moxifloxacin safety - lippincott williams & wilkins

Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – of 29

Drugs in R&D

Moxifloxacin Safety An Analysis of 14 Years of Clinical Data

P.M. Tulkens, et al.

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Adis © 2012 Tulkens et al., publisher and licensee Springer International Publishing AG. This is an open access article published under the terms of the Creative Commons License “Attribution-NonCommercial-NoDerivative 3.0” (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits non-commercial use, distribution, and reproduction, provided the original work is properly cited and not altered.


Table SDC-I

List of Standard MedDRA Query (SMQ) and Bayer MedDRA Query (BMQ) included in investigation of rare but major selected

adverse events associated with fluoroquinolone use:

SMQs Drug related hepatic disorders – comprehensive search

Drug related hepatic disorders – severe events only

Convulsions

Anaphylactic reaction (narrow search) Only narrow search terms have been used.

Severe cutaneous adverse reactions

Risk: Psychiatric disorders SMQs (i) Depression and suicide/self-injury (ii) Psychosis and psychotic disorders and (iii) Hostility/aggression. The PTs of all three SMQs have been combined.

BMQs

Relevant clinical outcome of QTc prolongation (subset of BMQ ‘Search for Torsades de pointes/QT prolongation’)

Photosensitivity reactions

Tendinopathies Only narrow search terms have been used.

SMQ / BMQs

Risk: Dysglycemia SMQ ‘Hyperglycemia/New onset diabetes mellitus’ (only narrow search terms to be used) and BMQ ‘Hypoglycemic conditions’ (only narrow search terms have been used). The PTs from the SMQ and the BMQ have been combined.


Table SDC-II

Demographic parameters of the patients valid for the safety analysis stratified by route of administration (PO: oral; IV/PO:

intravenous followed by oral [sequential]; IV: intravenous only) and by study design (double-blind vs open-label)

A. Double-blind studies

Parameter

Treatment route PO

(n=17 465) IV/PO

(n=3745) IV

(n=1159) Moxifloxacin

(n=8822) Comparator


(n=1889) Comparator


(n=588) Comparator

(n=571) Age (years)

Mean ± SD Median Range

47.4 ± 18.0 46.0

16.0–97.0

47.3 ± 17.8 46.0

17.0–95.0

58.2 ± 18.5 60.0

17.0–100.0

57.7 ± 18.6 59.0

17.0–101.0

45.6 ± 17.9 45.0

18.0–88.0

45.2 ± 18.3 44.0

18.0–93.0 Sex, n (%) Male 3920 (44.4) 3869 (44.8) 1140 (60.3) 1138 (61.3) 377 (64.1) 387 (67.8)

Female 4902 (55.6) 4774 (55.2) 749 (39.7) 718 (38.7) 211 (35.9) 184 (32.2) BMI (kg/m2)


25.8 ± 5.9 24.8

12.4–72.7

25.7 ± 5.7 24.7

13.1–66.3

27.7 ± 7.0 26.5

13.2–81.6

27.4 ± 6.9 26.2

12.4–75.5

24.9 ± 4.6 24.0

15.3–44.3

24.8 ± 4.4 24.1

14.4–44.1 Race, n (%)

White Asian Black Others a Missing b

5571 (63.1) 1040 (11.8) 1023 (11.6)

144 (1.6) 1044 (11.8)

5456 (63.1) 1059 (12.3) 934 (10.8) 123 (1.4)

1071 (12.4)

1443 (76.4) 17 (0.9)

165 (8.7) 248 (13.1)

16 (0.8)

1414 (76.2) 16 (0.9)

178 (9.6) 234 (12.6)

14 (0.8)

370 (62.9) 180 (30.6)

22 (3.7) 1 (0.2) 15 (2.6)

348 (60.9) 184 (32.2)

19 (3.3) 4 (0.7) 16 (2.8)


Indications c, n (%) ABS 1545 (17.5) 1583 (18.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) AECB 3210 (36.4) 3026 (35.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) CAP 1604 (18.2) 1632 (18.9) 812 (43.0) 822 (44.3) 0 (0.0) 0 (0.0) uPID 946 (10.7) 919 (10.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) uSSSI 587 (6.7) 582 (6.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) cSSSI 0 (0.0) 0 (0.0) 724 (38.3) 680 (36.6) 0 (0.0) 0 (0.0) cIAI 0 (0.0) 0 (0.0) 329 (17.4) 327 (17.6) 588 (100) 571 (100) Othersd 930 (10.5) 901 (10.4) 24 (1.3) 27 (1.5) 0 (0.0) 0 (0.0)

Pre-existing risk factorse, n (%) Age ≥65 years 1904 (21.6) 1833 (21.2) 800 (42.4) 769 (41.4) 110 (18.7) 117 (20.5) Renal impairment 1086 (12.3) 1020 (11.8) 458 (24.2) 460 (24.8) 126 (21.4) 132 (23.1) Hepatic impairment 133 (1.5) 144 (1.7) 82 (4.3) 89 (4.8) 39 (6.6) 41 (7.2) Diabetes mellitus 615 (7.0) 565 (6.5) 590 (31.2) 558 (30.1) 53 (9.0) 42 (7.4) Cardiac disorders 1182 (13.4) 1142 (13.2) 740 (39.2) 737 (39.7) 74 (12.6) 66 (11.6) BMI <18 kg/m2 288 (3.3) 307 (3.6) 56 (3.0) 55 (3.0) 19 (3.2) 16 (2.8)

B. Open-label studies

Parameter

Treatment route PO

(n=3833) IV/PO

(n=3101) IV


(n=1791) Comparator


(n=1542) Comparator


(n=349) Comparator

(n=352) Age (years)


52.1 ± 17.7 52.0

18.0–98.0

51.0 ± 17.8 50.0

18.0–94.0

55.0 ± 19.8 57.0

18.0–96.0

54.3 ± 19.7 55.0

17.0–98.0

49.0 ± 15.4 51.0

18.0–76.0

50.1 ± 15.7 52.0

18.0–75.0 Sex, n (%) Male 920 (51.4) 999 (48.9) 942 (61.1) 954 (61.2) 193 (55.3) 206 (58.5) Female 871 (48.6) 1043 (51.1) 600 (38.9) 605 (38.8) 156 (44.7) 146 (41.5) BMI (kg/m2)


26.7 ± 5.8 25.8

12.9–66.6

26.9 ± 6.0 26.0

12.8–58.8

25.9 ± 5.8 25.1

11.1–62.4

25.8 ± 5.7 25.0

12.8–64.6

22.5 ± 3.4 22.3

15.6–38.1

22.5 ± 3.6 22.4

14.6–34.6


Race, n (%)

White Asian Black Others a Missing b

1277 (71.3) 94 (5.2) 61 (3.4) 38 (2.1)

321 (17.9)

1541 (75.5) 93 (4.6) 60 (2.9) 34 (1.7)

314 (15.4)

838 (54.3) 90 (5.8) 80 (5.2) 87 (5.6)

447 (29.0)

864 (55.4) 76 (4.9) 79 (5.1) 82 (5.3)

458 (29.4)

0 (0.0) 349 (100)

0 (0.0) 0 (0.0) 0 (0.0)

0 (0.0) 352 (100)

0 (0.0) 0 (0.0) 0 (0.0)

Indicationsc, n (%) ABS 786 (43.9) 1058 (51.8) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) AECB 819 (45.7) 794 (38.9) 0 (0.0) 0 (0.0) 96 (27.5) 100 (28.4) CAP 186 (10.4) 190 (9.3) 699 (45.3) 717 (46.0) 253 (72.5) 252 (71.6) cSSSI 0 (0.0) 0 (0.0) 406 (26.3) 397 (25.5) 0 (0.0) 0 (0.0) cIAI 0 (0.0) 0 (0.0) 289 (18.7) 295 (18.9) 0 (0.0) 0 (0.0) Others d 0 (0.0) 0 (0.0) 148 (9.6) 150 (9.6) 0 (0.0) 0 (0.0)

Pre-existing risk factors e, n (%) Age ≥65 years 547 (30.5) 570 (27.9) 573 (37.2) 565 (36.2) 60 (17.2) 74 (21.0) Renal impairment 197 (11.0) 209 (10.2) 430 (27.9) 403 (25.8) 77 (22.1) 86 (24.4) Hepatic impairment 13 (0.7) 19 (0.9) 101 (6.5) 107 (6.9) 7 (2.0) 5 (1.4) Diabetes mellitus 162 (9.0) 152 (7.4) 336 (21.8) 359 (23.0) 27 (7.7) 30 (8.5) Cardiac disorders 294 (16.4) 262 (12.8) 427 (27.7) 399 (25.6) 32 (9.2) 38 (10.8) BMI <18 kg/m2 30 (1.7) 58 (2.8) 60 (3.9) 60 (3.8) 26 (7.4) 37 (10.5)

a American Indian, Alaska natives or Hispanic. b In some countries, due to legal reasons, the patients’ race was not documented. c ABS: acute bacterial sinusitis; AECB: acute exacerbation of chronic bronchitis; CAP: community-acquired pneumonia; uPID:

uncomplicated pelvic inflammatory disease; uSSSI: uncomplicated skin and skin structures infection; cSSSI: complicated skin and

skin structure infection; cIAI: complicated intra-abdominal infection. d Complicated and uncomplicated urinary tract infection, streptococcal pharyngitis in PO studies, hospital-acquired pneumonia,

aspiration pneumonia/lung abscess in IV/PO studies. e See definitions for each of these factors in the Methods section.


Table SDC-III

Adverse events (AE) occurring in patients valid for safety analysis treated with moxifloxacin (MXF) or a comparator (COMP) and

stratified by route of administration (PO: oral; IV/PO: intravenous followed by oral [sequential]; IV: intravenous only) and by study

design. Figures in bold correspond to treatment (MXF or COMP) causing an AE in ≥5 % of patients. Differences between groups that

are ≥2.5% for events with an incidence ≥2.5% in both groups, or ≥2-fold for events with incidence <2.5% in one or both groups are

highlighted by surrounding them with a solid line if in disfavour of MXF and by a dotted lined if in disfavour of COMP (calculations

were made using patients number [no rounding]; in case of null value for one treatment, only situations where ≥2 cases were

observed in the other treatment are boxed). Where the number of patients experiencing an event was ≥10 in either group, the data

are highlighted in orange or green to indicate disfavour of MXF or of COMP, respectively, according to the above rules.

A. Double-blind studies.

System organ class Adverse events

Treatment route, n (%) PO

IV/PO

IV MXF

(n=8822) COMP

(n=8643)

MXF (n=1889)

COMP (n=1856)

MXF (n=588)

COMP (n=571)

Blood and lymphatic system disorders

Anemia 34 (0.4) 34 (0.4)

85 (4.5) 71 (3.8)

9 (1.5) 8 (1.4)

Leukocytosis 8 (<0.1) 1 (<0.1)

2 (0.1) 10 (0.5)

3 (0.5) 3 (0.5)

Thrombocytosis 16 (0.2) 22 (0.3)

7 (0.4) 10 (0.5)

1 (0.2) 0 (0.0)

Cardiac disorders

Atrial fibrillation 16 (0.2) 3 (<0.1)

23 (1.2) 31 (1.7)

2 (0.3) 5 (0.9)

Cardiac arrest 1 (<0.1) 1 (<0.1)

7 (0.4) 7 (0.4)

8 (1.4) 2 (0.4)

Cardiac failure congestive 7 (<0.1) 13 (0.2)

17 (0.9) 21 (1.1)

1 (0.2) 1 (0.2)


Myocardial infarction 2 (<0.1) 12 (0.1)

5 (0.3) 10 (0.5)

0 (0.0) 0 (0.0)

Tachycardia 22 (0.2) 21 (0.2)

6 (0.3) 8 (0.4)

3 (0.5) 5 (0.9)

Ear and labyrinth disorders

Vertigo 50 (0.6) 42 (0.5)

3 (0.2) 2 (0.1)

0 (0.0) 1 (0.2)

Gastrointestinal disorders

Abdominal discomfort 69 (0.8) 57 (0.7)

6 (0.3) 4 (0.2)

0 (0.0) 0 (0.0)

Abdominal distension 24 (0.3) 21 (0.2)

14 (0.7) 9 (0.5)

3 (0.5) 1 (0.2)

Abdominal pain 119 (1.3) 110 (1.3)

55 (2.9) 59 (3.2)

10 (1.7) 1 (0.2)

Abdominal pain upper 107 (1.2) 115 (1.3)

13 (0.7) 7 (0.4)

5 (0.9) 1 (0.2)

Constipation 75 (0.9) 89 (1.0)

145 (7.7) 113 (6.1)

7 (1.2) 13 (2.3)

Diarrhea 547 (6.2) 425 (4.9)

153 (8.1) 146 (7.9)

37 (6.3) 25 (4.4)

Dry mouth 71 (0.8) 67 (0.8)

4 (0.2) 4 (0.2)

0 (0.0) 0 (0.0)

Dyspepsia 87 (1.0) 84 (1.0)

33 (1.7) 34 (1.8)

6 (1.0) 2 (0.4)

Flatulence 56 (0.6) 41 (0.5)

9 (0.5) 14 (0.8)

0 (0.0) 0 (0.0)

Ileus 0 (0.0) 0 (0.0)

9 (0.5) 4 (0.2)

0 (0.0) 3 (0.5)

Intestinal fistula 0 (0.0) 0 (0.0)

0 (0.0) 2 (0.1)

1 (0.2) 3 (0.5)

Intestinal obstruction 2 (<0.1) 1 (<0.1)

1 (<0.1) 2 (0.1)

5 (0.9) 0 (0.0)

Nausea 701 (7.9) 534 (6.2)

137 (7.3) 117 (6.3)

32 (5.4) 20 (3.5)

Pancreatic disorder 0 (0.0) 0 (0.0)

1 (<0.1) 0 (0.0)

3 (0.5) 2 (0.4)

Peritonitis 1 (<0.1) 0 (0.0)

2 (0.1) 1 (<0.1)

5 (0.9) 2 (0.4)

Vomiting 213 (2.4) 203 (2.3)

62 (3.3) 79 (4.3)

16 (2.7) 16 (2.8)


General disorders and administration site conditions

Asthenia 59 (0.7) 51 (0.6)

16 (0.8) 11 (0.6)

2 (0.3) 0 (0.0)

Chest pain 52 (0.6) 47 (0.5)

25 (1.3) 25 (1.3)

0 (0.0) 5 (0.9)

Edema peripheral 24 (0.3) 26 (0.3)

41 (2.2) 43 (2.3)

1 (0.2) 1 (0.2)

Impaired healing 0 (0.0) 0 (0.0)

2 (0.1) 6 (0.3)

3 (0.5) 3 (0.5)

Infusion site extravasation 0 (0.0) 0 (0.0)

33 (1.7) 29 (1.6)

0 (0.0) 0 (0.0)

Injection site pain 1 (<0.1) 1 (<0.1)

10 (0.5) 11 (0.6)

0 (0.0) 1 (0.2)

Multi-organ failure 0 (0.0) 1 (<0.1)

2 (0.1) 6 (0.3)

4 (0.7) 3 (0.5)

Pain 19 (0.2) 18 (0.2)

15 (0.8) 9 (0.5)

0 (0.0) 0 (0.0)

Pyrexia 45 (0.5) 43 (0.5)

65 (3.4) 53 (2.9)

12 (2.0) 13 (2.3)

Unevaluable event 11 (0.1) 10 (0.1)

1 (<0.1) 0 (0.0)

4 (0.7) 2 (0.4)

Infections and infestations

Abdominal abscess 0 (0.0) 0 (0.0)

11 (0.6) 16 (0.9)

3 (0.5) 1 (0.2)

Abdominal infection 0 (0.0) 0 (0.0)

4 (0.2) 2 (0.1)

5 (0.9) 1 (0.2)

Bronchitis 45 (0.5) 45 (0.5)

6 (0.3) 5 (0.3)

1 (0.2) 1 (0.2)

Candidiasis 16 (0.2) 22 (0.3)

6 (0.3) 10 (0.5)

0 (0.0) 1 (0.2)

Cellulitis 6 (<0.1) 6 (<0.1)

15 (0.8) 16 (0.9)

2 (0.3) 1 (0.2)

Clostridial infection a 1 (<0.1) 4 (<0.1)

11 (0.6) 14 (0.8)

1 (0.2) 1 (0.2)

Oral candidiasis 24 (0.3) 26 (0.3)

24 (1.3) 27 (1.5)

0 (0.0) 0 (0.0)

Pneumonia 46 (0.5) 28 (0.3)

38 (2.0) 26 (1.4)

4 (0.7) 7 (1.2)

Post-operative wound infection 0 (0.0) 1 (<0.1)

4 (0.2) 6 (0.3)

8 (1.4) 6 (1.1)


Rhinitis 28 (0.3) 47 (0.5)

4 (0.2) 0 (0.0)

0 (0.0) 0 (0.0)

Sepsis 5 <0.1) 3 (<0.1)

7 (0.4) 8 (0.4)

3 (0.5) 2 (0.4)

Septic shock 3 (<0.1) 1 (<0.1)

7 (0.4) 3 (0.2)

3 (0.5) 0 (0.0)

Urinary tract infection 30 (0.3) 47 (0.5)

25 (1.3) 13 (0.7)

1 (0.2) 4 (0.7)

Vulvovaginal candidiasis 57 (0.6) 49 (0.6)

0 (0.0) 2 (0.1)

0 (0.0) 0 (0.0)

Vulvovaginal mycotic infection 39 (0.4) 40 (0.5)

9 (0.5) 12 (0.6)

0 (0.0) 0 (0.0)

Wound infection 1 (<0.1) 1 (<0.1)

18 (1.0) 21 (1.1)

69 (11.7) 42 (7.4)

Wound sepsis 0 (0.0) 0 (0.0)

0 (0.0) 0 (0.0)

3 (0.5) 2 (0.4)

Injury, poisoning and procedural complications

Incision site pain 0 (0.0) 0 (0.0)

21 (1.1) 10 (0.5)

1 (0.2) 2 (0.4)

Procedural pain 1 (<0.1) 0 (0.0)

31 (1.6) 30 (1.6)

1 (0.2) 2 (0.4)

Wound dehiscence 0 (0.0) 0 (0.0)

5 (0.3) 2 (0.1)

5 (0.9) 2 (0.4)

Wound evisceration 0 (0.0) 0 (0.0)

0 (0.0) 0 (0.0)

3 (0.5) 0 (0.0)

Investigationsb

ALT increased 54 (0.6) 61 (0.7)

32 (1.7) 37 (2.0)

16 (2.7) 10 (1.8)

AST increased 34 (0.4) 38 (0.4)

26 (1.4) 30 (1.6)

9 (1.5) 9 (1.6)

Blood albumin decreased 1 (<0.1) 2 (<0.1)

10 (0.5) 8 (0.4)

0 (0.0) 1 (0.2)

Blood ALP increased 25 (0.3) 29 (0.3)

17 (0.9) 16 (0.9)

4 (0.7) 4 (0.7)

Blood amylase increased 7 (<0.1) 13 (0.2)

14 (0.7) 12 (0.6)

9 (1.5) 11 (1.9)

Blood glucose increased 14 (0.2) 8 (<0.1)

9 (0.5) 13 (0.7)

2 (0.3) 1 (0.2)

Blood LDH increased 10 (0.1) 19 (0.2)

10 (0.5) 4 (0.2)

1 (0.2) 0 (0.0)

Blood magnesium decreased 0 (0.0) 0 (0.0)

11 (0.6) 15 (0.8)

0 (0.0) 0 (0.0)

Blood phosphorus decreased 1 (<0.1) 0 (0.0)

14 (0.7) 18 (1.0)

1 (0.2) 0 (0.0)


Blood potassium decreased 1 (<0.1) 3 (<0.1)

12 (0.6) 10 (0.5)

2 (0.3) 1 (0.2)

Blood urea increased 9 (0.1) 12 (0.1)

8 (0.4) 12 (0.6)

0 (0.0) 0 (0.0)

ECG QT prolonged 5 (<0.1) 1 (<0.1)

20 (1.1) 16 (0.9)

0 (0.0) 0 (0.0)

GGT increased 20 (0.2) 41 (0.5)

31 (1.6) 29 (1.6)

16 (2.7) 21 (3.7)

Hematocrit decreased 6 (<0.1) 6 (<0.1)

12 (0.6) 6 (0.3)

0 (0.0) 0 (0.0)

Hemoglobin decreased 7 (<0.1) 6 (<0.1)

16 (0.8) 8 (0.4)

0 (0.0) 0 (0.0)

Hepatic enzyme increased 17 (0.2) 23 (0.3)

6 (0.3) 8 (0.4)

6 (1.0) 6 (1.1)

Lipase increased 0 (0.0) 0 (0.0)

1 (<0.1) 2 (0.1)

27 (4.6) 27 (4.7)

Platelet count increased 10 (0.1) 13 (0.2)

18 (1.0) 22 (1.2)

1 (0.2) 0 (0.0)

Urine output decreased 1 (<0.1) 0 (0.0)

8 (0.4) 12 (0.6)

2 (0.3) 0 (0.0)

WBC count increased 4 (<0.1) 5 (<0.1)

11 (0.6) 5 (0.3)

2 (0.3) 0 (0.0)

Metabolism and nutrition disorders

Decreased appetite 46 (0.5) 47 (0.5)

13 (0.7) 7 (0.4)

0 (0.0) 1 (0.2)

Dehydration 7 (<0.1) 8 (<0.1)

11 (0.6) 18 (1.0)

0 (0.0) 1 (0.2)

Diabetes mellitus 13 (0.1) 13 (0.2)

15 (0.8) 11 (0.6)

0 (0.0) 0 (0.0)

Hyperglycemia 17 (0.2) 11 (0.1)

33 (1.7) 22 (1.2)

3 (0.5) 0 (0.0)

Hyperkalemia 4 (<0.1) 4 (<0.1)

12 (0.6) 15 (0.8)

0 (0.0) 0 (0.0)

Hypoalbuminemia 2 (<0.1) 1 (<0.1)

22 (1.2) 19 (1.0)

1 (0.2) 1 (0.2)

Hypocalcemia 0 (0.0) 1 (<0.1)

26 (1.4) 21 (1.1)

2 (0.3) 0 (0.0)

Hypoglycemia 3 (<0.1) 1 (<0.1)

16 (0.8) 11 (0.6)

3 (0.5) 0 (0.0)

Hypokalemia 10 (0.1) 8 (<0.1)

96 (5.1) 93 (5.0)

9 (1.5) 11 (1.9)

Hypomagnesemia 0 (0.0) 0 (0.0)

36 (1.9) 29 (1.6)

0 (0.0) 0 (0.0)

Hypophosphatemia 0 (0.0) 1 (<0.1)

16 (0.8) 3 (0.2)

1 (0.2) 0 (0.0)


Musculoskeletal and connective tissue disorders

Arthralgia 35 (0.4) 34 (0.4)

11 (0.6) 12 (0.6)

1 (0.2) 1 (0.2)

Back pain 79 (0.9) 84 (1.0)

24 (1.3) 22 (1.2)

3 (0.5) 0 (0.0)

Muscle spasms 12 (0.1) 25 (0.3)

10 (0.5) 7 (0.4)

1 (0.2) 0 (0.0)

Musculoskeletal pain 10 (0.1) 12 (0.1)

3 (0.2) 10 (0.5)

0 (0.0) 0 (0.0)

Pain in extremity 24 (0.3) 20 (0.2)

18 (1.0) 25 (1.3)

1 (0.2) 1 (0.2)

Nervous system disorders

Dizziness 336 (3.8) 288 (3.3)

29 (1.5) 32 (1.7)

4 (0.7) 1 (0.2)

Dysgeusia 74 (0.8) 179 (2.1)

4 (0.2) 4 (0.2)

0 (0.0) 0 (0.0)

Headache 417 (4.7) 401 (4.6)

106 (5.6) 110 (5.9)

9 (1.5) 7 (1.2)

Psychomotor hyperactivity 3 (<0.1) 0 (0.0)

1 (<0.1) 0 (0.0)

3 (0.5) 1 (0.2)

Tremor 35 (0.4) 15 (0.2)

10 (0.5) 5 (0.3)

0 (0.0) 1 (0.2)

Psychiatric disorders

Agitation 2 (<0.1) 5 (<0.1)

40 (2.1) 23 (1.2)

2 (0.3) 3 (0.5)

Anxiety 44 (0.5) 33 (0.4)

68 (3.6) 43 (2.3)

1 (0.2) 1 (0.2)

Confusional state 9 (0.1) 7 (<0.1)

29 (1.5) 27 (1.5)

2 (0.3) 1 (0.2)

Depression 18 (0.2) 12 (0.1)

15 (0.8) 4 (0.2)

0 (0.0) 0 (0.0)

Disorientation 3 (<0.1) 1 (<0.1)

7 (0.4) 0 (0.0)

2 (0.3) 3 (0.5)

Hallucination 5 (<0.1) 4 (<0.1)

10 (0.5) 6 (0.3)

2 (0.3) 0 (0.0)

Initial insomnia 1 (<0.1) 0 (0.0)

0 (0.0) 0 (0.0)

3 (0.5) 0 (0.0)

Insomnia 78 (0.9) 106 (1.2)

136 (7.2) 133 (7.2)

11 (1.9) 3 (0.5)

Restlessness 7 (<0.1) 7 (<0.1)

10 (0.5) 7 (0.4)

0 (0.0) 1 (0.2)


Renal and urinary disorders

Hematuria 14 (0.2) 13 (0.2)

10 (0.5) 8 (0.4)

2 (0.3) 2 (0.4)

Renal failure 6 (<0.1) 0 (0.0)

11 (0.6) 6 (0.3)

1 (0.2) 1 (0.2)

Renal failure acute 1 (<0.1) 3 (<0.1)

7 (0.4) 10 (0.5)

5 (0.9) 1 (0.2)

Urinary retention 1 (<0.1) 7 (<0.1)

12 (0.6) 7 (0.4)

0 (0.0) 1 (0.2)

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome

0 (0.0) 0 (0.0)

2 (0.1) 7 (0.4)

3 (0.5) 1 (0.2)

Atelectasis 1 (<0.1) 3 (<0.1)

14 (0.7) 8 (0.4)

2 (0.3) 1 (0.2)

COPDc 34 (0.4) 41 (0.5)

27 (1.4) 19 (1.0)

0 (0.0) 0 (0.0)

Cough 77 (0.9) 74 (0.9)

7 (0.4) 15 (0.8)

5 (0.9) 7 (1.2)

Dyspnea 80 (0.9) 60 (0.7)

24 (1.3) 29 (1.6)

1 (0.2) 1 (0.2)

Hypoxia 3 (<0.1) 4 (<0.1)

12 (0.6) 16 (0.9)

0 (0.0) 0 (0.0)

Oropharyngeal pain 40 (0.5) 34 (0.4)

32 (1.7) 17 (0.9)

1 (0.2) 0 (0.0)

Pleural effusion 12 (0.1) 5 (<0.1)

34 (1.8) 39 (2.1)

8 (1.4) 6 (1.1)

Pulmonary edema 0 (0.0) 1 (<0.1)

11 (0.6) 12 (0.6)

1 (0.2) 0 (0.0)

Respiratory failure 9 (0.1) 12 (0.1)

18 (1.0) 14 (0.8)

4 (0.7) 2 (0.4)

Wheezing 27 (0.3) 30 (0.3)

11 (0.6) 9 (0.5)

1 (0.2) 0 (0.0)

Skin and subcutaneous tissue disorders

Decubitus ulcer 0 (0.0) 2 (<0.1)

5 (0.3) 3 (0.2)

3 (0.5) 1 (0.2)

Dermatitis allergic 6 (<0.1) 8 (<0.1)

2 (0.1) 2 (0.1)

3 (0.5) 0 (0.0)

Erythema 14 (0.2) 11 (0.1)

19 (1.0) 6 (0.3)

2 (0.3) 0 (0.0)

Hyperhidrosis 36 (0.4) 16 (0.2)

7 (0.4) 10 (0.5)

0 (0.0) 2 (0.4)

Pruritus 47 (0.5) 67 (0.8)

33 (1.7) 33 (1.8)

1 (0.2) 1 (0.2)


Rash 51 (0.6) 66 (0.8)

30 (1.6) 24 (1.3)

0 (0.0) 5 (0.9)

Vascular disorders

Hypertension 40 (0.5) 43 (0.5)

42 (2.2) 41 (2.2)

10 (1.7) 12 (2.1)

Hypotension 18 (0.2) 16 (0.2)

29 (1.5) 25 (1.3)

3 (0.5) 4 (0.7)

Phlebitis 2 (<0.1) 0 (0.0)

15 (0.8) 17 (0.9)

18 (3.1) 17 (3.0)

a Includes Clostridial infection, Clostridium colitis, and Clostridium difficile colitis

b ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gammaglutamyl transferase;

LDH: lactate dehydrogenase; ECG: electrocardiogram; WBC: white blood cell

c Chronic obstructive pulmonary disease



System organ class Adverse events

Treatment route, n(%)

PO IV/PO IV

MXF (n=1791)

COMP (n=2042)

MXF (n=1542)

COMP (n=1559)

MXF (n=349)

COMP (n=352)


Anemia 1 (<0.1) 4 (0.2) 36 (2.3) 37 (2.4) 1 (0.3) 1 (0.3)

Eosinophilia 1 (<0.1) 2 (<0.1) 7 (0.5) 11 (0.7) 0 (0.0) 0 (0.0)

Thrombocytopenia 2 (0.1) 2 (<0.1) 4 (0.3) 9 (0.6) 0 (0.0) 0 (0.0)

Thrombocytosis 1 (<0.1) 1 (<0.1) 18 (1.2) 13 (0.8) 0 (0.0) 0 (0.0)

Cardiac disorders

Atrial fibrillation 2 (0.1) 3 (0.1) 22 (1.4) 13 (0.8) 0 (0.0) 0 (0.0)

Cardiac failure congestive 3 (0.2) 2 (<0.1) 8 (0.5) 6 (0.4) 0 (0.0) 0 (0.0)

Cardiac failure 5 (0.3) 6 (0.3) 3 (0.2) 9 (0.6) 0 (0.0) 0 (0.0)

Ear and labyrinth disorders Ear pain 11 (0.6) 18 (0.9) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0)


Abdominal discomfort 4 (0.2) 2 (<0.1) 2 (0.1) 4 (0.3) 0 (0.0) 2 (0.6)

Abdominal pain 18 (1.0) 22 (1.1) 17 (1.1) 16 (1.0) 0 (0.0) 1 (0.3)

Abdominal pain upper 31 (1.7) 23 (1.1) 10 (0.6) 16 (1.0) 1 (0.3) 1 (0.3)

Breath odour 18 (1.0) 22 (1.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Constipation 24 (1.3) 4 (0.2) 36 (2.3) 43 (2.8) 0 (0.0) 0 (0.0)

Diarrhea 65 (3.6) 152 (7.4) 94 (6.1) 101 (6.5) 1 (0.3) 2 (0.6)

Dry mouth 9 (0.5) 6 (0.3) 3 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)


Dyspepsia 13 (0.7) 12 (0.6) 13 (0.8) 10 (0.6) 0 (0.0) 0 (0.0)

Nausea 91 (5.1) 50 (2.4) 65 (4.2) 66 (4.2) 5 (1.4) 5 (1.4)

Vomiting 31 (1.7) 19 (0.9) 43 (2.8) 49 (3.1) 1 (0.3) 2 (0.6)


Asthenia 11 (0.6) 6 (0.3) 1 (<0.1) 5 (0.3) 1 (0.3) 0 (0.0)

Chest pain 6 (0.3) 19 (0.9) 13 (0.8) 22 (1.4) 1 (0.3) 0 (0.0)

Edema peripheral 3 (0.2) 5 (0.2) 16 (1.0) 18 (1.2) 0 (0.0) 0 (0.0)

Facial pain 18 (1.0) 15 (0.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Fatigue 24 (1.3) 16 (0.8) 6 (0.4) 4 (0.3) 0 (0.0) 0 (0.0)

Pain 3 (0.2) 0 (0.0) 6 (0.4) 11 (0.7) 0 (0.0) 0 (0.0)

Pyrexia 4 (0.2) 3 (0.1) 37 (2.4) 28 (1.8) 1 (0.3) 0 (0.0)

Hepatobiliary disorders

Hepatic function abnormal 1 (<0.1) 1 (<0.1) 9 (0.6) 4 (0.3) 10 (2.9) 6 (1.7)


Bronchitis 57 (3.2) 60 (2.9) 1 (<0.1) 4 (0.3) 0 (0.0) 0 (0.0)

Oral candidiasis 9 (0.5) 4 (0.2) 7 (0.5) 10 (0.6) 0 (0.0) 0 (0.0)

Pneumonia 5 (0.3) 4 (0.2) 28 (1.8) 20 (1.3) 0 (0.0) 0 (0.0)

Pyothorax 2 (0.1) 1 (<0.1) 8 (0.5) 3 (0.2) 0 (0.0) 0 (0.0)

Sepsis 0 (0.0) 3 (0.1) 14 (0.9) 4 (0.3) 0 (0.0) 0 (0.0)

Septic shock 2 (0.1) 1 (<0.1) 12 (0.8) 14 (0.9) 0 (0.0) 0 (0.0)

Urinary tract infection 2 (0.1) 5 (0.2) 19 (1.2) 20 (1.3) 3 (0.9) 2 (0.6)

Wound infection 0 (0.0) 0 (0.0) 29 (1.9) 19 (1.2) 0 (0.0) 0 (0.0)


Investigations a

ALT increased 5 (0.3) 5 (0.2) 40 (2.6) 39 (2.5) 14 (4.0) 11 (3.1)

AST increased 2 (0.1) 4 (0.2) 31 (2.0) 29 (1.9) 8 (2.3) 2 (0.6)

Blood albumin decreased 2 (0.1) 1 (<0.1) 2 (0.1) 10 (0.6) 0 (0.0) 0 (0.0)

Blood ALP increased 3 (0.2) 4 (0.2) 12 (0.8) 17 (1.1) 0 (0.0) 1 (0.3)

Blood amylase increased 2 (0.1) 2 (<0.1) 7 (0.5) 9 (0.6) 0 (0.0) 0 (0.0)

Blood cholesterol increased 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 4 (1.1) 1 (0.3)

Blood LDH increased 6 (0.3) 3 (0.1) 14 (0.9) 17 (1.1) 2 (0.6) 3 (0.9)

Blood triglycerides increased 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 3 (0.9) 5 (1.4)

Blood urea increased 2 (0.1) 2 (<0.1) 2 (0.1) 2 (0.1) 1 (0.3) 2 (0.6)

ECG QT prolonged 0 (0.0) 0 (0.0) 20 (1.3) 8 (0.5) 2 (0.6) 0 (0.0)

GGT increased 4 (0.2) 4 (0.2) 29 (1.9) 43 (2.8) 1 (0.3) 3 (0.9)

Hepatic enzyme increased 4 (0.2) 2 (<0.1) 20 (1.3) 25 (1.6) 1 (0.3) 2 (0.6)

Liver function test abnormal 0 (0.0) 1 (<0.1) 2 (0.1) 8 (0.5) 0 (0.0) 0 (0.0)

LDL increased 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.3) 2 (0.6)

Platelet count increased 3 (0.2) 0 (0.0) 10 (0.6) 13 (0.8) 1 (0.3) 0 (0.0)

Transaminases increased 1 (<0.1) 2 (<0.1) 8 (0.5) 4 (0.3) 0 (0.0) 2 (0.6)

WBC count decreased 3 (0.2) 6 (0.3) 0 (0.0) 1 (<0.1) 1 (0.3) 5 (1.4)


Diabetes mellitus 5 (0.3) 4 (0.2) 4 (0.3) 10 (0.6) 1 (0.3) 1 (0.3)

Hyperglycemia 2 (0.1) 2 (<0.1) 19 (1.2) 18 (1.2) 0 (0.0) 0 (0.0)


Hyperlipidemia 2 (0.1) 0 (0.0) 0 (0.0) 2 (0.1) 2 (0.6) 1 (0.3)

Hypoglycemia 2 (0.1) 3 (0.1) 10 (0.6) 8 (0.5) 0 (0.0) 0 (0.0)

Hypokalemia 9 (0.5) 5 (0.2) 25 (1.6) 24 (1.5) 0 (0.0) 0 (0.0)


Back pain 7 (0.4) 9 (0.4) 9 (0.6) 13 (0.8) 0 (0.0) 1 (0.3)

Pain in extremity 2 (0.1) 4 (0.2) 11 (0.7) 9 (0.6) 0 (0.0) 0 (0.0)

Neoplasm benign, malignant and unspecified (incl. cysts and polyps)

Bronchial carcinoma 0 (0.0) 2 (<0.1) 7 (0.5) 9 (0.6) 0 (0.0) 0 (0.0)


Dizziness 45 (2.5) 9 (0.4) 26 (1.7) 13 (0.8) 8 (2.3) 6 (1.7)

Dysgeusia 14 (0.8) 5 (0.2) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)

Headache 47 (2.6) 56 (2.7) 47 (3.0) 58 (3.7) 5 (1.4) 5 (1.4)

Hyposmia 10 (0.6) 10 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Parosmia 11 (0.6) 9 (0.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Somnolence 12 (0.7) 3 (0.1) 4 (0.3) 2 (0.1) 0 (0.0) 0 (0.0)

Tension headache 14 (0.8) 12 (0.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)


Agitation 2 (0.1) 1 (<0.1) 7 (0.5) 11 (0.7) 0 (0.0) 0 (0.0)

Anxiety 9 (0.5) 3 (0.1) 11 (0.7) 14 (0.9) 0 (0.0) 0 (0.0)

Confusional state 3 (0.2) 0 (0.0) 12 (0.8) 9 (0.6) 0 (0.0) 0 (0.0)

Insomnia 27 (1.5) 21 (1.0) 27 (1.8) 37 (2.4) 1 (0.3) 2 (0.6)



Hematuria 3 (0.2) 1 (<0.1) 15 (1.0) 7 (0.4) 0 (0.0) 0 (0.0)

Renal failure 3 (0.2) 1 (<0.1) 11 (0.7) 10 (0.6) 0 (0.0) 0 (0.0)

Renal failure acute 0 (0.0) 0 (0.0) 6 (0.4) 10 (0.6) 0 (0.0) 0 (0.0)


Asthma 10 (0.6) 3 (0.1) 4 (0.3) 1 (<0.1) 0 (0.0) 0 (0.0)

Bronchospasm 1 (<0.1) 3 (0.1) 7 (0.5) 8 (0.5) 0 (0.0) 0 (0.0)

COPD b 13 (0.7) 6 (0.3) 13 (0.8) 9 (0.6) 0 (0.0) 0 (0.0)

Cough 41 (2.3) 50 (2.4) 12 (0.8) 11 (0.7) 0 (0.0) 0 (0.0)

Dyspnea 12 (0.7) 13 (0.6) 20 (1.3) 17 (1.1) 0 (0.0) 0 (0.0)

Epistaxis 8 (0.4) 5 (0.2) 4 (0.3) 8 (0.5) 0 (0.0) 0 (0.0)

Hemoptysis 2 (0.1) 2 (<0.1) 3 (0.2) 9 (0.6) 0 (0.0) 0 (0.0)

Hypoxia 0 (0.0) 1 (<0.1) 1 (<0.1) 8 (0.5) 0 (0.0) 0 (0.0)

Nasal congestion 22 (1.2) 17 (0.8) 4 (0.3) 2 (0.1) 0 (0.0) 0 (0.0)

Pleural effusion 1 (<0.1) 6 (0.3) 15 (1.0) 15 (1.0) 0 (0.0) 0 (0.0)

Pulmonary embolism 2 (0.1) 2 (<0.1) 5 (0.3) 13 (0.8) 0 (0.0) 0 (0.0)

Pulmonary edema 1 (<0.1) 1 (<0.1) 9 (0.6) 6 (0.4) 0 (0.0) 0 (0.0)

Respiratory failure 3 (0.2) 3 (0.1) 13 (0.8) 22 (1.4) 0 (0.0) 1 (0.3)

Rhinorrhea 18 (1.0) 16 (0.8) 2 (0.1) 0 (0.0) 1 (0.3) 0 (0.0)

Upper airway obstruction 12 (0.7) 7 (0.3) 1 (<0.1) 2 (0.1) 1 (0.3) 0 (0.0)



Dermatitis 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 2 (0.6)

Erythema 1 (<0.1) 0 (0.0) 7 (0.5) 2 (0.1) 2 (0.6) 0 (0.0)

Pruritus 8 (0.4) 13 (0.6) 8 (0.5) 10 (0.6) 1 (0.3) 0 (0.0)

Rash 20 (1.1) 9 (0.4) 14 (0.9) 12 (0.8) 8 (2.3) 3 (0.9)

Skin edema 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.6) 0 (0.0)

Urticaria 2 (0.1) 4 (0.2) 7 (0.5) 2 (0.1) 2 (0.6) 0 (0.0)

Vascular disorders

Hypertension 5 (0.3) 4 (0.2) 20 (1.3) 25 (1.6) 0 (0.0) 0 (0.0)

Hypotension 2 (0.1) 2 (<0.1) 16 (1.0) 9 (0.6) 0 (0.0) 0 (0.0)

Phlebitis 1 (<0.1) 3 (0.1) 23 (1.5) 39 (2.5) 4 (1.1) 1 (0.3)

Thrombophlebitis 0 (0.0) 0 (0.0) 6 (0.4) 9 (0.6) 0 (0.0) 0 (0.0)

a ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gammaglutamyl transferase;

LDH: lactate dehydrogenase; ECG: electrocardiogram; LDL: low density lipoprotein; WBC: white blood cell b COPD: chronic obstructive pulmonary disease


Table SDC-IV

Serious adverse drug reactions (SADR) by organ classes and, within each class, by most frequent Preferred Terms if occurring in at

least 2 patients valid for safety analysis treated with moxifloxacin (MXF) or a comparator (COMP) and stratified by route of

administration (PO: oral; IV/PO: intravenous followed by oral [sequential]; IV: intravenous only) and by study design. Figures in bold

correspond to treatment (MXF or COMP) causing an SADR in ≥0.5% of patients. Differences between groups that are ≥2.5% for

events with an incidence ≥2.5% in both groups or ≥2-fold for events with incidence <2.5% in one or both groups are highlighted by

surrounding them with a solid line if in disfavor of MXF and by a dotted lined if disfavor of COMP (calculations were made using

patients raw numbers [no rounding]; in case of null value for one treatment, only situations where ≥2 cases were observed in the

other treatment are boxed). Where the number of patients experiencing an event was ≥10 in either group, the data are highlighted in

orange or green to indicate disfavor of MXF or of COMP, respectively, according to the above rules.

A. Double-blind studies

System organ class

Preferred Term

Treatment route, n (%) PO IV/PO IV

MXF (n=8822)

COMP (n=8643)

MXF (n=1889)

COMP (n=1856)

MXF (n=588)

COMP (n=571)

Total no. patients with events a 47 (0.5) 48 (0.6) 53 (2.8) 46 (2.5) 9 (1.5) 7 (1.2)


Any 4 (<0.1) 1 (<0.1) 1 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Neutropenia 2 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Cardiac disorders

Any 4 (<0.1) 2 (<0.1) 2 (0.1) 10 (0.5) 1 (0.2) 2 (0.4)


Atrial fibrillation 2 (<0.1) 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 2 (0.4)

Cardiac failure congestive 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0)

Cardio-respiratory arrest 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0)

Myocardial infarction 0 (0.0) 0 (0.0) 1 (<0.1) 2 (0.1) 0 (0.0) 0 (0.0)

Tachycardia 2 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Ventricular tachycardia 0 (0.0) 1 (<0.1) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Eye disorders

Any 1 (<0.1) 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 7 (<0.1) 12 (0.1) 7 (0.4) 6 (0.3) 1 (0.2) 1 (0.2)

Abdominal pain 1 (<0.1) 3 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Diarrhea 3 (<0.1) 3 (<0.1) 2 (0.1) 3 (0.2) 0 (0.0) 0 (0.0)

Dysphagia 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Vomiting 2 (<0.1) 3 (<0.1) 0 (0.0) 0 (0.0) 1 (0.2) 0 (0.0)


Any 3 (<0.1) 4 (<0.1) 5 (0.3) 4 (0.2) 0 (0.0) 1 (0.2)

Asthenia 0 (0.0) 0 (0.0) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 0 (0.0) 1 (<0.1) 1 (<0.1) 0 (0.0) 1 (0.2) 0 (0.0)

Immune system disorders

Any 2 (<0.1) 3 (<0.1) 1 (<0.1) 2 (0.1) 0 (0.0) 0 (0.0)

Hypersensitivity 1 (<0.1) 0 (0.0) 1 (<0.1) 2 (0.1) 0 (0.0) 0 (0.0)



Any 13 (0.1) 8 (<0.1) 13 (0.7) 15 (0.8) 1 (0.2) 3 (0.5)

Abdominal abscess 0 (0.0) 0 (0.0) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Clostridium difficile colitis 1 (<0.1) 1 (<0.1) 0 (0.0) 4 (0.2) 1 (0.2) 1 (0.2)

Pneumonia 6 (<0.1) 3 (<0.1) 4 (0.2) 3 (0.2) 0 (0.0) 0 (0.0)

Sepsis 2 (<0.1) 2 (<0.1) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)

Wound infection 0 (0.0) 0 (0.0) 2 (0.1) 3 (0.2) 0 (0.0) 0 (0.0)

Injury, poison and procedural complications

Any 1 (<0.1) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Investigations b

Any 2 (<0.1) 3 (<0.1) 13 (0.7) 6 (0.3) 2 (0.3) 0 (0.0)

ECG QTc prolonged 0 (0.0) 1 (<0.1) 11 (0.6) 4 (0.2) 0 (0.0) 0 (0.0)

Hepatic enzyme increased 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.3) 0 (0.0)


Any 1 (<0.1) 3 (<0.1) 2 (0.1) 1 (<0.1) 1 (0.2) 0 (0.0)

Dehydration 0 (0.0) 2 (<0.1) 1 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)


Any 2 (<0.1) 4 (<0.1) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Migraine 0 (0.0) 2 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)



Any 0 (0.0) 2 (<0.1) 3 (0.2) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 1 (<0.1) 2 (<0.1) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Renal failure acute 0 (0.0) 2 (<0.1) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Reproductive system and breast disorders

Any 4 (<0.1) 3 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Pelvic pain 3 (<0.1) 2 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)


Any 8 (<0.1) 5 (<0.1) 3 (0.2) 3 (0.2) 2 (0.3) 0 (0.0)

Dyspnea 2 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Respiratory failure 2 (<0.1) 1 (<0.1) 1 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 6 (<0.1) 5 (<0.1) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Rash 1 (<0.1) 2 (<0.1) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)

Urticaria 2 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Vascular disorders

Any 2 (<0.1) 1 (<0.1) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

a Patients may have experienced more than one event

b ECG: electrocardiogram



System organ class

Preferred Term

Treatment route, n (%) PO IV/PO IV

MXF (n=1 791)

COMP (n=2 042)

MXF (n=1 542)

COMP (n=1 559)

MXF (n=349)

COMP (n=352)

Total no. patients with events a 12 (0.7) 5 (0.2) 42 (2.7) 19 (1.2) 0 (0.0) 0 (0.0)


Any 1 (<0.1) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Cardiac disorders

Any 2 (0.1) 0 (0.0) 3 (0.2) 1 (<0.1) 0 (0.0) 0 (0.0)

Atrial fibrillation 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Ventricular tachycardia 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Eye disorders

Any 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)


Any 1 (<0.1) 1 (<0.1) 8 (0.5) 1 (<0.1) 0 (0.0) 0 (0.0)

Diarrhea 0 (0.0) 0 (0.0) 5 (0.3) 0 (0.0) 0 (0.0) 0 (0.0)


Any 3 (0.2) 3 (0.1) 4 (0.3) 0 (0.0) 0 (0.0) 0 (0.0)

Drug ineffective 3 (0.2) 2 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Treatment failure 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)


Any 1 (<0.1) 0 (0.0) 4 (0.3) 2 (0.1) 0 (0.0) 0 (0.0)

Hepatic function abnormal 0 (0.0) 0 (0.0) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)


Immune system disorders

Any 0 (0.0) 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 0 (0.0) 0 (0.0) 11 (0.7) 8 (0.5) 0 (0.0) 0 (0.0)

Cellulitis 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0)

Pneumonia 0 (0.0) 0 (0.0) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Pyothorax 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Wound infection 0 (0.0) 0 (0.0) 3 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)

Injury, poisoning and procedural complications

Any 0 (0.0) 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)

Investigations b

Any 1 (<0.1) 0 (0.0) 10 (0.6) 1 (<0.1) 0 (0.0) 0 (0.0)

ALT increased 1 (<0.1) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

ECG QTc prolonged 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)

GGT increased 1 (<0.1) 0 (0.0) 2 (0.1) 1 (<0.1) 0 (0.0) 0 (0.0)

Hepatic enzyme increased 0 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 0 (0.0) 0 (0.0)


Any 0 (0.0) 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 2 (0.1) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)


Any 2 (0.1) 1 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)



Any 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Renal and urinary disorders Any 0 (0.0) 0 (0.0) 1 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0)


Any 0 (0.0) 1 (<0.1) 1 (<0.1) 2 (0.1) 0 (0.0) 0 (0.0)


Any 0 (0.0) 0 (0.0) 2 (0.1) 2 (0.1) 0 (0.0) 0 (0.0)

Surgical and medical procedures

Any 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)

Vascular disorders

Any 0 (0.0) 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)

a Patients may have experienced more than one event b ALT: alanine aminotransferase; ECG: electrocardiogram; GGT: gammaglutamyl transferase


Table SDC-V

Summary of safety data for patients valid for the safety analysis and stratified (i) by comparator (A to D), and (ii) for each of these

groups, by route of administration (PO: oral; IV/PO: intravenous followed by oral [sequential]; IV: intravenous only).

A. MXF vs β-lactam(s) in oral (PO), sequential (IV/PO) or intravenous (IV) studies

Adverse event Treatment route, n (%)

PO IV/PO IV MXF

(n=3709) β-lactam(s)

(n=3405) MXF


(n=1581) MXF


(n=390) Adverse events (AEs) 1535 (41.4) 1320 (38.8) 922 (56.5) 869 (55.0) 242 (59.3) 204 (52.3) Adverse drug reactions (ADRs) 790 (21.3) 608 (17.9) 323 (19.8) 299 (18.9) 77 (18.9) 74 (19.0) Serious AEs 149 (4.0) 137 (4.0) 239 (14.7) 222 (14.0) 60 (14.7) 48 (12.3) Serious ADRs 7 (0.2) 16 (0.5) 31 (1.9) 24 (1.5) 9 (2.2) 6 (1.5) Discontinuation due to AEs 150 (4.0) 104 (3.1) 119 (7.3) 96 (6.1) 11 (2.7) 6 (1.5) Discontinuation due to ADRs 111 (3.0) 81 (2.4) 54 (3.3) 46 (2.9) 4 (1.0) 3 (0.8) AEs with fatal outcome 16 (0.4) 17 (0.5) 42 (2.6) 49 (3.1) 21 (5.1) 12 (3.1) ADRs with fatal outcome 2 (<0.1) 1 (<0.1) 0 (0) 1 (<0.1) 0 (0) 1 (0.3)


B. MXF vs macrolide(s) in oral studies

Adverse event MXF, n (%) (n=3946)

Macrolide(s), n (%) (n=3210)

Adverse events (AEs) 1629 (41.3) 1368 (42.6) Adverse drug reactions (ADRs) 818 (20.7) 664 (20.7) Serious AEs 173 (4.4) 126 (3.9) Serious ADRs 22 (0.6) 16 (0.5) Discontinuation due to AEs 170 (4.3) 125 (3.9) Discontinuation due to ADRs 115 (2.9) 84 (2.6) AEs with fatal outcome 15 (0.4) 18 (0.6) ADRs with fatal outcome 3 (<0.1) 3 (<0.1)

C. MXF vs other fluoroquinolone(s) (FQ) in oral (PO), sequential (IV/PO) or intravenous (IV) studies

Adverse event Treatment route, n (%)

PO IV/PO IV MXF

(n=2509) FQ

(n=2557) MXF

(n=444) FQ

(n=457) MXF

(n=349) FQ

(n=352) Adverse events (AEs) 892 (35.6) 935 (36.6) 370 (83.3) 356 (77.9) 86 (24.6) 84 (23.9) Adverse drug reactions (ADRs) 563 (22.4) 530 (20.7) 149 (33.6) 148 (32.4) 49 (14.0) 50 (14.2) Serious AEs 66 (2.6) 60 (2.3) 103 (23.2) 95 (20.8) 0 (0) 1 (0.3) Serious ADRs 6 (0.2) 4 (0.2) 15 (3.4) 17 (3.7) 0 (0) 0 (0) Discontinuation due to AEs 82 (3.3) 93 (3.6) 40 (9.0) 46 (10.1) 21 (6.0) 11 (3.1) Discontinuation due to ADRs 56 (2.2) 73 (2.9) 25 (5.6) 25 (5.5) 17 (4.9) 9 (2.6) AEs with fatal outcome 7 (0.3) 3 (0.1) 28 (6.3) 23 (5.0) 0 (0) 0 (0) ADRs with fatal outcome 0 (0) 0 (0) 3 (0.7) 2 (0.4) 0 (0) 0 (0)


D. MXF vs β-lactam(s) plus macrolide(s) in oral studies

Adverse event MXF, n (%)

(n=460) β-lactam(s) + macrolide(s), n (%)

(n=345) Adverse events (AEs) 244 (53.0) 197 (57.1) Adverse drug reactions (ADRs) 102 (22.2) 96 (27.8) Serious AEs 56 (12.2) 49 (14.2) Serious ADRs 13 (2.8) 7 (2.0) Discontinuation due to AEs 36 (7.8) 25 (7.2) Discontinuation due to ADRs 21 (4.6) 15 (4.3) AEs with fatal outcome 10 (2.2) 12 (3.5) ADRs with fatal outcome 2 (0.4) 0 (0)

E. Moxifloxacin vs β-lactam(s) ± macrolide(s) in sequential (IV/PO) studies

Adverse event MXF, n (%) (n=532)

β-lactam(s) ± macrolide(s), n (%) (n=549)

Adverse events (AEs) 303 (57.0) 359 (65.4) Adverse drug reactions (ADRs) 159 (29.9) 166 (30.2) Serious AEs 72 (13.5) 86 (15.7) Serious ADRs 16 (3.0) 11 (2.0) Discontinuation due to AEs 47 (8.8) 58 (10.6) Discontinuation due to ADRs 32 (6.0) 35 (6.4) AEs with fatal outcome 15 (2.8) 25 (4.6) ADRs with fatal outcome 1 (0.2) 2 (0.4)

moxifloxacin safety - lippincott williams & wilkins

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