Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 1 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.
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 2 of 29
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.
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 3 of 29
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=8643) Moxifloxacin
(n=1889) Comparator
(n=1856) Moxifloxacin
(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)
Mean ± SD Median Range
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 4 of 29
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=701) Moxifloxacin
(n=1791) Comparator
(n=2042) Moxifloxacin
(n=1542) Comparator
(n=1559) Moxifloxacin
(n=349) Comparator
(n=352) Age (years)
Mean ± SD Median Range
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)
Mean ± SD Median Range
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
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 5 of 29
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.
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 6 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 7 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 8 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 9 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 10 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 11 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 12 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 13 of 29
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
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 14 of 29
B. Open-label studies
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)
Blood and lymphatic system disorders
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)
Gastrointestinal disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 15 of 29
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)
General disorders and administration site conditions
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)
Infections and infestations
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 16 of 29
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)
Metabolism and nutrition disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 17 of 29
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)
Musculoskeletal and connective tissue disorders
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)
Nervous system disorders
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)
Psychiatric disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 18 of 29
Renal and urinary disorders
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)
Respiratory, thoracic and mediastinal disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 19 of 29
Skin and subcutaneous tissue disorders
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
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 20 of 29
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)
Blood and lymphatic system disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 21 of 29
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)
Gastrointestinal disorders
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)
General disorders and administration site conditions
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)
Hepatobiliary disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 22 of 29
Infections and infestations
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)
Metabolism and nutrition disorders
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)
Musculoskeletal and connective tissue disorders
Any 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)
Nervous system disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 23 of 29
Psychiatric disorders
Any 0 (0.0) 2 (<0.1) 3 (0.2) 1 (<0.1) 0 (0.0) 0 (0.0)
Renal and urinary disorders
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)
Respiratory, thoracic and mediastinal disorders
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)
Skin and subcutaneous tissue disorders
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
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 24 of 29
B. Open-label studies
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)
Blood and lymphatic system disorders
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)
Gastrointestinal disorders
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)
General disorders and administration site conditions
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)
Hepatobiliary disorders
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 25 of 29
Immune system disorders
Any 0 (0.0) 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)
Infections and infestations
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)
Metabolism and nutrition disorders
Any 0 (0.0) 0 (0.0) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0)
Musculoskeletal and connective tissue disorders
Any 2 (0.1) 0 (0.0) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)
Nervous system disorders
Any 2 (0.1) 1 (<0.1) 1 (<0.1) 0 (0.0) 0 (0.0) 0 (0.0)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 26 of 29
Psychiatric disorders
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)
Respiratory, thoracic and mediastinal disorders
Any 0 (0.0) 1 (<0.1) 1 (<0.1) 2 (0.1) 0 (0.0) 0 (0.0)
Skin and subcutaneous tissue disorders
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
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 27 of 29
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=1631) β-lactam(s)
(n=1581) MXF
(n=408) β-lactam(s)
(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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 28 of 29
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)
Tulkens et al. – Moxifloxacin Safety: 14 Years of Clinical Data – Page 29 of 29
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)
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