Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

Fluoroquinolone-associated tendon-rupture:
a summary of reports in the Food and Drug
Administration’s adverse event reporting system

Rasha M Arabyat, Dennis W Raisch PhD, June M McKoy & Charles L Bennett

To cite this article: Rasha M Arabyat, Dennis W Raisch PhD, June M McKoy & Charles L Bennett
(2015): Fluoroquinolone-associated tendon-rupture: a summary of reports in the Food and
Drug Administration’s adverse event reporting system, Expert Opinion on Drug Safety, DOI:
10.1517/14740338.2015.1085968

To link to this article: http://dx.doi.org/10.1517/14740338.2015.1085968

Published online: 22 Sep 2015.

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 Original Research

Fluoroquinolone-associated
tendon-rupture: a summary of
reports in the Food and Drug
1. Introduction
2. Materials and methods
Administration’s adverse event
3. Results reporting system
4. Discussion
5. Conclusions Rasha M Arabyat, Dennis W Raisch†, June M McKoy & Charles L Bennett
†
University of New Mexico, College of Pharmacy, Albuquerque, NM, USA

Objective: To review and summarize reports of tendon rupture associated

with each fluoroquinolone (FQ) currently marketed in the United States
Downloaded by [University of Windsor] at 03:23 01 October 2015

(US), as reported to the FDA’s Adverse Event Reporting System (FAERS).

Methods: FAERS data were reviewed for reports of tendon rupture associated
with each FQ from their respective approval date through September 2012.
Disproportional reporting signal detection was estimated using empirical
Bayes geometric mean (EBGM) with 95% confidence intervals (CI).
Results: There were 2495 FAERs reports of tendon rupture associated with
currently approved FQs. Most FAERS reports were associated with levofloxacin
(n = 1555) followed by ciprofloxacin (n = 606) and moxifloxacin (n = 230).
Signal detection results for FQs were as follows: levofloxacin (EBGM = 55.2,
95% CI = 52.3 -- 58.0), ciprofloxacin (EBGM = 20.0, 95% CI = 18.2 -- 21.6),
moxifloxacin (EBGM = 13.3, 95% CI = 11.7 -- 15.1), norfloxacin (EBGM = 9.6,
95% CI = 6.5 -- 13.5), ofloxacin (EBGM = 8.2, 95%CI = 6.3 -- 10.2) and gemiflox-
acin (EBGM = 1.9, 95% CI = 0.7 -- 4.5). The mean age of affected individuals
was 59.6 ± 5.1 years. Corticosteroids were administered concomitantly with
FQs in 21.2% of cases.
Conclusion: As noted in boxed warnings, FQ use is associated with increased
tendon rupture risk. Risk factors for FQ associated tendon rupture include
use in the elderly, and in patients with concomitant corticosteroids. Further
monitoring may be needed due to antibiotic overuse and marketing of newer
FQs.

Keywords: adverse events, fluoroquinolones, pharmacovigilance, tendon rupture

Expert Opin. Drug Saf. [Early Online]

1. Introduction

Fluoroquinolone (FQs) antibiotics were first approved by the FDA for marketing in
the 1980s [1]. Since then, FQs have been used extensively to treat a wide range of
infections and, although not approved by the FDA for prevention, are also increas-
ingly used as prophylaxis against infection among persons with cancer and other
immune compromised states [2]. Initially, these agents were FDA approved to treat
infections caused by Gram-negative bacteria. However, newer agents in this class
have gained FDA approvals for additional coverage against Gram positive bacteria,
atypical bacteria (e.g., Legionella, Chlamydia, and Mycoplasma), and even anae-
robes [3]. FQs have a distinctive mechanism of action as they are the only class of
antimicrobial agents in clinical use that are direct inhibitors of bacterial DNA
synthesis [4].

10.1517/14740338.2015.1085968 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 1

All rights reserved: reproduction in whole or in part not permitted
 R. M. Arabyat et al.
Overall, FQ antibiotics appear to be well tolerated, but can
cause a range of serious adverse events. The most commonly
reported adverse events associated with this class of antibiotics
include gastrointestinal distress (2 -- 20%), central nervous
system disturbances (1 -- 2%), and cardiovascular manifesta-
tions (< 1%) [5]. Other reported adverse events associated
with FQs include hepatotoxicity, hypoglycemia, or hypergly-
cemia, increased sensitivity to light, allergic reactions, tendon-
itis, and tendon rupture [4]. The overall estimated occurrence
of tendonitis or tendon rupture episodes associated with FQs
ranges from 0.14 to 0.4% [5]. Risks of tendonitis and tendon
rupture were emphasized by issuance of a boxed warning by
the FDA for FQs in July 2008 in response to a Citizen’s Peti-
tion filed by Public Health Group in conjunction with Illinois
Attorney General, Lisa Madigan [6]. The petition reported
number of MedWatch cases of tendon rupture (total = 262)
Downloaded by [University of Windsor] at 03:23 01 October 2015
by individual FQ with levofloxacin, ciprofloxacin, and moxi-
floxacin comprising 61, 23 and 9% of cases respectively [6].
FQ-associated tendon rupture injury is more frequently
reported among persons with concomitant renal [7], pulmo-
nary, or cardiovascular diseases [5]. Other risk factors include
older age and concomitant corticosteroid use [5,7,8].
The boxed warning issued by the FDA for tendinitis and
tendon rupture was for FQs as a class and did not discriminate
between individual agents. A systematic literature review of
FQ-associated tendon injury reports published from 1966 to
2001 revealed that pefloxacin and ciprofloxacin were the
most frequently implicated agents. This review, however,
was completed before issuance of the boxed warning and
was limited to 98 reports [1]. A recent case-crossover study
based on The Health Improvement Network (THIN) data-
base was conducted to identify risk factors for FQ-associated
tendon injury. The study concluded that tendon rupture
risk is more evident among persons who are elderly, lean,
and/or who receive corticosteroids concomitantly [7].
Nonetheless, risks were assessed for FQs as a class and not
for individual agents.
The mechanism by which FQs cause tendon injury is
unclear. Pathological features include: degenerative lesions,
fissures, interstitial edema without cellular infiltration,
necrosis or neovascularization [9]. FQs cause oxidative stress
in tenocyte cells through overproduction of reactive oxygen
species (ROS). This overproduction has direct toxic effects
in the extracellular matrix. In addition, FQs cause mitochon-
drial toxicity and apoptosis [10].
To gain further insight into this serious adverse event,
reports of tendon rupture associated with each FDA-approved
and marketed FQ in the United States (US) and contained in
the FDA’s Adverse Event Reporting System (FAERS) were
reviewed. FAERs reports were dated from the respective
approval date for each drug through September 26, 2012.
Pharmacovigilance methods for quantitative signal detection
were used, where a safety signal infers a possible causal associ-
ation between a drug and a suspected adverse event [11]. The
current analysis was limited to tendon rupture because other
2 Expert Opin. Drug Saf. (2015) 14(11)
forms of tendinopathy (e.g., tendonitis) are subject to greater
misclassification bias. Tendon rupture is less prone to misdi-
agnosis due to its severity and distinctive clinical features [12].
2. Materials and methods
2.1 Data sources
This study is an analysis of reports of tendon rupture
contained in the FAERS database, which includes informa-
tion about reports of all adverse events submitted to the
FDA [13]. The FAERS database is updated quarterly and
contains over nine million adverse event reports [14]. FAERS
is utilized to support the FDA’s post marketing safety moni-
toring program for drug and therapeutic biologic products.
Reporting an adverse event to the FDA is performed voluntar-
ily by healthcare professionals and consumers via MedWatch.
On the other hand, MedWatch reporting is mandatory for
manufacturers, distributors, and importers. Reporting can be
conducted online, by phone, or by submitting a MedWatch
form by mail or facsimile [15]. If a potential safety concern is
identified by review of the FAERS database by FDA pharma-
covigilance personnel, further assessment maybe performed. If
a safety signal is confirmed, FDA may take regulatory actions,
such as limiting the use of the drug, issuance of boxed
warning or even withdrawal of the product from the market.
Data recorded in the FAERS database include patient demo-
graphics, administrative information, drug, dose, duration,
concomitant medicines, multiple reaction terms, outcomes
of the adverse event, and source of the reports [16]. There are
also narrative descriptions of the reactions and laboratory
test results. Details of MedWatch reports may be obtained
through Freedom of Information Act (FOIA) requests [17].
2.2 Search of FAERS database
Prior to analysis, a list of all the FDA-approved and marketed
FQs in the USA was obtained by reviewing the FDA’s web-
site. FQs were excluded if they were no longer marketed in
the USA (alatrofloxacin, enoxacin, gatifloxacin, grepafloxacin,
lomefloxacin, sparfloxacin, and trovafloxacin) or not intended
for systemic use (besifloxacin). The study was therefore
limited to ciprofloxacin, gemifloxacin, levofloxacin, moxiflox-
acin, norfloxacin, and ofloxacin.
In the FAERS database, adverse events are coded using pre-
ferred terms (PTs) in the Medical Dictionary for Regulatory
Activities (MedDRA) terminology. Version 15.0 of MedDRA
was utilized. The preferred event term was limited to tendon
rupture, excluding all other forms of tendinopathy. Tendon
rupture is severe and distinguishable, thus reducing the
possibility of bias from misdiagnoses. All reports of tendon
rupture in the FAERS database in which an FQ was involved
were included in the analysis.
All searches were conducted from the respective FDA
approval dates for each specific drug product (earliest was
December 1996 for levofloxacin and latest was March
2003 for gatifloxacin) through September 2012. Reporting
 Fluoroquinolone-associated tendon-rupture: a summary of reports in the FAERS
Table 1. Number of cases, mean age, concomitant corticosteroids, and the empirical Bayes geometric mean (EBGM)
for tendon rupture cases associated with FQs in the FAERS database.
Drug No. of cases Mean age (±SD)‡
Any fluoroquinolone* 2495 59.6 (± 5.1)
Levofloxacin 1555 60.0 (± 14.6)
Ciprofloxacin 606 54.5 (± 14.8)
Moxifloxacin 230 54 (± 13.4)
Ofloxacin 70 66.7 (± 12.3)
Norfloxacin 30 57.7 (± 16.7)
Gemifloxacin 4 55.7 (± 2.5)
*Only currently approved FQs.
z
SD: Standard deviation
§
Empirical Bayes geometric mean (EBGM): is the disproportionality reporting signal detection test used in this study.
FQ: Fluoroquinolone; FAERS: FDA’s adverse event reporting system.
sources, country of occurrence, and patient’s outcomes, age,
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gender, and drug indications were summarized for all tendon
rupture cases associated with the currently approved FQs.
Between 2004 and 2013, 66.6% of reports found in
FAERS were from the USA [18]. Reports from other countries
are included because the FDA mandates manufacturers to
report all adverse events that occur in market settings world-
wide even if they were not in the USA. Therefore, FAERS
includes reports worldwide with the majority of non-US
reports being from other developed countries such as United
Kingdom, Japan, France, and Canada. The nature of sponta-
neously reported adverse events limited the uniformity and
completeness of information, and the missing data were
specified when possible.
2.3 Signal detection
Additionally, disproportionate reporting signal detection
ratios were calculated to estimate signal strength associated
with tendon rupture among patients receiving FQs. The
empirical Bayes geometric mean (EBGM) with the accompa-
nying 95% CIs was calculated. EBGM is based on the
statistical approach of disproportionality analysis to determine
whether the number of tendon rupture cases associated with
each FQ was greater than for other drugs [19]. EBGM is a
novel data mining method that is used frequently by the
FDA and the WHO for monitoring of safety signals within
their spontaneous reporting system databases. EBGM quanti-
fies the extent to which a drug and adverse event combination
occurs disproportionally to what would be expected if there
was no association [20]. A significant safety signal occurs
when a drug-adverse event combination is reported more
frequently than expected relative to the general reporting of
the drug and the general reporting of the adverse drug event.
The Bayesian approach provides the advantage of accounting
for uncertainty and missing data in the spontaneous reporting
system databases [19]. Judgment about the existence of a safety
signal and signal strength are made based on the number of
reported cases, the EBGM value, and the associated 95%
CI. A significant signal is defined as an EBGM value of at
Expert Opin. Drug Saf. (2015) 14(11)
Concomitant corticosteroids EBGM§ EBGM (95%CI)
21.2% 27.9 26.7 -- 29.1
27.1% 55.2 52.3 -- 57.9
10.4% 20.0 18.2 -- 21.6
14.7% 13.3 11.6 -- 15.1
5.3% 8.6 6.3 -- 10.2
2.4% 9.6 6.5 -- 13.5
0.0% 1.9 0.7 -- 4.5
least 2, (lower limit of 95% CI ‡ 2), and the existence of at
least two cases [21,22].
3. Results
The FAERS database contained 2495 reports of cases of ten-
don rupture associated with currently marketed FQs. The
EBGM for tendon rupture and FQs use was 27.9 (95% CI
26.7 -- 29.1), with most cases (n = 1555) being attributed to
levofloxacin (EBGM, 55.2; 95% CI 52.3 -- 57.9) followed
by ciprofloxacin (n = 606; EBGM, 20.0; 95%
CI 18.2 -- 21.6) and moxifloxacin (n = 230; EBGM, 13.3;
95% CI 11.6 -- 15.1) (Table 1). Significant safety signals
existed for all currently marketed FQs, except for gemifloxa-
cin. Corticosteroids were concomitantly administered with
FQs in 21.2% of tendon rupture cases. Specifically,
corticosteroids were administered concomitantly with
levofloxacin in 27.1%, with moxifloxacin in 14.7%,
with ciprofloxacin in 10.4%, with ofloxacin in 5.3%, and
with norfloxacin in 2.4% of tendon rupture cases. It has
been shown that reporting to FDA’s MedWatch of over the
counter medications, such as non-steroidal anti-inflammatory
drugs (NSAIDs), is markedly low [23]. Timeline of safety
reporting for FQs as a class is depicted in (Figure 1).
The mean age was 59.6 ± 5.1 (Table 1) and the ratio of men
to women was 1.16:1. Almost all of the tendon rupture cases
were considered to be serious adverse events (97.2%). The
most commonly reported outcomes were hospitalization
(35.6%) and disabling events (20.8%). Health professionals
submitted ~ 18.6% of reports, followed by consumers
(6.4%) and company representatives (3.6%). However, the
reporter identity was missing for the majority of reports
(64.1%). Analysis by country of occurrence revealed that the
majority of cases were from the USA (n = 1706), followed
by Japan (n = 190), Great Britain (n = 80), and France
(n = 35).
Indications listed in FAERS are shown in (Table 2). Among
reported tendon rupture cases found in FAERS, > 50% of
FQ-indications related to infectious diseases were for
3
 R. M. Arabyat et al.

600

500
# of cases submitted to FAERS
Linear trendline
400
Cases

300

200

100
Downloaded by [University of Windsor] at 03:23 01 October 2015

0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Before boxed warning After boxed warning

Years

Figure 1. Case reports in the FAERS database for FQ-associated tendon rupture by year.
Note: Cases reported in year 2012 are not shown due to incompleteness of reported data for this year.
FQ: Fluoroquinolone; FAERS: FDA’s adverse event reporting system.

Table 2. Indications and comorbid conditions associated with each FQ involved in tendon rupture cases in the
FAERS database.

Indications Levofloxacin Ciprofloxacin Moxifloxacin Ofloxacin Norfloxacin Gemifloxacin Total (%)

(%) (%) (%) (%) (%) (%)

Total respiratory tract 824 (64.0%) 166 (31.0%) 135 (79.4%) 6 (30.0%) 0 (0.0%) 6 (100%) 1137 (56.1%)
infections
Sinusitis 256 (19.9%) 43 (8.0%) 63 (37.1%) 0 (0.0%) 0 (0.0%) 2 (33.3%) 364 (18.0%)
Bronchitis 214 (16.6%) 35 (6.5%) 32 (18.8%) 2 (10.0%) 0 (0.0%) 2 (33.3%) 285 (14.1%)
Pneumonia 178 (13.8%) 39 (7.3%) 20 (11.8%) 2 (10.0%) 0 (0.0%) 2 (33.3%) 241 (11.9%)
Other respiratory tract 176 (13.7%) 49 (9.2%) 20 (11.8%) 2 (10.0%) 0 (0.0%) 0 (0.0%) 247 (12.2%)
infections
Cellulitis 26 (2.0%) 6 (1.1%) 3 (1.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 35 (1.7%)
Prophylaxis 39 (3.0%) 17 (3.2%) 0 (0.0%) 1 (5.0%) 1 (12.5%) 0 (0.0%) 58 (2.9%)
Urinary tract infection 114 (8.9%) 124 (23.2%) 2 (1.2%) 4 (20.0%) 7 (87.5%) 0 (0.0%) 251 (12.4%)
Other infectionsz 285 (22.1%) 222 (41.5%) 30 (17.6%) 9 (45.0%) 0 (0.0%) 0 (0.0%) 546 (26.9%)
Total indications listed n = 1288 n = 535 n = 170 n = 20 n =8 n =6 n = 2027
for infectious diseases*
No indication specified 317 (20.4%) 96 (15.8%) 66 (28.7%) 4 (5.7%) 10 (33.3%) 1 (25.0%) 494 (24.0%)
Chronic obstructive 60 (4.7%) 20 (3.7%) 9 (5.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 89 (4.4%)
pulmonary disease
Asthma 31 (2.4%) 10 (1.9%) 4 (2.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 45 (2.2%)
Total tendon rupture n = 1555 n = 606 n = 230 n = 70 n = 30 n=4 n = 2495
cases

*Total indications may exceed the total number of reported tendon rupture cases because some cases list more than one specific indication.
z
Other infections include: Cystitis, diverticulitis, epididymitis, prostatitis, and unspecified bacterial infections.
FQ: Fluoroquinolone; FAERS: FDA’s adverse event reporting system.

4 Expert Opin. Drug Saf. (2015) 14(11)

 Fluoroquinolone-associated tendon-rupture: a summary of reports in the FAERS
respiratory tract infections; specifically, sinusitis was the most
common indication (18%) followed by bronchitis (14.1%)
and pneumonia (11.9%). Other common indications include
urinary tract infection (12.4%), prophylaxis (2.9%), and cel-
lulitis (1.7%). Chronic obstructive pulmonary disease
(4.4%) and asthma (2.2%) were among the most commonly
reported comorbid conditions, particularly with moxifloxa-
cin, levofloxacin, and ciprofloxacin. However, MedWatch
reports do not consistently include comorbidities because
the focus is upon the indication for the drug suspected of
causing the reaction.
4. Discussion
To our knowledge, this is the first review of adverse events
reported to the FDA for tendon rupture cases associated
Downloaded by [University of Windsor] at 03:23 01 October 2015
with FQs. The results of the current study are in accordance
with previous findings that FQ use may be associated with
increase the risk of tendon rupture. [1,7,8,24,25]. However, this
study is unique in assessing the effect and the strength of asso-
ciation of all currently marketed FQ agents relative to the risks
of tendon rupture. Levofloxacin might be associated with the
greatest risk of tendon rupture followed by ciprofloxacin and
moxifloxacin. Although gemifloxacin was not shown to have a
significant safety signal and it is possible that gemifloxacin
carries a lower risk of tendon rupture, further research is
needed because the finding may be a reflection of lower pre-
scribing frequency, a more recent FDA approval date, and
low reporting rates of adverse events to the FDA. For exam-
ple, levofloxacin was approved by the FDA for marketing in
1996 whereas gemifloxacin was approved by the FDA for
marketing in 2003. Other possible explanations for the
elevated number of tendon rupture cases reported with levo-
floxacin include being the FQ with the highest number of
concomitant corticosteroid cases (27.1%), more frequently
reported among elderly patients (mean age = 60 years),
and the high utilization rate of levofloxacin in clinical
practice [26,27]. There is, however, limited evidence from the
literature regarding the comparative safety of FQs using data
from animal studies. Thus, it is difficult to conclude that
intrinsic differences in the chemical structures of FQs might
lead to the differential toxicity profiles. Most of the published
studies regarding FQs-associated tendon rupture are based on
case series observed from clinical practice, and thus may also
reflect the prescription pattern of these drugs [11].
Previous studies are inconsistent regarding the most
frequently implicated FQ with tendon rupture. For example,
Khaliq and Zhanel, in a systematic literature review, found
pefloxacin and ciprofloxacin to be the most frequently impli-
cated agents [1]. In contrast, Van der Linden et al., in a
population-based case-control study, examined the risk of
tendon rupture associated with individual quinolones and
found that the risk was greatest for current exposure to oflox-
acin (OR = 28.4, 95% CI 7.0 -- 115.3), whereas the ORs for
ciprofloxacin and norfloxacin were 3.6 (95% CI 1.4 -- 9.1)
Expert Opin. Drug Saf. (2015) 14(11)
and 14.2 (95% CI 1.6 -- 128.6), respectively [8]. Our findings
are different than those reported by Khaliq and Zhanel due to
the following reasons: i) our study is particularly relevant to
tendon rupture because other forms of tendon injury were
excluded; ii) only FQ agents approved and marketed in the
USA were included (pefloxacin is not approved by the FDA
in the USA); and iii) the Khaliq and Zahnel study was con-
ducted before the issuance of boxed warning in 2008 and
included only 98 case reports. Our results are also different
from those reported by Van der linden et al. (2003) because
in their study i) only ofloxacin, ciprofloxacin, norfloxacin,
and nalidixic acid were included; and ii) the risk of tendon
rupture was assessed only among those 60 years and older.
The presence of inconsistencies regarding the risk of tendon
rupture associated with individual FQ use may be due to
differences in prescribing habits, the time period over which
the study was conducted, different methodologies applied in
each study, and high rates of underreporting.
In the current study, the mean age of persons who experi-
enced FQ-associated tendon rupture (59 years) was similar
to what was found in a systematic review of FQ-associated
tendon injuries [1]. In a case-cross over study, Wise et al.
found a median age of 55.8 years for quinolone-associated
tendon rupture and the risk was more pronounced among
persons aged > 60 years [7]. Several other epidemiological
studies are also consistent with these age-related find-
ings [7,25,28]. The results of our study, based on FAERS, are
similar to the reports in the literature and call for application
of extra caution when prescribing FQs to older persons,
particularly in the presence of other risk factors.
The association between FQs and occurrence of tendon
rupture was similar between men and women. This finding
is consistent with a previous study that assessed risks of ten-
don rupture among quinolone users [8]. Wise et al., however,
found that the tendonitis and tendon rupture risks were
greater in women than men [7]. Use of corticosteroids was
documented for 20.6% of the FQ-associated tendon rupture
cases reported to the FDA. Several other studies have also
found that the use of glucocorticoids along with FQs increases
risks of tendon rupture [7,8,24]. An in vitro study found a syn-
ergistic toxicity between quinolones and corticosteroids on
tenocyte cells [29]. Corticosteroids potentiate risks of tendon
rupture through tendon degeneration and weakening [7].
The timeline for safety reporting of FQs as a class is
illustrated in (Figure 1) and shows a steady increase in the vol-
untary reporting of tendon rupture cases associated with FQs.
This may be due to the issuance of the boxed warning in
2008, which may have increased awareness and/or reporting
of this adverse event to the FDA. It has been found that issu-
ance of boxed warnings can lead to significant increases in
reporting serious adverse events, which could partly explain
the continuous rise of tendon rupture reporting [30,31]. Future
studies could examine the impact of issuance of boxed
warnings on FAERS reporting of tendon injuries associated
with FQs.
5
 R. M. Arabyat et al.
Our review of MedWatch reports showed that the vast
majority of tendon rupture cases associated with FQs led to
serious outcomes, including hospitalization and disabling
events. Therefore, it is essential that healthcare professionals
familiarize themselves with this adverse event and associated
risk factors. However, despite the elevated number of tendon
rupture cases reported with FQs and the seriousness of the
outcomes, causality cannot be established based only on data
from FAERS. Due to the spontaneous nature of reporting,
causality between the drug and the adverse event is not
required to be proven before submission of a MedWatch
report. In addition, most submitted reports do not
consistently contain the necessary information to evaluate
causality [16]. Additional issues with the FAERS are men-
tioned in the limitation section.
Analysis by the source of reporting countries showed that
Downloaded by [University of Windsor] at 03:23 01 October 2015
most of tendon rupture cases associated with FQs were
reported from the United States. Underreporting rates in
other countries may be partly due to unfamiliarity with volun-
tary reporting systems. Other countries, however, have their
own reporting systems, such as the Yellow Card Scheme in
the UK [32] and the MedEffect program in Canada [33]. In
addition, the VigiBase pharmacovigilance database, managed
by the WHO, contains the world’s largest collection of drug
safety information [34].
In the current study the majority of FQ indications were
related to respiratory tract infections (Table 2). Newer FQs
(such as levofloxacin and moxifloxacin) have better coverage
against Gram-positive bacteria such as streptococcus pneumonia,
which could explain their increase use to treat community
acquired pneumonia and acute exacerbation of COPD [35,36].
Such patients may be at higher risk for tendon rupture due to
the presence of a combination of hypoxemia, respiratory insuf-
ficiency, advanced age and concomitant corticosteroid
use [37,38]. Another important finding regarding indications is
that 3% of cases occurred in patients using FQs for prophylaxis.
FQs are considered one of the most commonly prescribed
antibiotics with documented patterns of unnecessary and
overuse [39]. Although the occurrence of tendon rupture may
be rare (0.14 -- 0.40%) [5] it should be considered in the
assessment of risk-benefit profile especially when the indica-
tion for use is uncertain or for prophylaxis. Following the
clinical guidelines for duration and indications of antimicro-
bial therapy could decrease FQs overuse and consequently
prevent adverse events.
Another important issue to consider is that adverse events do
not necessarily occur during or immediately after taking the
drug. In fact a considerable number of adverse events start
days or weeks after the last dose [40]. The latency period between
the exposure to FQ and the onset of tendon rupture has been
found to range between a few hours to months [41]. Physicians
and patients may not relate the onset of tendon rupture to
FQ intake for an infection treated earlier. This latency period
might be another contributing factor for underreporting of
adverse drug events including tendon rupture.
6 Expert Opin. Drug Saf. (2015) 14(11)
4.1 Limitations
This study has limitations. First, the analysis was limited to
FDA approved and marketed drugs. FQs that did not receive
FDA approval for marketing in the USA were excluded, such
as pefloxacin. One might obtain different results if these drugs
were included in the analysis. Second, only tendon rupture
was investigated; other forms of tendinopathy were not
evaluated. Third, the voluntary nature of adverse drug event
reporting to the FDA may affect the reporting rate. It is
estimated that ~ 1% of adverse drug events are reported to
MedWatch [42], a finding that makes it impossible to estimate
true incidence of adverse events from FAERS, even if utiliza-
tion data is available. Fourth, EBGM results are not used as
definitive evidence association between the drug and the
event; EBGM (and reporting to FAERS) is impacted by exter-
nal factors such as the time a product has been marketed and
publicity about an event due, for example, to the issuance of
boxed warning [30]. Due to the previously mentioned factors,
causality cannot be established between tendon rupture and
any of the FQs based on FAERS data alone.
5. Conclusions
The current study, based on analysis of the FAERS’ database,
confirms that FQ use is associated with increases in tendon
rupture reporting. This review of MedWatch reports showed
that the vast majority of tendon rupture cases associated
with FQs led to serious outcomes, including hospitalization
and disabling events. The results of this study should be inter-
preted with caution due to the limitations of FAERS. Most
cases were reported from the USA, which may be due to
underreporting of adverse reactions in other countries,
although empirical estimates from Canada match those from
the United States (i.e., 1% reporting rate) [43]. Prescribing of
FQs should be avoided in patients at high risk for tendon
rupture, such as the elderly, and patients on concomitant
corticosteroids. For patients for whom FQs are especially
indicated, they should be used for the shortest period possible
and at the lowest effective dose. Finally, continuous monitor-
ing of FQ use is required due to changing in prescription
patterns, discontinuation of some FQs, availability of newer
FQs, overuse of FQ antibiotics [39], and a wide range of FQ-
associated adverse events that have not been fully evaluated.
Declaration of interest
The authors have no relevant affiliations or financial involve-
ment with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.

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Affiliation
Rasha M Arabyat1, Dennis W Raisch†1 PhD,
June M McKoy2 & Charles L Bennett3
†
Author for correspondence
1
University of New Mexico, College of
Pharmacy, Albuquerque, NM 87131, USA
E-mail: draisch@salud.unm.edu
2
Northwestern University Feinberg School of
Medicine, Medicine and Preventive Medicine,
750 N Lakeshore Drive, Chicago, IL 60611, USA
3
University of South Carolina, Pharmacy,
Columbia, SC, USA