Mucosa**

**61.8 **_**+**_** 27.3**
**5.5 **_**+**_** 1.3**
**24.4 **_**+**_** 14.7**

**3.3 **_**+**_** 0.7**
**3.3 **_**+**_** 0.7**
**3.3 **_**+**_** 0.7**

_***Respiratory***_
**Alveolar Macrophages**
**Bronchial Mucosa**
**Epithelial Lining Fluid**

***Tissue or Fluid******Concentration* (************g/ml************or ************g/g)***

***Plasma Concentration* (************g/ml)***

***Tissue or Fluid***

- 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

## Moxifloxacin Pharmacokinetics/Pharmacodynamics

**PK/PD Parameters that best correlate with Quinolone Efficacy***
**C****max**** / MIC****90 **_**>**_** 8-10**
**AUC / MIC****90 ****> 100**

***for review, see Craig, 1998**

## Cmax/MIC90* Data for Selected Quinolones^

**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**

**C****max****/****MIC****90***** ****Data for Selected**** ****Quinolones^**

|  |
| --- |
| S. pneumoniae
H. influenzae
M. catarrhalis |

| MXF | LEV | CIP | SPFX | GREP |
| --- | --- | --- | --- | --- |
| 18
150
75 | 5.7
190
95 | 4.3
143
72 | 2.2
37
37 | 5.4
90
90 |

*** For optimal antibiotic effect and to minimize development of resistance, the C****max****/MIC****90**** ratio should be at least 8-10 (for review, see Craig 1998)**
**^ Clinical correlation not confirmed**

## AUC/MIC90* Data for Selected Quinolones^

**AUC/MIC****90***** Data for Selected Quinolones^**

**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.**

*** For optimal antimicrobial effect and to minimize resistance, AUC/MIC****90**** should be > 100 (for review, see Craig 1998)**
**^ Clinical correlation not confirmed**

|  |
| --- |
| S. pneumoniae
H. influenzae
M. catarrhalis |

| MXF | LEV | CIP | SPFX | GREP |
| --- | --- | --- | --- | --- |
| 192
1600
800 | 47.5
1583
792 | 20.2
673
337 | 37
940
623 | 56.4
623
940 |

## Summary of Moxifloxacin PK/PD Attributes

**Moxifloxacin PK supports qd dosing and provides plasma and tissue levels above the MIC****90**** 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 (C****max****/MIC;AUC/MIC) compared with other fluoroquinolones**

## Moxifloxacin
Clinical Development

**Clinical Development**

## 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**

## 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

**	****	****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**

**Phase II/Phase III ****Clinical Development Program**** (*****continued)***

## 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)**

## Moxifloxacin
NDA Phase III
Acute Sinusitis
Clinical Program

**NDA Phase III**
**Acute Sinusitis**
**Clinical Program**

## Acute Sinusitis (North America)

**Clinical Resolution at Test-of-Cure**

| 100107
D96-024
D96-023 | Double-Blind ProspectiveMulti-center
Double-Blind Prospective Multi-center
Open Non-comparative |
| --- | --- |

| Moxifloxacin
400 mg qd | Cefuroxime
250 mg BID |
| --- | --- |

**Acute Sinusitis (North America)**

| Study # |
| --- |

**% Cure**
**89**
**91**
**-**

**Total # Pts.**
**234**
**193**
**-**

**% Cure**
**90**
**-**
**-**

**Total # Pts.**
**223**
**-**
**-**

**% Cure**
**-**
**81**
**80**

**Total # Pts.**
**-**
**191**
**336**

*** ******10 Days***

***10 Days***

***7 Days***

## Acute Sinusitis (Ex-North America)

**Acute Sinusitis (Ex-North America)**

**Clinical Response at Test-of-Cure**

| Moxifloxacin
400 mg qd | Cefuroxime
250 mg BID  |
| --- | --- |

**% Cure**
**84**
**95**

**Total # Pts.**
**212**
**222**

**% Cure**
**-**
**94**

**Total # Pts.**
**-**
**217**

**% Cure**
**90**
**-**

**Total # Pts.**
**195**
**-**

*** ******10 Days***

***10 Days***

***7 Days***

| Study #   Study Design |
| --- |

| 
Double-Blind Prospective Multi-center
Double-Blind Prospective Multi-center
 |
| --- |

## Acute Sinusitis: Pathogen Eradication Rates at Test-of-Cure Visit*

**Acute Sinusitis: Pathogen Eradication Rates at Test-of-Cure Visit***

***  Eradication + presumed eradication, Pathogens isolated by needle aspiration**

**Moxifloxacin 400 mg**

**         ****Cefuroxime 250 mg BID**

- %erad

- #isolates

**98**

**46**

**88**

**86**

**25**

**42**

***7 Days***

- %erad

- #isolates

**95**

**20**

**67**

**85**

**3**

**13**

***10 Days  ***

## 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**

## Moxifloxacin NDAPhase IIIAcute Exacerbation ofChronic Bronchitis (AECB)Clinical Program

## AECB: (North America and Ex-North America) 

**AECB: ****(North America and Ex-North America)**

**Clinical Resolution at Test-of-Cure**

**91**
**-**

**256**
**-**

**% cure**

**# pts**

***D96-027 – Clarithromycin 500 mg BID x 10 days**
**124 – Clarithromycin 500 mg BID x 7 days**
** **

**89**
**89**

**250**
**322**

**% cure**

**# pts**

**89**
**88**

**251**
**327**

**% cure**

**# pts**

## AECB: Overall Pathogen Eradication Rates* at Test-of-Cure (All studies pooled)

**#isolates**
**81**
**54**
**50**
**17**
**20**
**25**

**%erad**
**90**
**89**
**86**
**94**
**85**
**84**

**#isolates**
**84**
**59**
**48**
**19**
**11**
**18**

**%erad**
**64**
**95**
**98**
**84**
**91**
**100**

***includes eradication + presumed eradication**
****10 day regimen for D96-027, 7 day regimen for 124**

## 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**

## Moxifloxacin

**NDA Phase III****in**
**Community-Acquired**
**Pneumonia (CAP)**

## CAP: (North America and Ex-North America)

**CAP: ****(North America and Ex-North America)**

**Clinical Resolution at Test-of-Cure**

***119 and D96-026 – Clarithromycin 500 mg bid x 10 days**** 0140 - Amoxicillin 1 gm tid x 10 days**

**95**
**93**
**93**
**89**

**194**
**196**
**152**
**160**

**% cure**

**# pts**

**95**
**-**
**92**
**89**

**188**
**-**
**153**
**178**

**% cure**

**# pts**

## Community-Acquired Pneumonia: Pathogen Eradication Rates* by Culture at Test-of-Cure

***    Eradication + presumed eradication                 ^by culture and/or serology**
****  Clarithromycin 500 mg BID X 10 days or**
**     ****Amoxicillin 1 gm tid X 10 days**

**Community-Acquired Pneumonia: Pathogen Eradication Rates* by Culture at Test-of-Cure**

## 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**

## Moxifloxacin

**NDA Phase III**
**Clinical Program**
**Skin and Skin**
**Structure Infections****(SSSI)**

## Uncomplicated Skin and SkinStructure Infections

********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**

**Uncomplicated Skin and Skin****Structure Infections**

**Clinical Response Rate (%) at Test-of-Cure**

**97-005**
**0131**

**89**
**95**

**% cure**

**145**
**132**

**# pts.**

**90**
**93**

**% cure**

**136**
**150**

**# pts.**

**Double-Blind Prospective, Multi-center ****Double-Blind Prospective, Multi-national **

## Uncomplicated SSSI: Pathogen Eradication Rates* in Microbiologically Evaluable Patients: 

**Uncomplicated SSSI:** **Pathogen Eradication Rates* in Microbiologically Evaluable Patients: **

***   ****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.  **

## 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**

## 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 ***

## Additional 

**Analyses**

## Penicillin intermediate and resistant isolates of S. pneumoniae from pivotal trials (400 mg moxifloxacin and control)

***(87)***
***(87)***

***(75)***
***(100)***

***(89)***
***(75)***

***(88)***
***(100)***

***87***
***87***

***31***
***15***

***I***
***R***

***All Studies***

***% eradication*****
***(% Cure)***

***75***
***100***

***4***
***1***

***I***
***R***

***AECB***

***89***
***75***

***19***
***8***

***I***
***R***

***CAP***

***88***
***100***

***8***
***6***

***I***
***R***

***Sinusitis***

***# isolates****** ***

***Penicillin Susceptibility****

***Indication***

**Overall, 146 of 207 isolates (71%) of *****S. pneumoniae***** were penicillin susceptible**

**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**

***(82)***
***(80)***

***(100)***
***(75)***

***(80)***
***(100)***

***82***
***80***

***11***
***5***

***% eradication*****
***(% Cure)***

***100***
***75***

***1***
***4***

***80***
***100***

***10***
***3***

***# isolates****** ***

***Moxifloxacin***

***Control***

***-***
***-***

***-***
***-***

***-***
***-***

## Activity of Moxifloxacin Against Drug-Resistant S. pneumoniae

**Forty-six (37%) of the *****S. pneumoniae***** isolates recovered from patients treated with moxifloxacin had MICs in the penicillin-intermediate/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**

## 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**

## Outcome Analysis: Worsening of Respiratory Conditions Resulting In Hospitalization (AECB and CAP Studies)

***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)**

## 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 penicillin-intermediate/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**

## Review ofMoxifloxacin Safety Profile

## 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 P****450**** enzyme system**
**Moxifloxacin has no apparent clinical effects on cytochrome P****450**** enzyme system**
**Moxifloxacin exhibits balanced excretion by both renal and biliary (fecal) route**

## 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)**

## Moxifloxacin Safety Profile

**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.**

## Safety Procedures

**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 C****max****.**
**4 SAE monitored throughout follow-up.**

**Safety Procedures**

**X**
**X**
**X**
**X**
**X**

## Moxifloxacin Safety Profile

**Extent of ****Moxifloxacin Exposure**

## Patient Exposure to Moxifloxacin and Comparators

**Number of Patients**

***4008***

***618***

***456***

***701***

***1009***

***1224***

***400 mg MXF Controlled***

***3689***

***580***

***450***

***705***

***1030***

***924***

***Comparator***

***625***

***5189***

***556***

***Total (21)***

***0***

***618***

***Others (3)***

***400 mg MXF Uncontrolled***

***0***

***486***

***30***

***SSSI (3)***

***254***

***1222***

***267***

***CAP (5)***

***371***

***1406***

***26***

***AS (6)***

***0***

***1457***

***233***

***AECB (4)***

***All MXF****** ***

***200 mg MXF***

***Indication (# Trials)***

***NA***

## Incidence of Adverse Events of Body System:  Controlled Studies with 400 mg Moxifloxacin and Control:  All Indications (Worldwide)*

**Any Event**
**Nausea**
**Diarrhea**
**Headache**
**Dizziness**
**Abdominal Pain**
**Vomiting**
**Asthenia**
**Liver Functions Abnormal **
**Dyspepsia**
**Rhinitis**
**Rash**
**Taste Perversion**
**GGTP**

## Premature Discontinuations Due to Adverse Events: Moxifloxacin 400 mg and Controlled Studies (Worldwide)*

**Premature Discontinuations Due to Adverse Events: Moxifloxacin 400 mg and Controlled Studies (Worldwide)***

## Incidence of Serious Adverse Events in Patients Valid for Safety Analysis*

**Incidence of Serious Adverse Events in Patients Valid for Safety Analysis***

## Adverse Event Profile: Controlled Trials

**	****	****Most adverse events reported were mild to moderate ****	****	****in severity and required no therapy**
** **

**Adverse Event Profile: ****Controlled Trials**

## Mortality Rates* Moxifloxacin 400 mg Controlled Studies (Worldwide)

****Deaths recorded through 30 days post study drug administration.***

## Adverse Event	Moxifloxacin 400mg	Comparators 
		(n=4008)	(n=3689)

Seizures	1 (<0.1%)	2 (<0.1%)
Pain in Achilles tendon	2 (<0.1%)	0
Tendon Rupture	0	0
Phototoxicity	2 (<0.1%) 	3 (<0.1%)
Elevated LFTs	63 (1.6%)	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

**	****	****(n=4008)****	****(n=3689)**
**Seizures****	****1 (<0.1%)****	****2 (<0.1%)**
**Pain in Achilles tendon****	****2 (<0.1%)****	****0**
**Tendon Rupture****	****0****	****0**
**Phototoxicity****	****2 (<0.1%) ****	****3 (<0.1%)**
**Elevated LFTs****	****63 (1.6%)****	****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**

**Selected Events Associated with Some Quinolones**

## 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)**

## Incidence Rates of Lab Abnormalities:  (LFTs) 400mg Moxifloxacin vs Control Pool: Controlled Studies (Worldwide)

**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.**

## 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**

## 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 P****450 ****system**
**No significant drug-drug interactions **
**Favorable morbidity and mortality trends**** **
**Favorable safety profile, including hepatic safety and phototoxicity**

## 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**

## Slide 81

## QTc Background

**Joel Morganroth, M.D.**
**Clinical Professor of Medicine**
**University of Pennsylvania**
**and**
**CEO, Premier Research**

## ECG Grid Paper

**1 mm**

**5 mm**

**1.0 sec**

**0.04 sec = 40 msec**

**0.20 sec = 200 msec**

## 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)**__**	**_**                **_**Male**__**	**__**	**__**Female**_
-   Normal		     <430	 	 <450
-   Borderline		   431-450		451-470
-   Prolonged		     >450	  	>470
- Risk of Arrhythmia	     >500	 	>500
_**Change in QTc, msec**_**	**_**Implications**_
- 	    <30			No concern
- 	   31-60			Possible drug effect
- 	    >60			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_	flecainide 	sotalol 	 	**quinidine**
- _procainamide__	_disopyramide_	__ibutilide__	__	_**moricizine**
- _astemizole__	__cisapride__	_**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****	****	****	**

## Approved Drugs Not Listed in PDR as QT Prolonging, but Listed in Literature, in Other Drug Labels, or by Other Regulatory Agencies

**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****	****	**
**	****	****	**

**Approved Drugs Not Listed in PDR as QT Prolonging, but Listed in Literature, in Other Drug Labels, or by Other Regulatory Agencies**

## 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                    8.3	         Stambler, Circ ‘96
- Quinidine                 1.5	         Roden, AHJ ‘86
-                                  12	         Hohnloser, JACC ‘95
- Sotalol	       	2.4	         MacNeil, AJC ‘95
- Amiodarone    	1.0	         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

## Introduction

**During pre-clinical and Phase I development of moxifloxacin a 6 msec mean prolongation of the corrected QT (QTc) interval was observed**

## 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.**

##     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**

## ECG Complexes and Intervals

**ECG Complexes and Intervals**

**QRS**

**P**

**complexes**
**and waves**

**intervals and**
**segments**

**T**

**U**

**Q**

**T**

**P**

**R**

## 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/********RR**

## Action Potential and Potassium Currents

**Action Potential and Potassium Currents**

**membrane**
**potential (mV)**

- -90

- 0

- 1

- 2

- Early After Depolarization

## Moxifloxacin Preclinical Studies

**Blockade of repolarizing K****+**** channels (I****kr**** and I****ks****)**
**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**

## 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**

## Rabbit Arrhythmia ModelSparfloxacin vs. Moxifloxacin

**Rabbit Arrhythmia Model****Sparfloxacin vs. Moxifloxacin**

## Moxifloxacin Effects on QTc:  Clinical Studies

**Moxifloxacin Effects on QTc:  ****Clinical Studies**

**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**

## Mean + S.D. QTc Change from Baseline (msec): All Comparative Studies 

_**Data Pool**_		_**Worldwide**_		_**North America**_  		 _**n**_** ****          **_****__**QTc**__** **_**	****	****     **** **_**n**_**     **_****__**QTc**_
**	**
**Moxifloxacin 400 mg****	****787****	****6 ± 26****	****	****595  ****	****8 ± 20**
**All Comparators****	****759****	****    1 ± 23****	****	****562****	****2 ± 18**
**	****Clarithromycin****	****136        2 **_**+**_** 23****	****    ****	****104   6 **_**+**_** 20**
**	****Cephalexin****	****	****167****	****3 ± 16****	****	****167****	****3 ± 16**
**	****Cefuroxime 250****	****266****	**** 2 ± 20****	****	****244****	****2 ± 19**
**	****Cefuroxime 500****	****  ****	****47****	****-8 ± 15****	****	****  47****	****-8 ± 15**
**	****Amoxicillin****	****110****	****-4 ± 30**

**Mean **_**+**_** S.D. QTc Change from Baseline (msec): All Comparative Studies **

## Antibiotics with QTc Prolongation:Clinical Studies

**	****	****	****	****	****	****    ****Drug   ****	****Elimination**
_**	**__**Drug**_**	****   **_**QTc Prolongation**_**      **_**Interactions**_**        **_**Issues**_
**erythromycin        oral 13.8 msec****1****	****       yes  ****	****   Hepatic****	****	****         i.v. 51 msec****2**
**clarithromycin          3 - 11 msec****3-5****	****       yes****	****	****    Renal**
**grepafloxacin             10 msec****6****	****	****       yes****	****	****   Hepatic**
**sparfloxacin               11 msec****1,4,5,7****	****        ---****	****    ****	****    Renal**
**1.  Jaillon P, et al., J Antimicrob Chemother 1996; 37 (Suppl A): 161.**
**2.  Oberg KC, Bauman JL, Pharmacother 1995; 15: 687.**
**3.  van Haarst AD, et al., Clin Pharmacol Ther 1998; 64: 542.**
**4.  Henry DC, et al., Clin Ther 1999; 21: 340.**
**5.  Ramirez J, et al., Clin Ther 1999; 21: 103.**
**6.  Glaxo-Wellcome, data on file, 1997.**
**7.  Lipsky BA, et al., Clin Ther 1999; 21: 675.**

## QTc versus Moxifloxacin Concentration  Phase I Data at Cmax

**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**

## Committee for Proprietary Medicinal Products (CPMP) Criteria

** **_**QTc (msec)**__**	**_**                **_**Male**__**	**__**	**__**Female**_
**  ****Normal****	****	****     <430****	****  <450****	**
**  ****Borderline****	****	****   431-450****	****451-470**
**  ****Prolonged****	****	****     >450****	****  >470**
**Risk of Arrhythmia****	****     >500****	****  >500**
_**Change in QTc, msec**_**	****	**_**Implications**_
**	****    ****<30****	****	****	**** No concern**
**	****   ****31-60****	****	****	****Possible drug effect**
**	****    ****>60****	****	****	****Concern for Arrhythmias**
**QTc dispersion > 100 msec, or increase > 100%**
**	*****European Union Regulatory Authority***

## Outlier Frequency by Drug Treatment: Modified CPMP Criteria 

**	****	****	****	****                                     ****QTc ******** **_**>**_
**	****	****                         ****Any QTc         ********QTc       30 msec    %********QTc    Any QTc**
**	****	****                **_**n**_**     **_**> 500 msec**_**   **_**> 60 msec**_**   **_**to abnl**_**     **_** > 15%**_**       **_**Outlier**_
**Moxifloxacin****          787      3 (0.4%)   ****	****   10 (1.3%)     13 (1.7%)   13 (1.7%)     21 (2.7%) **
**All Comparators****    759      1 (0.1%)            2 (0.3%)     13 (1.7%)     4 (0.5%)     17 (2.2%)**
**   ****Clarithromycin    136         0                      0                5 (3.7%)        0               5 (3.7%)**
**   ****Cephalexin          167         0                      0                   0                 0                 0**
**   ****250 Cefuroxime-**
**	**** ****Axetil b.i.d       266         0                      0                4 (1.5%)     2 (0.8%)      6 (2.3%)**
**   ****500 Cefuroxime-**
**	**** ****Axetil b.i.d.       47          0****	****       0                   0                0                 0**
**   ****Amoxicillin         110       1 (0.9%)          1 (0.9%)        4 (3.6%)     1 (0.9%)     5 (4.5%)**
**   ****Doxycycline-**
**	**** ****Metronidazole  23          0                   1 (4.3%)           0             1 (4.3%)     1 (4.3%)**
***All paired valid, Worldwide***

## Effects of Moxifloxacin on QTc Dispersion (Phase I)

**QT and QTc Interval Dispersion (msec) at expected C****max**
**(N=17)**

- *arithmetic means/standard deviation
- ** QTcB:  QT corrected by Bazett’s formula

**Effects of Moxifloxacin on QTc Dispersion (Phase I)**

## Reverse Rate Dependency

**Conclusion:  No reverse-rate dependency was observed with moxifloxacin**

## Change in QTc for Patients in Top Quartile for Baseline QTc

**	****	****	****	****	****	****	****Mean **_**+**_** SD**
**	****	****	****	****	****	****	****Change in**
**	****	****	****	****	****	**_**n**_**	**_**QTc, msec**_
**	****Moxifloxacin 400 mg              312****	****   -8 **_**+**_** 25**
**	****All Comparators****	****	****          273****	**** -12 **_**+**_** 26**
**	****	****Clarithromycin****	****	**** 58         -8 **_**+**_** 25**
**Conclusion:  Patients with longer baseline QTc are not at greater risk for QTc prolongation.**
***Expanded ITT, All Studies***

## Summary of ECG Risk Factors for QT Prolongation in Moxifloxacin Studies

**Magnitude****	****-****	****mean 6 msec**
**Dose/Concentration ****	****-****	****yes, shallow****Dependence**
**QT Outliers (CPMP ****	****-****	****no overall difference Criteria)****	****    **
**QTc Dispersion****	****-****	****no effect**
**Reverse Rate Dependency****	****-****	****none**
**Long Baseline QTc****	****-  QTc decreases**
**QRS Widening****	****-****	****none**
**T Wave Abnormalities****	****-****	****unchanged**
**New U Waves****	****-****	****no differences**

## QT Prolongation-Associated Clinical Risk Factors

**Cardiovascular disease **
**Age **
**Gender**
**Electrolyte abnormalities, ********K****+**
**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**

## Clinical Risk Factors

**	****	****	****	****	****	****       ****Mean **_**+**_** S.D. QTc**
**	****       ****	****	****	****	****          **_**n**_**         **_**Change, msec**_
**Cardiovascular Disease**
**Present****	****	****	****           122****	****    4 **_**+**_** 28 **
**Absent****	****	****	****           665****	****    7 **_**+**_** 25 **
**Age**
**< 65 years****	****	****           651****	****    7 **_**+**_** 25 ****	****          **
_**>**_** 65 years****	****	****           136****	****    2 **_**+**_** 28**
**Gender**
**Male****	****	****	****           353****	****     5 **_**+**_** 26**
**Female****	****	****	****           434****	****     7 **_**+**_** 25**
**All Comparative Studies, Worldwide**

## Clinical Risk Factors 

**	****	****	****	****	****	****    ****Mean **_**+**_** S.D. QTc**
**	**_**Risk Factor**_**	****	****   **_**n**_**	****     **_**Change, msec**_
**Electrolyte Imbalance**
**Normal****	****	****	****  764****	****	****6 **_**+**_** 24**
**K****+**** < 3.5****	****	****	****    22^****	****	****5 **_**+**_** 26**
**Heart Rate**
**Normal****	****	****	****  707****	****	****6 **_**+**_** 23**
**Bradycardia*****	****	****    80****	****             0 **_**+**_** 24**
**^ excludes one patient with all intervals doubled**
*** < 60/min, absolute QT**
**All Comparative Studies, Worldwide**

## 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 co-administration of inhibitors**

## Moxifloxacin Drug Interaction Studies

**	****	****	****Metabolizing CYP**
_**Drug**_**	****	****	****      **_**Isoenzyme**_**	****	**_**Results**_
**Theophylline****	****	****	****1A2****	****	****No Change**
**Glyburide****	****	****	****3A4****	****	****Glyburide Sl. ******
**Warfarin****	****	****	****2C9****	****	****No Change**
**Ranitidine****	****	****   weak inhibitor****	****No Change**
**	****Conclusion:  No increase in moxifloxacin levels, nor          ****	****in those of concomitant drugs.**

## Clinical Risk Factors 

**	****	****	****	****	****	****         ****Mean **_**+**_** SD QTc**
**	**_**Risk Factor**_**	****	****	****	**_**n**_**        **_**Change, msec**_
**QT Prolonging Drugs***
**Present****	****	****	****            61****	****     6 **_**+**_** 44**
**Absent****	****	****	****        1085****	****     7 **_**+**_** 25**
**Renal Function******	****	**
**Normal****	****	****	****	****8****	****      5 **_**+**_** 14**
_**<**_** 30 ml/min****	****	****	****8****	****      6 **_**+**_** 14**
**Hepatic Function****
**Normal****	****	****	****              8****	****      7 **_**+**_** 18**
**Reduced****	****	****	****            10****	****      4 **_**+**_** 26**
***All Comparative Studies, Worldwide**
****Phase I studies**

## Summary: Clinical Risk Factors for QT Prolongation in Moxifloxacin Studies

**Cardiovascular disease****	****- no change in ********QTc**
**Age, gender****	****- no change in ********QTc **
**Drug Interactions****	****- no metabolic interactions**
**Concomitant “QT” drugs****	****- no change in ********QTc **
**Organ Dysfunction****	****- no drug accumulation, ****	****  ****	****     no change in ********QTc **
**Electrolyte imbalances****	****- no change in ********QTc**
**Bradycardia****	****- no change in ********QT**

## Is There an Increased Risk for Cardiovascular AEs in Patients Who Are QTc Outliers?

**	****                                         ********QTc**
**	****                                                 ****Outliers**
**	**_**Drug**_**                 **_**n**_**                 **_**n**_**	****      **_**CV Events***_
**Moxifloxacin       4008             38****	****1  [sinus tachycardia]**
**Comparators      3689             28****	****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**

## Incidence of Treatment-Emergent Clinical AEs Considered Surrogates for QTc Prolongation

**Worldwide, 400 mg, Controlled Trials**

**Clinical Event**

**Moxifloxacin-**
**   ****Treated**
**  ****(n = 4008)**

**All Comparator-**
**    ****Treated**
**  ****(n = 3689)**

**Tachycardia****	****	****        19 (0.5%)****	****  ****15 (0.4%)**
**Angina, Chest Pain, MI  11 (0.3%)****	****  10 (0.3%)**
**Palpitation****	****	****        11 (0.3%)****	****  10 (0.3%)**
**CHF/LV Failure****	****        10 (0.2%)****	****    8 (0.2%)**
**Syncope****	****	****          9 (0.2%)****	****    7 (0.2%)**
**Arrhythmia****	****	****          3 (0.1%)****	****    3 (0.1%)**

## Deaths in Moxifloxacin Clinical Development Program in Relation to Therapy

- *  Within 30 days of study drug discontinuation
- ** Within one day of last dose of study drug

## 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**

## MoxifloxacinBenefit - Risk Evaluation

**	**_**Benefit**_**	****	****	****	****           **_**Risk**_
**Broader spectrum of coverage**
**Improved efficacy ratios****	****	****      -QTc prolongation **
**Superior resistance characteristics         without other ECG,**
**Straightforward PK, elimination****	****         subpopulation, or **
**Short duration, once daily therapy****	****          clinical evidence**
**No dose adjustments****	****	****	****  of risk.**
**No CYP 450 interactions**
**No liver, CNS, phototoxicity**
**Favorable morbidity and mortality**
** ****	****   ****trends**

## Proposed QT Labeling

**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).**

**Warnings**

## Moxifloxacin Summary

**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

**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

**Moxifloxacin **_**is**_** safe and effective for**

**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.**

** ****Acute Exacerbations of Chronic Bronchitis**
** ****Community Acquired Pneumonia**
** ****Acute Sinusitis**
** ****Skin and Skin Structure Infection**

## 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.***

**New antimicrobials are needed ****in today’s clinical environment**

## Moxifloxacin:In-vitro activity against common RTI pathogens

**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

**Activity of moxifloxacin against RTI organisms is not affected by B-lactam or macrolide resistance**

_**Organism **__**	**__**	**__**MXF**__**	**__**LEV**__**	**__**	**_
***S pneumoniae***
- 	**pen-s*****	******	******	*****0.25****	****1.0****	****	****pen-r*****	******	******	*****0.25****	****1.0****	****	**
***H influenzae*****B-lactamase -****	****	****0.06****	****0.03****	****	**
***	*****B-lactamase +****	****	****0.06****	****0.03****	****	**
***M catarrhalis***
**	****B-lactamase -****	****	****0.06****	****0.06****	****	**
***	*****B-lactamase +****	****	****0.06****	****0.06****	****	**

_**	**__**	**__**CLR**__**	**__**AM/C**__**	**__**CXM**_
**	****	**_**<**_**0.03****	****0.03****	**_**<**_**0.12****	****>32****	****4.0****	****8.0**
**	****	****8.0****	****2.0****	****1.0**
**	****	****8.0****	****2.0****	****2.0**
**	****	****0.12****	****0.06****	****0.05**
**	****	****0.12****	****0.06****	****2.0**

- - MXF = moxifloxacin		- CLR= Clarithromycin
- - LEV= Levofloxacin 			- AM/C- Amoxicillin Clavulante
- 				- CXM = Cefuroxime

## Antimicrobial Resistance

**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

**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

**Moxifloxacin:****Pharmacokinetics/Pharmacodynamics**

**>90% Bioavailable; ****C****max ****= 4.5 mg/l**
**Long *****T******1/2****** - *****12 hours**
**High serum and tissue levels**
**>MIC****90 ****for most RTI pathogens over entire dosing interval**
**C****max****/MIC****90**** (*****S. pneumoniae) -- *****18**
**AUC/MIC****90**** (*****S. pneumoniae) -- *****192**
**Rapidly bactericidal***** ***

## Moxifloxacin: Clinical Profile

**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**

## Moxifloxacin: Safety Profile

**No hepatotoxicity**
**No nephrotoxicity**
**No phototoxicity**
**QTc prolongation comparable to commonly used antimicrobials**
** ****no cardiac events related to QTc **

**Moxifloxacin: Safety Profile**

## Moxifloxacin: Clinical Pharmacology Supports Complete Safety Profile

**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

**Unanticipated Outcomes**

**Lower overall mortality rate in****RTI studies**** **
**Lower rates of hospitalization than comparators in RTI treated patients**

## Summary

**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)

**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**