This document summarizes information about the antibiotic Avalox (moxifloxacin) presented over multiple slides: 1) Avalox has a novel molecular structure that allows it to act on two bacterial targets, minimizing resistance. It demonstrates broad-spectrum in vitro activity against Gram-positive and Gram-negative respiratory pathogens. 2) Clinical studies showed Avalox to be effective in treating complicated skin and skin structure infections when administered sequentially via IV then oral routes, with clinical cure rates comparable to piperacillin-tazobactam/amoxicillin-clavulanate. 3) For diabetic foot infections specifically, clinical cure rates for Avalox were 68% compared to 61% for the

1. Avalox® …IV Momentum
in CAP and SSSI
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2. The Goal of Antimicrobial Therapy
Hit Early! Hit Hard!
Hit Appropriately!
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3. Agenda
Mode of Action
Spectrum of Activity
Tissue Concentration/In Vitro Activity
Clinical Efficacy
Important Safety Considerations
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4. Avalox® … Novel Molecular Structure
O OH
Moxifloxacin
F
O
H
N N
NH O 8-methoxy subgroup minimizes
H3C ability of Gram-positive bacteria to
H acquire resistance.
8-methoxy subgroup
Avalox® acts at two target sites to exert its bactericidal action:
• Topoisomerase II (DNA gyrase): mainly in Gram-negative bacteria
• Topoisomerase IV: mainly in Gram-positive bacteria
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5. Avalox® … Dual Target Action
Super coiled DNA
Topoisomerase
Ava
Ava
Relaxed DNA
llox
ox
Topoisomerase
Topoisomerase II (i.e. gyrase) in Gram-negative bacteria
Topoisomerase IV in Gram-positive bacteria
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6. Avalox MIC90s Against Common
Respiratory Pathogens
Organism Moxifloxacin
S. pneumoniae (PenS) 0.06-0.25
S. pneumoniae (PenR) 0.12-0.25
H. influenzae BL (–) 0.03-0.06
H. influenzae BL (+) 0.03-0.06
M. catarrhalis BL (–) 0.012-0.06
M. catarrhalis BL (+) 0.012-0.06
BL = β-lactamase; MIC = minimum inhibitory concentration (mg/L).
Blondeau JM. J Antimicrob Chemother. 1999;43(suppl B):1-11.
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7. Moxifloxacin: in vitro activity against
common Respiratory pathogens
MIC90 (mg/mL)
Organism Avalox Amoxicillin/
Levofloxacin Amoxicillin clavulanic Clarithromycin Cefuroxime
acid
Moxifloxacin
S. pneumoniae
0.06–0.25 1–2 0.03–0.06 0.03 0.03–0.25 0.06–0.25
(PenS)
S. pneumoniae
0.12–0.25 1–2 8 4 32–>256 8–16
(PenR)
H. influenzae BL
0.03–0.06 0.03–0.32 1 1–2 8–24 2–8
(–)
H. influenzae BL
0.03–0.06 0.03–0.47 8–128 1–2 8–16 2–4
(+)
M. catarrhalis BL
0.012–0.06 0.06 0.25 0.38 0.06–4 2
(–)
M. catarrhalis BL
0.012–0.06 0.06–0.094 >16 0.38 <0.06–0.38 3
(+)
PenS, penicillin-susceptible; PenR, penicillin-resistant; BL, β-lactamase
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7

8. Avalox® … Broad Spectrum of Activity
In vitro activity of Avalox® against pathogens commonly implicated in
uncomplicated SSSIs and cSSSIs.
Micro-organism MIC90
Gram-positive bacteria
S. aureus 0.03
S. Aureus (methicillin-sensitive)* 0.06
S. aureus (methicillin-resistant)
4
S. Pyogenes 0.25
S. Pyogenes 0.25
(constitutive resistance) S. 0.25
Pyogenes (inducible resistance) 0.25
S. pyogenes (M-
phenotype)
*Methicillin-sensitive = MIC ≤8.0 mg/l
Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557
Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.
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9. Avalox® … Broad Spectrum of Activity
In vitro activity of Avalox® against pathogens commonly implicated in
uncomplicated SSSIs and cSSSIs.
Micro-organism MIC90
Enterobacteriaceae
Escherichia coli 0.015
Klebsiella pneumoniae 0.125
Proteus mirabilis 0.25
Enterobacter cloacae 0.06
Enterobacter spp. 0.062
Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557
Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.
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10. Avalox® … Broad Spectrum of Activity
In vitro activity of Avalox® against pathogens commonly implicated in
uncomplicated SSSIs and cSSSIs.
Micro-organism MIC90
Anaerobes
Bacteroides fragilis 1.0
Clostridium perfringens 0.5
Peptostreptococcus spp. 1.0
Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557
Edlund C, Eur J Clin Microbiol Infect Dis 1998;17:193–195.
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11. Avalox® … Broad Spectrum of Activity
In vitro activity of Avalox® against aerobic and anaerobic isolates caused
by animal and human bites.
Micro-organism MIC90
Aerobes
Eikenella corrodens 0.06
Pasteurella canis –
P. multocida subsp. multocida 0.016
P. multocida subsp. septica 0.016
Pasteurella spp.* 0.03
Staphylococcus epidermidis 0.06
Staphylococcus spp.† –
EF-4b 0.25
Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557
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12. Avalox® … Broad Spectrum of Activity
In vitro activity of Avalox® against aerobic and anaerobic isolates caused
by animal and human bites.
Micro-organism MIC90
Anaerobes
F. nucleatum 4.0
Fusobacterium spp. 8.0
Prevotella heparinolytica
0.125
Prevotella spp.
0.5
Goldstein EJ, Antimicrob Agents Chemother 1997;41:1552–1557
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13. Rapid Penetration of Moxifloxacin Into
relevant Tissues
1000
100
Macrophages
Conc. (mg/l. mg/kg)
10
Epithelial lining fluid (ELF)
1 Bronchial Mucosa
Serum
0,1 MIC90 of S. pneumoniae and M. catarrhalis (0.12 mg/l)
MIC90 of H. influenzae (0.06 mg/l)
0,01
3 12 24 TIME (h)
Andrews J et al., 1998
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14. Avalox® … Rapid Tissue Penetration
10
Concentration of Moxifloxacin (mg/l)
8 7.6
6
4.6
4
3.1
2
1.7
1.0
*
0 **
Bone, Muscle Skin blister Subcutaneous Serum level
Spongiosa fluid tissue
* MIC90 ==0.25 mg/l, Enterococcus agalactiae, P. mirabilis, S.pyogenes
MIC90 0.5
mg/l, S. aureus, S.
faecalis
**
Gusinde A., et al., Klinik & Forschung 2004, 10 (suppl. 1):44-45
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15. Avalox® … Higher Conc. in Infected Tissue
Relative time (h) Concentration of
Moxifloxacin (mcg/l)
Relative time (h)
Concentrations measured in inflamed and normal tissue at the start of a 1-hour infusion of 400mg moxifloxacin I.v.
and at 30-minutes intervals thereafter in subjects with cSSSI (geometric means and SD, N=6)
Stass et al. Eur Congress Clin Microbiol Infect April 24 – 27, 2002, Milan,
Italy. Abstract O178
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16. Avalox® … Optimum Pharmacokinetics
Avalox® … Oral
Elimination half-life: ~12 hours
Bioavailability: ~ 91%
Protein binding
48 ± 2.5%
Tmax: 0.5 – 4 hours
Cmax (high): 3.1 - 4.5 mg/l
Following a 400 mg Oral single dose
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17. Avalox® … Optimum Pharmacokinetics
Avalox® … I.V.
Administration: I.V. drip within
1 hour
AUC value (high): 39 mg.h/L
Cmax (high) : 4.1 - 5.9 mg/L
Following a 400 mg Oral single dose
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18. Avalox® … Optimum Pharmacokinetics
Oral dose Urinary
Cmax (mg/L) T1/2 (hours)
(mg) recovery (%)
Avalox® 1,2 400 4.5 12.7 19
Levofloxacin3 750 5.7 7.6 87
Ciprofloxacin4 500 3.6 4 40–50
†
Data shown are for the doses used in ABS
1) AVALOX® tablets US prescribing information, 2007
2) AVALOX® tablets UK prescribing information, 2006
3) LEVAQUIN® tablets US prescribing information, 2007
4) CIPRO® tablets US prescribing information, 2007
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19. Avalox® …Fast Bacterial Eradication
Survival (%) Over 99% killing after 150 minutes
99%
Time (min)
Bactericidal activity of maxifloxacin at 1.0 mg/l against a clinical
isolate of staphybcoocus aureus in nutrient broth, sensitive to
moxi.oxacin (mic 0.05 mg/l)
Lister et al. Clin Infect Dis 2001; 32 (suppl) : S33-8
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20. Avalox® Clinical Study in cSSSI
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21. Sequential intravenous/oral moxifloxacin versus intravenous
piperacillin-tazobactam followed by oral amoxicillin-
clavulanate for the treatment of complicated skin and skin
structure infection
Giordano P, Song J, Pertel P, Herrington J, Kowalsky S
Int J Antimicrob Agents 2005; 26: 357–365
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Dec-05

22. Study protocol
Study design: Prospective, randomized, double-blind, double-dummy,
multicenter study
Treatments: Sequential IV/oral moxifloxacin, 400 mg once daily
IV piperacillin-tazobactam, 3.0/0.375 g 6-hourly, followed by
oral amoxicillin-clavulanate, 800 mg, b.i.d
Duration: The total treatment duration: 7–14 days
The IV treatments were given for at least 3 days
Switch to oral therapy made at the discretion of the investigator
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23. Patients:
Disposition: 617 patients randomized
367 satisfied the criteria for evaluation of efficacy
601 evaluable for safety
Diagnosis: • Hospitalized patients aged ≥ 18 years
• Complicated skin and skin structure infections
- Ischemic ulcers
- Diabetic foot,
- Decubitus ulcers
- Major abscesses, carbuncles
- SSSIs needing surgery
- Deep soft tissue infections (including
surgical wounds),
- Human or animal bite infections
Expected to require ≥ 1 week of antibiotic treatment
Over half had polymicrobial infections
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24. Results:
Clinical cure by infection type
Moxifloxacin Control (n=187)*
(n=180)*
Overall 143/180 (79%) 153/187 (82%)
Abscess 42/53 (79%) 52/56 (93%)
Cellulitis 36/43 (84%) 38/43 (88%)
Diabetic foot infection 25/37 (68%) 25/41 (61%)
Ischemic/decubitus ulcer infection 10/13 (77%) 6/10 (60%)
Surgical wound infection 11/12 (92%) 8/8 (100%)
Complicated erysipelas 0/0 2/2 (100%)
Infection with traumatic lesion 11/12 (92%) 10/13 (77%)
Other 8/10 (80%) 12/14 (86%)
*Efficacy-valid population
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25. Subset with Diabetic Foot Infections
Moxifloxacin IV/PO
Piperacillin-Tazobactam IV Amoxicillin-Clavulanate
80 75 PO 76
68 68
70 63
61
60
52 50
Patients (%)
50
40
30
20
10
0
Per investigator n/N Per investigator with Any foot infection + Any foot infection with
25/37 25/41 ulcer n/N 21/28 13/25 history of diabetes n/N ulceration + history of
28/41 29/46 diabetes n/N 22/29
*P=0.054
13/26
Efficacy-valid population.
n=number of patients with response of clinical cure; N=total number of
patients.
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26. Results:
Bacteriologic Eradication*
Moxifloxacin Control
Staphylococcus aureus 50/64 (78%) 47/59 (80%)
Streptococcus pyogenes 13/18 (72%) 8/12 (67%)
Streptococcus agalactiae 7/13 (54%) 20/25 (80%)
Enterococcus faecalis 12/18 (67%) 9/12 (75%)
Escherichia coli 7/8 (88%) 11/12 (92%)
Klebsiella pneumoniae 5/6 (83%) 4/7 (57%)
Proteus mirabilis 3/5 (60%) 5/6 (83%)
Enterobacter cloacae 4/5 (80%) 1 / 2 (50%)
Peptostreptococcus spp. 6/10 (60%) 11/12 (92%)
Bacteroides spp. 9/9 (100%) 9/10 (90%)
Prevotella spp. 9/14 (64%) 9/11 (82%)
Monomicrobial infection 50/59 (85%) 55/65 (85%)
Polymicrobial infection 42/60 (70%) 41/53 (77%)
*Confirmed and presumed eradication
Data from selected causative pre-therapy skin organisms (microbiologically-valid population)
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27. Summary
Overall clinical cure rates were similar in the moxifloxacin (79%) and
comparator (82%) groups
• Differences in the clinical cure/eradication rates within subgroups could not
be attributed directly to the treatments
Moxifloxacin was as effective as the comparator in eradicating the most
common pathogens
In the treatment of cSSSIs, IV/oral moxifloxacin once daily is at least as
effective and well tolerated as IV piperacillin-tazobactam four times daily
followed by oral amoxicillin-clavulanate twice daily
Results from this study support the role of moxifloxacin as monotherapy
for the treatment of patients with moderate to severe DFI
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28. Avalox® …Fast Cure Rate
Avalox®
Amoxicillin Clavulanate
45%
20%
0% 10% 20% 30% 40% 50%
Clinical cure rate on day 7 in patients with cSSSIs (%)
n=29 patients; all diabetic foot infections, n.s.
Bogner JR et al., Chemother Journal, 13 (26) 2004
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29. Avalox® …Shorter Therapy
Avalox®
Amoxicillin Clavulanate
4.3 days
I.V. therapy
7 days
15 days
Hospitalization
19 days
17 days
General therapy
32 days
0 5 10 15 20 25 30 35
Duration of therapy in patients with cSSSIs (days)
n=29 patients; all diabetic foot infections, n.s.
Bogner JR et al., Chemother Journal, 13 (26) 2004
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30. Avalox® In Community Acquired
Pneumonia.
Hazem Sharaf
Product Specialist

31. Treatment with sequential (I.V. /oral) moxifloxacin was associated with faster
clinical improvement than was standard therapy for hospitalized patients with
community-acquired pneumonia who received initial parenteral therapy
Welte T, Petermann W, Schuermann D, Bauer TT, Reimnitz P and the MOXIRAPID
Study Group
Clin Infect Dis 2005; 41: 1697–1705

32. Study protocol
Prospective, multicenter, randomized, open-label,
controlled trial in Europe.
Interventions:
• Moxifloxacin, 400 mg, once daily, given IV for at least 3 days;
switch to oral at discretion of clinician; overall treatment duration
7–14 days.
• IV ceftriaxone, 2 g, once daily ± IV erythromycin, 1 g, every 6–8
hours (if ‘atypical’ pathogen was proven or suspected).
Clinical responses assessed at days 3–5, 7–14
(end of treatment) and 5–20 (test of cure) after final
dose.
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33. Study Design
Randomization
Moxifloxacin 400 mg once daily IV or orally for 7-14 days
Patients with
community acquired 3-5 Days 7-10 Days 5-20 Days
Pneumonia
Ceftriaxone 2gm IV once daily + erythromycin 1 gm 3-4 times
daily IV if atypical pathogen suspected for 7-14 days
Time of End of Test of cure
Base Line therapy 5-20 days after
therapy
switch
7-10 days the final dose
3-5 Days
Clinical infectious disease 2005:41:1697-705
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34. Patients
Aged ≥ 18 years.
Admitted to hospital within the last 5 days, with a diagnosis
of community-acquired pneumonia.
Requiring initial IV treatment.
161 per protocol patients received moxifloxacin.
156 per protocol patients received ceftriaxone (59 also
received erythromycin).
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35. Results: clinical success at test of cure
100
87.6 88.5
80 Moxifloxacin
Ceftriaxone ±
60 erythromycin
Patients (%)
40
20 141/161 138/156
0
Clinical cure
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36. Results: clinical success amongst elderly and more severe
CAP patients
Ceftriaxone ±
Moxifloxacin erythromycin P value
Fine class IV+V 77.8% 70.4% 0.534
(21/27) (19/27)
Age >74 years 81.5% 70.6% 0.326
(22/27) (24/34)
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37. Results: speed of defervescence
100 98 100
Moxifloxacin (n=82)
Patients with fever (%)
81
80
Ceftriaxone ±
65
61 erythromycin (n=74)
60
42 40
40 38
22
20 18
0
1 2 3 4 5
Duration of treatment (days)
Defervescence was more rapid for moxifloxacin (median 3 days) than with
ceftriaxone ± erythromycin (median 4 days; P < 0.003)
Fever: body temperature > 38.5°C
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38. Results: patient-reported relief from symptoms
Compared to ceftriaxone + erythromycin,
moxifloxacin-treated patients reported a consistently
faster improvement in signs and symptoms specific to
CAP
• Chest pain (P = 0.021)
• Weakness (P = 0.015)
• Sputum color (P = 0.002)
Median time to feeling better:
• Moxifloxacin: 3 days
• Ceftriaxone + erythromycin: 4 days
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39. Results: duration of hospitalization
Shorter mean duration of hospitalization with moxifloxacin
(P < 0.001)
• Moxifloxacin: 9.8 days.
• Ceftriaxone + erythromycin: 11.1 days.
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40. Equivalent tolerability and safety
Number (%) of patients
Moxifloxacin Ceftriaxone +
(n = 200) erythromycin
Variable (n = 197)
Treatment emergent AE 114 (57.0) 125 (63.5)
Drug-related AE 65 (32.5) 76 (38.6)
Serious AE 31 (15.5) 29 (14.7)
Drug-related serious AE 5 (2.5) 4 (2.0)
Drug-related AEs with an incidence > 3%
- Gastrointestinal symptoms 24 (12.0) 34 (17.3)
- Phlebitis 3 (1.5) 12 (6.1)
- Elevated γ- glutamyl transferase 2 (1.0) 7 (3.6)
- Abnormal liver function tests 16 (8.0) 26 (13.2)
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41. Conclusion
Sequential moxifloxacin is at least as effective in terms of clinical cure
as ceftriaxone ± erythromycin in the treatment of community-acquired
pneumonia requiring initial parenteral therapy.
Moxifloxacin is superior to ceftriaxone ± erythromycin in terms of:
• Speed of defervescence.
• Duration of hospital stay.
Moxifloxacin has advantages over ceftriaxone ± erythromycin in terms
of relief from symptoms like chest pain, weakness and sputum colour.
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42. Summary of clinical moxifloxacin experience in patients with
CAP:
Moxifloxacin;
Covers all the key pathogens including atypical and typical
species.
Accumulates in alveolar macrophages and epithelial lining
fluids.
Maintains bactericidal activity in macrophages.
Achieves clinical response 94.4%
bacteriological response 91%
with 400 mg once daily given for 10 days.
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43. Summary of clinical moxifloxacin experience in patients with
CAP (2)
Moxifloxacin
Has excellent clinical and bacteriological efficacy
independent from resistance to beta-lactams or
macrolides.
Has high clinical cure rates in polymicrobial community-
aquired pneumonia.
Offers clinical hints for a rapid onset of action.
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44. Avalox® … Metabolism & Elimination
Metabolites Elimination
Sulfo-compound (M-1) LIVER Hepatic ~ 60%
Acyl-glucuronide (M-2) inactive Renal ~ 40%
BILE
Parent + M-1, M-2
STOMACH
Enterohepatic cycling:
Parent + M-2
BLOOD KIDNEY
Fecal excretion:
M-1 (35% of dose)
Fecal excretion: unchanged Urine:
26% of dose M-1 (2.5% of dose)
M-2 (14% of dose)
Urinary excretion:
~ 20% of dose unchanged
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45. Avalox - Metabolism
®
• Avalox® is metabolised by conjugate formation
(Phase II metabolism), not by cytochrome P450
• The conjugates of Avalox® are pharmacologically
inactive (M1 and M2)
Hence, there is minimal risk of
drug–drug interactions during
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combination/concomitant therapy
45

46. Renal impairment
Pharmacokinetics of moxifloxacin p.o.
Mild-to-moderate renal dysfunction
• no clinically significant effect on PK*
Renally-impaired patients undergoing hemodialysis or peritoneal
dialysis
• PK after single-dose and at steady-state comparable to healthy subjects
and renally-impaired patients
No adjustments to dose or timing relative to hemodialysis or peritoneal
dialysis required
Stass et al 2002a,b,c
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47. Important Safety Considerations
Moxifloxacin is contraindicated in persons with a history of
hypersensitivity to moxifloxacin or any member of the
quinolone class of antimicrobial agents.
Anaphylactic reactions, some following the first dose, have
been reported in patients receiving quinolone therapy including
moxifloxacin.
The safety and effectiveness of moxifloxacin in pediatric
patients, adolescents (less than 18 years of age), pregnant
women, and lactating women have not been established.
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48. Moxifloxacin use in the elderly
Low risk of toxicity expected with MXF use in the elderly
• No CYP450 interactions, thus reduced risk of common drug-
drug interactions
• No need for dose adjustment in presence of mild-moderate
hepatic or severe renal dysfunction
MXF PK are unaffected by age and no dosage adjustments are
necessary
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49. Moxifloxacin
Interactions
No interaction with • calcium
• food / dairy products
• glyburide • p.o. contraceptives
• ranitidine • morphine
• theophylline
• itraconazole
• warfarin
• digoxin
Not metabolized by, nor affect, CYP 450 system
Decreased absorption with antacids (↓60% AUC) and iron
(↓40% AUC)*
*MXF should be taken at least 4 h before or 8 h after these agents
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50. Avalox® … Safety & Tolerability
Dose adjustment Dose adjustment
CYP450
for mild/moderate for severe renal
metabolism
hepatic impairment impairment
Avalox® 1 No No No
Levofloxacin2 Not stated No Yes
Caution and
Amoxicillin/ clavulanate 3 Not stated monitoring Yes
recommended
Cefuroxime axetil4 Not stated Not stated in SPC No
1) AVALOX® tablets UK prescribing information, 2006
2) TAVANIC® tablets UK prescribing information, 2006
3) AUGMENTIN® tablets US prescribing information, 2006
4) ZINNAT® tablets UK prescribing information, 2007
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51. Avalox® … Contraindications
Known hypersensitivity to moxifloxacin or other quinolones.
Pregnancy and lactation.
Children and adolescents.
Impaired liver function.
QTc-related contraindications.
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52. Avalox® … Dosage
Tablets 400 mg
I.V. 400 mg, 250 ml
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53. Avalox® … A jump ahead in the treatment of
SSSIs
Avalox® has many of the ideal features of an emperical treatment of CAP&SSSIs
Effective:
Broad spectrum of activity 
Eradicates bacteria Fast 
Highly active at sites of infection for 24 hrs. 
High cure rates 
Safe:
• Minimal interactions 
• Low resistance potential 
• Suitable for all adult patient types 
• Well tolerated 
Simple:
• Once-daily administration 
• Short treatment duration 
• Cost effectiveness 
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