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Quinolones
Review of Psychiatric and Neurological Adverse Reactions
Ana M. Tome
´and Augusto Filipe
Medical Department, Grupo Tecnimede, Sintra, Portugal
Contents
Abstract................................................................................. 465
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
1.2 Adverse Drug Reaction Profile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
2. Literature Search Strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
3. Search Findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.1 Suspected Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.2 SexandAge...................................................................... 470
3.3 Dose ............................................................................ 470
3.4 Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
3.5 Ambulatory versus Hospital-Based Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
3.6 Seriousness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
3.7 Concomitant Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
4. Discussion ............................................................................ 478
5. Conclusions........................................................................... 484
Abstract Quinolones are a class of antibacterial agents for the treatment of several
infectious diseases (e.g. urinary and respiratory tract infections). They are
used worldwide due to their broad spectrum of activity, high bioavailability
and good safety profile. The safety profile varies from quinolone to quinolone.
The aim of this article was to review the neurological and psychiatric
adverse drug reaction (ADR) profile of quinolones, using a literature search
strategy designed to identify case reports and case series. A literature search
using PubMed/MEDLINE (from inception to 31 October 2010) was per-
formed to identify case reports and case series related to quinolone-associated
neurological and psychiatric ADRs. The search was conducted in two phases:
the first phase was the literature search and in the second phase relevant
articles were identified through review of the references of the selected arti-
cles. Relevant articles were defined as articles referring to adverse events/
reactions associated with the use of any quinolone. Abstracts referring to
animal studies, clinical trials and observational studies were excluded. Iden-
tified case reports were analysed by age group, sex, active substances, dosage,
concomitant medication, ambulatory or hospital-based event and seriousness,
after Medical Dictionary for Regulatory Activities (MedDRA
) coding.
From a total of 828 articles, 83 were identified as referring to nervous
system and/or psychiatric disorders induced by quinolones. 145 individual
REVIEW ARTICLE Drug Saf 2011; 34 (6): 465-488
0114-5916/11/0006-0465/$49.95/0
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case reports were extracted from the 83 articles. 40.7%of the individual case
reports belonged to psychiatric disorders only, whereas 46.9%related to
neurological disorders only. Eight (5.5%) individual case reports presented
both neurological and psychiatric ADRs. Ciprofloxacin, ofloxacin and pe-
floxacin were the quinolones with more neurological and psychiatric ADRs
reported in the literature. Ciprofloxacin has been extensively used worldwide,
which may explain the higher number of reports, while for ofloxacin and
pefloxacin, the number of reports may be over-representative. A total of 232
ADRs were identified from the selected articles, with 206 of these related to
psychiatric and/or neurological ADRs. The other 26 were related to other
body systems but were reported together with the reactions of interest.
Mania, insomnia, acute psychosis and delirium were the most frequently re-
ported psychiatric adverse events; grand mal convulsion, confusional state,
convulsions and myoclonus were the most frequently reported neurological
adverse events.
Several aspects should be taken into account in the development of CNS
adverse effects, such as the pharmacokinetics of quinolones, chemical struc-
ture and quinolone uptake in the brain. These events may affect not only
susceptible patients but also ‘healthy’ patients.
1. Introduction
Quinolones are a class of antibacterial agents
used for the treatment of several infectious diseases
(e.g. urinary and respiratory tract infections). These
drugs are used worldwide due to their broad
spectrum of activity, high bioavailability and good
safety profile.
[1]
Quinolones act by inhibiting type II topoisom-
erases DNA gyrase and topoisomerase IV. These
enzymes are involved in bacterial DNA synthesis,
being essential for bacterial DNA replication,
thereby enabling these agents to be specific and
bactericidal. Although some degree of overlap
may exist, DNA gyrase tends to be the primary
target for quinolones in Gram-negative organ-
isms, whereas topoisomerase IV is typically the
primary target in Gram-positive bacteria.
[2,3]
Nalidixic acid, a non-fluorinated drug, was
the first quinolone to be approved (in 1963, in the
US). Since then, structural modifications to the
quinolone nucleus and the side-chains produced
the first fluoroquinolones (norfloxacin and cipro-
floxacin), which have a fluorine atom attached to
the central ring system, typically at the 6-position
or C-7-position. Subsequent generations of
fluoroquinolones were developed to improve the
antimicrobial coverage of the previous synthe-
sized fluoroquinolones –high activity against
Gram-negative species and atypical patho-
gens, and good-to-moderate activity against Gram-
positive species.
[1,4-6]
Despite their broad spectrum
and clinical success, some fluoroquinolones were
withdrawn from worldwide markets because of
serious adverse drug reactions (ADRs), i.e. tema-
floxacin (serious idiosyncratic reactions, such as
haemolytic and aplastic anaemia), trovafloxacin
(hepatotoxicity), grepafloxacin (QTc interval
prolongation) and clinafloxacin (phototoxicity).
Gatifloxacin was recently removed from clinical
use because of the high incidence of hypo- and
hyperglycaemia.
[5-9]
Some fluoroquinolones are
unavailable in the US or other markets, or are
used with restrictions (e.g. moxifloxacin,
[10]
nor-
floxacin
[11]
). None of the fluoroquinolones were
withdrawn from the market because of neuro-
toxicity or psychiatric adverse events. Ciprofloxacin
and levofloxacin are currently marketed without
restrictions and thus are the most widely used
fluoroquinolones.
The structure of quinolones may influence the
safety profile of this drug class. Position 7 influ-
ences binding activity to GABA in the brain, while
positions 1 and 7 influence the drug’s potency,
466 Tome
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pharmacokinetics and potential for interaction with
theophylline,
[1]
which may account for differences in
CNS adverse events among quinolones. The risk of
seizures and other CNS adverse events may be in-
creasedbyanincreasedCNSpenetrationandeither
an unsubstituted piperazine (e.g. ciprofloxacin,
enoxacin and norfloxacin) or pyrrolidine (e.g. tosu-
floxacin and clinafloxacin) group at position 7.
[1,12]
1.1 Pharmacokinetics
Quinolones are well absorbed following oral
administration, with moderate to excellent bio-
availability (marginally affected by food), mod-
erate to long elimination half-lives (1.5–16 hours)
and volumes of distribution >1.5 L/kg. There are
differences in elimination patterns among quin-
olones, ranging from predominant renal excre-
tion (e.g. ofloxacin, levofloxacin, lomefloxacin,
gatifloxacin) to extensive hepatic metabolism (e.g.
nalidixic acid, pefloxacin, sparfloxacin and gre-
pafloxacin). Quinolones are also widely distribut-
ed throughout the body, with tissue penetration
being usually higher than the concentration
achieved in plasma, stool, bile, and prostatic and
lung tissues, which is not related to lipid sol-
ubility. Contrary to this, penetration into pro-
static fluid, saliva, bone and CSF does not exceed
serum drug levels. These drugs have a relatively
poor cerebrospinal fluid (CSF) penetration into
uninflamed meninges (table I), but in the presence
of an inflammation there is a moderate penetra-
tion of at least ciprofloxacin, pefloxacin, ofloxa-
cin and trovafloxacin.
[42,43]
Table I. Comparative adverse reaction profile of quinolones and their pharmacokinetic (PK) properties regarding brain tissue penetration
Quinolones Percentage of adverse reactions by SOC PK characteristics References
GI tract CNS skin hepatic musculoskeletal
Ciprofloxacin ++/+++ + 0/+ + 0/+ Distribution in the CSF in concentrations about
10%of those in plasma when meninges are not
inflamed
13-15
Gatifloxacin ++/++++ +/+++ 0 NA NA Distributes into theCNS (mean penetration 35%);
CSF: serum concentration ratio of 0.6 (range
0.21–0.45) during multiple-dose administration
(400 mg/day)
13-17
Grepafloxacin ++++ +++ ++ NA NA No data available 15
Levofloxacin +/++++ + 0/+ + 0/+ Poor penetration into the CNS 13-16,18-38
Moxifloxacin
(oral)
+/++++ +/++++ ++ NA NA No data available in humans;
Good penetration into CSF in rabbits was
achieved
13,15,39
Norfloxacin +++++ + Widely distributed in body fluids (limited
information)
13,15
Ofloxacin ++ ++ 0/+ + 0/+ Distribution in the CSF but concentrations are
higher when meninges are inflamed
13,15
Sparfloxacin ++/++++ ++/+++ +/++++ ++ 0/+ Widely distributed into body tissues and fluids
(limited information on CNS)
13-15
Lomefloxacin NA NA NA NA NA Widely distributed into body systems (such as
lungs and prostate)
14
Enoxacin NA NA NA NA NA Widely distributed in the body, and
concentrations higher than those in plasma
have been reported in lungs, kidney and
prostate
14
Pefloxacin NA NA NA NA NA Greatest lipophilic character and thus the
greatest CNS penetration
40,41
Alatrofloxacin NA NA NA NA NA Prodrug of trovafloxacin, which is widely
distributed into body tissues
14
CSF =cerebrospinal fluid; GI =gastrointestinal; NA =not available; SOC =System Organ Class; 0 indicates none or £1%,+indicates 1–2%,
++ indicates 2–3%,+++ indicates 3–5%,++++ indicates >5%.
Quinolones: Review of Adverse Reaction Reports 467
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The penetration of quinolones across the
blood-brain barrier (BBB) may be an important
factor in determining the relative frequency and
severity of CNS toxicity. In general, quinolones
have a low lipophilicity, but some can easily cross
the BBB.
[13,40]
Also, they differ considerably in
their CSF transport and disposition. For example,
pefloxacin has the greatest lipophilic character
and thus the greatest CNS penetration;
[40,41]
therefore, the convulsant activity may be related
to pefloxacin concentration in the brain and/or its
slow clearance from the cerebral area.
[40]
On the
other hand, ofloxacin and lomefloxacin cross the
BBB by a unidirectional efflux (sequestration)
process from the CSF into blood by saturable
active transport, similarly to that described for
some b-lactam antibiotics. It seems that there
is the involvement of the efflux transporter P-
glycoprotein (which transfers drugs from the
brain to the bloodstream, decreasing the appar-
ent distribution of several drugs in brain tissues)
or efflux systems, which transport anionic com-
pounds (e.g. multidrug resistance-associated
protein 1). The presence of multiple efflux trans-
porters in the brain may also be responsible
for the low accumulation of quinolones in this
tissue.
[40,44]
1.2 Adverse Drug Reaction Profile
The safety profile of this drug class differs from
quinolone to quinolone. Their most common
adverse events are gastrointestinal disturbances
(nausea, vomiting, diarrhoea and abdominal pain).
Less common events include neurotoxicity, blood
disorders, renal disorders, metabolic disturbances,
QTc interval prolongation, hypersensitivity (with
anaphylactic shock and anaphylactoid reactions)
and photosensitivity reactions.
[6,12,45]
Phototoxicity
is mainly associated with lomefloxacin and spar-
floxacin, when patients taking these drugs are
exposed to sunlight.
[12]
Putting ADRs into per-
spective, gastrointestinal disturbances occur in
2–20%of patients, while CNS events occur in
1–2%, dermatological effects in 0.5–3%, hepatic
abnormalities in 2–3%and musculoskeletal dis-
orders <1%.
[13]
The comparative ADR profile of
select fluoroquinolones (for which information
on the ADR profile and pharmacokinetics was
available) is presented in table I.
Neurological ADRs represent the second most
common group of ADRs of this drug class.
[13,40]
The most commonly reported neurological symp-
toms are dizziness, headache, insomnia and som-
nolence. Other less common neuropsychiatric
events include delirium, agitation, confusion,
psychosis and seizures/convulsions.
[1,6,12,13]
CNS
disturbances can be divided into those resulting
from direct effects and those resulting from drug-
drug interactions (see section 4).
[13]
This review aims to contribute to the char-
acterization of neurological and psychiatric ADR
profiles of quinolones using a literature search
strategy designed to identify case reports (defined
as ‘a detailed report of the symptoms, signs,
diagnosis, treatment and follow-up of an individual
patient’, containing, in general, unusual or novel
occurrences)
[46]
and case series (‘series of case
reports that provide evidence of an association
between a drug and an adverse event’, being
‘generally more useful for generating hypotheses
than for verifying an association between drug
exposure and outcome’).
[47]
2. Literature Search Strategy
A literature search was performed based on
PubMed/MEDLINE (from inception to 31 October
2010) using the following search terms: ‘quino-
lones’, ‘fluoroquinolones’, ‘cinoxacin’, ‘nalidixic
acid’, ‘oxolinic acid’, ‘piromidic acid’, ‘pipemidic
acid’, ‘ciprofloxacin’, ‘enoxacin’, ‘lomefloxacin’,
‘nadifloxacin’, ‘norfloxacin’, ‘ofloxacin’, ‘pefloxacin’,
‘rufloxacin’, ‘balofloxacin’, ‘gatifloxacin’, ‘levo-
floxacin’, ‘moxifloxacin’, ‘pazufloxacin’, ‘sparfloxacin’,
‘temafloxacin’, ‘tosufloxacin’, ‘garenoxacin’, ‘ge-
mifloxacin’, ‘clinafloxacin’, ‘prulifloxacin’, ‘sita-
floxacin’; no limits were placed on the search
function.
From the results obtained from the literature
search, two reviewers selected relevant English,
French, Spanish and Portuguese articles related
to quinolones by examining the abstracts (selec-
tion phase I) independently from each other.
Relevant articles were those referring to adverse
events or ADRs associated with the use of any
468 Tome
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quinolone, regardless of its role (suspected, con-
comitant or interacting). Abstracts referring to
animal studies, clinical trials and observational
studies were excluded. Clinical trials and ob-
servational studies, regardless of the safety aspect
they may cover, were excluded as the main pur-
pose of this review was to evaluate case reports
and case series from the literature. The selection
of the articles made by each reviewer was com-
pared to determine the abstracts to be included.
In the case of doubt or disagreement in the se-
lection of articles, the reviewers included those
articles in phase I of the selection process.
Full texts of the selected articles were obtained
and the references of those articles reviewed to
identify additional case reports and case series
(selection phase II). The second phase was con-
ducted using only the references, not the ab-
stracts. The criteria for this phase were the same
as mentioned above, as well as the method for the
inclusion or exclusion of the articles. Once the
selection of the articles was completed and all full
text of the selected articles (phase I plus phase II)
obtained, a new review of the selected articles was
performed to narrow the selection to case reports
and case series describing neurological and/or
psychiatric adverse event(s)/reaction(s). The se-
lected events belonged to the Medical Dictionary
for Regulatory Activities (MedDRA
) System
Organ Class (SOC) ‘Nervous system disorders’
and/or ‘Psychiatric disorders’. MedDRA
is the
international medical terminology developed under
the International Conference on Harmonization of
Technical Requirements for Registration of Phar-
maceuticals for Human Use (ICH). MedDRA
is
a registered trademark of the International Fed-
eration of Pharmaceutical Manufacturers and
Associations (IFPMA). The methodology used in
the literature search is detailed in figure 1.
From the full text of the selected articles, after
narrowing the results to neurological and psy-
chiatric adverse event(s)/reaction(s), data were
collected using an in-house developed Microsoft
Access
database. Each individual case report was
recorded using the following criteria, which were
according to the guidelines/recommendations by
Kelly et al.:
[48]
ADR verbatim and its description
(including information on dechallenge and re-
challenge); patients’ demographics (sex, age/age
group, weight); suspected medicinal product (do-
sage, pharmaceutical form/route of administra-
tion and indication of use); treatment duration;
outcome of the reaction; seriousness; causality
assessment (when assessed by the authors of the
articles); concomitant medication and diseases;
past medical and past drug histories, including
previous exposure to other quinolones; and place
where the event occurred (ambulatory or hospital-
based event). The individual case reports were
Literature search
(4820 articles)
Phase l of selection
(373 articles)
Selected articles final
phase l + phase lll
(828 articles)
Neurological and psychiatric
articles (83 articles)
206 neurological and psychiatric
adverse reactions
145 ICSRs
(within 83 articles)
232 adverse reactions
(within 145 ICSRs)
26 adverse reactions excluded
(other SOCs)
Phase ll: 455 articles added after
references review
745 articles excluded (other SOCs)
4447 articles excluded (language,
animal studies, clinical trials and
observational studies)
Fig. 1. Flow chart of methodology used in the literature search.
ICSRs =individual case safety reports; SOCs =System OrganClasses.
Quinolones: Review of Adverse Reaction Reports 469
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analysed by age group, sex, active substances,
dosage, concomitant medication, ambulatory or
hospital-based event and seriousness. Age group
was stratified by the following age intervals:
£18, 19–25, 26–35, 36–45, 46–55, 56–64, 65–74
and ‡75 years. Patients £18 years of age were
classified as children and adolescents, those aged
19–64 years as adults and those ‡65 years as
elderly.
ADRs were coded in MedDRA
version 13.1,
using the appropriate Preferred Term. For
MedDRA
coding, both reviewers coded each
event/reaction individually, and then compared
the coding results. In case of disagreement in the
MedDRA
coding, the terms coded by the med-
ical expert were the terms selected.
3. Search Findings
From a total of 4820 articles, only 373 were
selected as relevant in the first analysis of the
articles (phase I). In the second phase, a total of
455 additional articles were selected from the
references resulting in a total of 828. From these,
83 (10.0%) articles (case reports and case series)
describing neurological and psychiatric ADRs
related to one or more quinolones were identified.
145 individual case reports within the 83 articles
were analysed, being distributed per SOC, ac-
cording to the reported ADRs. From the 145 in-
dividual case reports, 8 (5.5%) presented both
neurological and psychiatric ADRs (belonging to
both SOCs), whereas 10 (6.9%) presented neuro-
logical and/or psychiatric ADRs combined with
ADRs from other SOCs (e.g. ‘Investigations’,
‘Cardiac disorders’, ‘Gastrointestinal disorders’).
A total of 59 (40.7%) of 145 individual case re-
ports belonged exclusively to ‘Psychiatric dis-
orders’, whereas 68 (46.9%) of 145 belonged to
‘Nervous system disorders’ only. Identified ADRs
are detailed in section 3.4.
3.1 Suspected Drugs
The number of individual case reports of each
suspected quinolone and the relevant percentage
are detailed in table II. Quinolones included
ciprofloxacin, ofloxacin, pefloxacin, norfloxacin,
nalidixic acid, levofloxacin, gatifloxacin, cinox-
acin, enoxacin, alatrofloxacin, oxolinic acid,
piromidic acid, pipemidic acid, lomefloxacin,
nadifloxacin, rufloxacin, balofloxacin, moxiflox-
acin, pazufloxacin, sparfloxacin, temafloxacin,
tosufloxacin, garenoxacin, gemifloxacin, clina-
floxacin, prulifloxacin and sitafloxacin.
Despite some quinolones no longer being mar-
keted (e.g. gatifloxacin, alatrofloxacin, cinoxacin),
the ADRs identified in this literature review were
discussed, together with themarketed quinolones.
In general, quinolones were used according to
their labelled indications, such as the treatment of
respiratory tract infections, urinary tract infec-
tions, skin infections and septicaemia. Also, in
the majority of the case reports, treatment dura-
tion followed the recommendations for treatment
durations according to the disease being treated.
3.2 Sex and Age
Data on sex and age were available in 140 in-
dividual case reports (96.6%), showing a slightly
higher number of ADR reports in women than in
men (56.6%vs 40.0%); this difference was not
statistically significant. More ADRs were identi-
fied in adults (57.2%) than elderly (31.7%)or
children/adolescents (6.2%). Among adults and
elderly population, there were no major differ-
ences in the stratified age groups.
3.3 Dose
Information on dose was available in 122 in-
dividual case reports (84.1%) and 104 (71.7%)
contained information on the route of adminis-
tration/pharmaceutical form. The route of ad-
ministration was mainly per os (78 cases [53.8%]).
Only two cases reported the administration of
topical ciprofloxacin (eye- and eardrops).
[49,50]
Patients were treated according to the recom-
mended dose, except in seven cases of overdose or
excessive dosage with nalidixic acid
[18,51]
and
ofloxacin
[19,20]
(two individual case reports each),
and ciprofloxacin
[21,52,53]
(three individual case re-
ports each). The individual case reports of over-
dose and excessive dosage with nalidixic acid
occurred in children. The first case was related to a
14-year-old girl who ingested 6.5 g,
[51]
where the rec-
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ommended daily dose of nalidixic acid in children
is 1–2 g. The second case involved a 4-year-old
girl who took 800 mg by mistake (excessive do-
sage).
[18]
Two cases of overdose after the ad-
ministration of ofloxacin were also reported: one
involved a 14-year-old girl who ingested an un-
known amount of ofloxacin and developed an
anticholinergic syndrome (concomitant adminis-
tration of diphenhydramine and chlormezanone);
[19]
the other occurred in an 81-year-old woman with
renal insufficiency who took pefloxacin by mis-
take after administration of ofloxacin.
[20]
Two
individual case reports of excessive dosage were
identified for ciprofloxacin, leading to neuro-
toxicity. This drug, in a higher than recommen-
ded dose for patients with renal impairment, was
administered to patients under a chronic dialysis
programme
[21]
and with chronic renal failure.
[52]
The third case resulted in ballismus, confusional
state and irritability in a liver cirrhotic patient,
[53]
which has a reduced capacity of drug metabolism.
3.4 Adverse Reactions
From a total of 145 individual case reports,
232 ADRs were identified, as some individual
Table II. Number and percentages of individual case reports and neurological and psychiatric adverse reactions per quinolone
Quinolone No. of individual case reports [n (%)] No. of adverse reactions [n (%)]
a
Ciprofloxacin 72 (49.7) 108 (52.4)
Ofloxacin
b
34 (23.4) 57 (27.7)
Pefloxacin
b
14 (9.7) 11 (5.3)
Levofloxacin 8 (5.5) 10 (4.9)
Norfloxacin
b
6 (4.1) 8 (3.9)
Nalidixic acid 4 (2.8) 4 (1.9)
Gatifloxacin
b
3 (2.1) 4 (1.9)
Gemifloxacin
b
2 (1.4) 2 (1.0)
Alatrofloxacin
b
1 (0.7) 1 (0.5)
Enoxacin
b
1 (0.7) 1 (0.5)
Balofloxacin
b
0(0) 0(0)
Cinoxacin
b
0(0) 0(0)
Clinafloxacin
b
0(0) 0(0)
Garenoxacin
b
0(0) 0(0)
Lomefloxacin
b
0(0) 0(0)
Moxifloxacin
b
0(0) 0(0)
Nadifloxacin
b
0(0) 0(0)
Oxolinic acid
b
0(0) 0(0)
Pazufloxacin
b
0(0) 0(0)
Pipemidic acid
b
0(0) 0(0)
Piromidic acid
b
0(0) 0(0)
Prulifloxacin
b
0(0) 0(0)
Rufloxacin
b
0(0) 0(0)
Sitafloxacin
b
0(0) 0(0)
Sparfloxacin
b
0(0) 0(0)
Temafloxacin
b
0(0) 0(0)
Tosufloxacin
b
0(0) 0(0)
Total (n) 145 206
a Percentage of neurological and psychiatric ADRs was calculated excluding the ADRs that did not belong to ‘Nervous system disorders’
and/or ‘Psychiatric disorders’.
b The quinolones that were withdrawn from the market are unavailable in certain countries or are used with restrictions.
ADRs =adverse drug reactions.
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case reports had more than one ADR. From the
232 ADRs, only 206 belonged to the selected
SOCs (‘Nervous system disorders’ and ‘Psychia-
tric disorders’). One of the ADRs, ‘EEG abnor-
mal’, was included as belonging to one of the
above-mentioned SOCs, due to its importance as
a tool to identify non-convulsive status epilepti-
cus (see section 4 for further details). The other
26 (11.2%) non-neurological and non-psychiatric
ADRs (e.g. palatal disorder, asthenia, fatigue,
visual field tests abnormal, liver function tests
abnormal, gastrointestinal disorders and cardiac
disturbances) were reported, together with the
neurological and psychiatric ADRs. For pur-
poses of evaluation, the number of ADRs is
considered to be 206 as we are evaluating the
profile of neurological and psychiatric ADRs of
quinolones.
A total of 111 ADRs (53.9%) belonged to the
SOC ‘Psychiatric disorders’, whereas 95 (46.1%)
belonged to the SOC ‘Nervous system disorders’.
Mania (38 cases; ciprofloxacin, ofloxacin and
norfloxacin), insomnia (10 cases; ciprofloxacin
and ofloxacin), acute psychosis (8 cases; all
ciprofloxacin) and delirium (8 cases; ciproflox-
acin, pefloxacin and levofloxacin) were the most
commonly reported psychiatric adverse events.
Grand mal convulsion (23 cases; all quinolones,
except alatrofloxacin and gemifloxacin), confu-
sional state (9 cases; ciprofloxacin, ofloxacin and
pefloxacin), convulsions (8 cases; ciprofloxacin,
ofloxacin, pefloxacin and gatifloxacin) and myo-
clonus (6 cases; ciprofloxacin, ofloxacin, pefloxacin
and gatifloxacin) were the most commonly re-
ported neurological events. Table III details the
neurological and psychiatric ADRs that were re-
ported for each quinolone.
We observed a total of 108 ADRs related to
ciprofloxacin, with psychiatric ADRs being the
most common (e.g. mania and acute psychosis).
Ciprofloxacin was followed by ofloxacin, pe-
floxacin, levofloxacin, norfloxacin, nalidixic acid,
gatifloxacin and gemifloxacin (table III). Alatro-
floxacin and enoxacin were associated with one
ADR each –clonus and grand mal convulsion,
respectively. In general, CNS adverse events de-
veloped within a few minutes or during the first
days of treatment (1–8 days). Only one case
developed after 5 months of chronic treatment
with pefloxacin.
[22]
In the majority of cases, patients recovered
without sequelae, and normally the events dis-
appeared on discontinuation of the drug.
For some CNS adverse events, such as delir-
ium or psychosis, the majority of patients had no
underlying diseases or concomitant medication
that could induce/precipitate the development of
delirium or psychosis. There were also cases show-
ing positive dechallenge, where patients recovered
within 1 day following drug withdrawal.
[23-32]
More-
over, the events developed within a few days after
starting the quinolone. Concomitant factors were
presented in some individual case reports of
quinolone-induced seizures, as further discussed
in section 4.
3.5 Ambulatory versus Hospital-Based Events
One hundred of 145 individual case reports
(69.0%) had information on whether the event was
ambulatory or hospital-based; 30 (20.7%) occurred
when the patient was hospitalized and 70 (48.3%)
occurred in outpatients (ambulatory care).
3.6 Seriousness
A serious ADR is any untoward medical oc-
currence that, at recommended dose, results in
death, is life-threatening, requires inpatient hos-
pitalization or prolongation of existing hospitali-
zation, results in persistent or significant disability/
incapacity, or is a congenital anomaly/birth de-
fect. Seventy (49.0%) individual case reports were
identified as serious, with 2 (2.8%) being fatal, 14
(19.7%) prolonging the patient’s hospitalization
and 55 (77.5%) requiring inpatient hospitaliza-
tion. None of the cases was life-threatening, re-
sulted in disability/incapacity or was a congenital
anomaly/birth defect. 51.0%of the individual
case reports did not provide information on the
seriousness criteria. One of the fatal events was
probably related to an interaction between
ciprofloxacin and theophylline. The patient had
several concomitant diseases that cannot be ruled
out as contributors.
[54]
The other fatal event was
not related to ciprofloxacin administration, but
was associated with the clinical condition of the
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Table III. Overview of neurological and psychiatric adverse reactions reported with quinolones
MedDRA
PT
a,b
CIP OFL PEF LEV NOR NAL GAT GEM ENO ALA Total no. of reactions [n (%)]
Abnormal dreams 2 NA NA NA NA NA NA NA NA NA 2 (1.0)
Absence seizure NA NA NA 1 NA NA NA NA NA NA 1 (0.5)
Acute psychosis 8 NA NA NA NA NA NA NA NA NA 8 (3.9)
Ageusia 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Agitation 5 2 NA NA NA NA NA NA NA NA 7 (3.4)
Agression 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Anticholinergic syndrome NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Anxiety 3 2 NA NA NA NA NA NA NA NA 5 (2.4)
Anxiety disorder due to a general medical condition 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Ballismus 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Brain injury 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Catatonia 1 NA NA 1 NA NA NA NA NA NA 2 (1.0)
Cerebellar syndrome NA NA 1 NA NA NA NA NA NA NA 1 (0.5)
Chorea 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Clonic seizures NA NA NA NA NA 1 NA NA NA NA 1 (0.5)
Clonus NA NA NA NA NA NA NA NA NA 1 1 (0.5)
Confusional state 4 3 2 NA NA NA NA NA NA NA 9 (4.4)
Convulsion 5 1 1 NA NA NA 1 NA NA NA 8 (3.9)
Delirium 4 NA 2 2 NA NA NA NA NA NA 8 (3.9)
Delusion NA NA NA NA 1 NA NA NA NA NA 1 (0.5)
Depression NA 1 NA 1 NA NA NA NA NA NA 2 (1.0)
Dizziness 1 1 NA NA NA NA NA NA NA NA 2 (1.0)
Dysarthria 2 NA NA NA NA NA NA NA NA NA 2 (1.0)
Dyskinesia 2 NA NA NA NA NA NA NA NA NA 2 (1.0)
Dysphonia 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Dystonia NA NA NA NA NA NA NA 1 NA NA 1 (0.5)
Electroencephalogram abnormal
c
NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Encephalopathy NA NA NA NA NA NA NA 1 NA NA 1 (0.5)
Epilepsy 1 1 NA NA NA NA NA NA NA NA 2 (1.0)
Euphoric mood NA 2 NA NA 1 NA NA NA NA NA 3 (1.4)
Extensor plantar response 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Extrapyramidal disorder NA NA 1 NA NA NA NA NA NA NA 1 (0.5)
Gait disturbances NA NA NA NA NA NA 1 NA NA NA 1 (0.5)
Continued next page
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Table III. Contd
MedDRA
PT
a,b
CIP OFL PEF LEV NOR NAL GAT GEM ENO ALA Total no. of reactions [n (%)]
Gaze palsy 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Grand mal convulsion 7 7 1 3 1 2 1 NA 1 NA 23 (11.2)
Grand mal seizure 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Grimacing 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Hallucination 1 1 NA NA NA NA NA NA NA NA 2 (1.0)
Hallucination, visual 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Hemiparesis 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Hostility 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Hyperkinesia NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Hyperacusis NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Insomnia 6 4 NA NA NA NA NA NA NA NA 10 (4.9)
Irritability 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Mania 22 12 NA NA 4 NA NA NA NA NA 38 (18.4)
Manic depression 2 NA NA NA NA NA NA NA NA NA 2 (1.0)
Mastication disorder 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Mood swings 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Muscle spasticity NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Myasthenia gravis 1 NA NA NA 1 NA NA NA NA NA 2 (1.0)
Myoclonus 3 1 1 NA NA NA 1 NA NA NA 6 (2.9)
Nervousness 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Neuropathy peripheral NA NA 1 NA NA NA NA NA NA NA 1 (0.5)
Nightmare NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Panic attack NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Paralysis NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Paranoia NA 2 NA NA NA NA NA NA NA NA 2 (1.0)
Parosmia NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Partial seizures NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Personality disorder NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Polineuropathy 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Psychotic disorder 2 NA NA 1 NA NA NA NA NA NA 3 (1.4)
Psychotic disorder due to a general medical condition NA 2 NA NA NA NA NA NA NA NA 2 (1.0)
Sedation 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Serotonin syndrome 2 NA NA NA NA NA NA NA NA NA 2 (1.0)
Continued next page
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patient.
[41]
A total of 78.9%of patients with a
serious ADR recovered without sequelae from the
CNS adverse reaction(s), while there is no in-
formation on outcome in 18.3%of the individual
case reports.
When analysing these cases, there were no
significant differences in the demographic char-
acteristics of the patients. Similarly to that pre-
sented in section 3.2, more individual case reports
of serious CNS adverse reactions refer to women
than to men (64.3%vs 32.9%). Serious CNS ad-
verse events developed more frequently in adults
(57.7%) and elderly (35.2%) than in children/
adolescents (5.6%). Ciprofloxacin, ofloxacin and
pefloxacin were the quinolones responsible for
the majority of the serious cases, consistent with
what has been reported in section 3.4.
Eight of these serious individual cases were
due to a possible interaction between the quino-
lone and theophylline (5 cases),
[33,34,54,55]
or with
an NSAID (2 cases)
[21,53]
or methadone (1 case).
[56]
The description of adverse events and concomitant
medication is detailed in section 3.7.
3.7 Concomitant Medication
Twenty-five individual case reports of neuro-
psychiatric ADRs due to the concomitant admin-
istration of a quinolone (ciprofloxacin, ofloxacin
or pefloxacin) and theophylline, NSAID or other
agents were identified (table IV). Seven individual
case reports included NSAIDs, such as indo-
methacin, ibuprofen, aspirin (acetylsalicylic acid)
and naproxen, while 12 reported an adverse event
due to an interaction between a quinolone and
theophylline. The majority of cases was related to
ciprofloxacin (18 cases), followed by pefloxacin
(4 cases) and ofloxacin (3 cases). Convulsion/
seizures was the most common ADR following a
drug interaction, while mania and delirium were
reported in 2 cases each.
Seizures have also been reported with the
concomitant administration of ciprofloxacin and
foscarnet,
[57]
predicting a possible interaction be-
tween these two drugs. Drug interactions with
vinca alkaloids
[22]
and chloroquine
[58]
have also
been reported. Additionally, a possible interaction
between ciprofloxacin and two potent serotonergic
Table III. Contd
MedDRA
PT
a,b
CIP OFL PEF LEV NOR NAL GAT GEM ENO ALA Total no. of reactions [n (%)]
Simple partial seizures NA NA 1 NA NA NA NA NA NA NA 1 (0.5)
Sleep disorder NA 2 NA NA NA NA NA NA NA NA 2 (1.0)
Somatic delusion 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Suicidal ideation NA NA NA 1 NA NA NA NA NA NA 1 (0.5)
Status epilepticus 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Tonic clonic jerking NA NA NA NA NA 1 NA NA NA NA 1 (0.5)
Toxic optic neuropathy 1 NA NA NA NA NA NA NA NA NA 1 (0.5)
Tourette’s disorder 1 1 NA NA NA NA NA NA NA NA 2 (1.0)
Tremor NA 1 NA NA NA NA NA NA NA NA 1 (0.5)
Total no. of reactions per active substance (n) 108 57 11 10 8 4 4 2 1 1 206
a This table excluded the ADRs from the selected individual case reports belonging to other SOCs rather than ‘Nervous system disorders’ and ‘Psychiatric disorders’. Percentages
were calculated using the total of neurological and psychiatric ADRs.
b The ADRs were identified from references.
[18-37,41,49-115]
c ADR ‘Electroencephalogram abnormal’ does not belong to the ‘Nervous system disorders’ or ‘Psychiatric disorders’, but was included in this table due to its relevance as a tool for
the non-convulsive status epilepticus.
ADRs =adverse drug reactions; ALA=alatrofloxacin; CIP =ciprofloxacin; ENO =enoxacin; GAT =gatifloxacin; GEM=gemifloxacin; LEV =levofloxacin; MedDRA
=Medical
Dictionary for Regulatory Activities; NA=not applicable; NAL =nalidixic acid; NOR =norfloxacin; OFL=ofloxacin; PEF =pefloxacin. PT =Preferred Term; SOC =System Organ Class.
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Table IV. Summary of individual case reports regarding neurological and psychiatric adverse reactions due to interactions between quinolones and other agents
Suspected
quinolone
Age (y)/
sex
Daily dose Time to onset
of reaction
Adverse reaction(s)
[MedDRA
PT]
a
Clinical history Concomitant medication
b
Reference
Ciprofloxacin 74/F 200 mg q12h 24 hours Grand mal seizure Pulmonary TE Theophylline 34
Ciprofloxacin 60/M 500 mg bid NR Grand mal convulsion COPD, CAP Theophylline 68
Ciprofloxacin 64/M 500 mg 8 hours Grand mal convulsion NR Indomethacin, prednisolone,
digoxin, glyburide, allopurinol
71
Ciprofloxacin 93/F 500 mg q12h 1 day Convulsion COPD, asthma Theophyllline, ranitidine, prednisolone 72
Ciprofloxacin 88/M 500 mg bid 2 days Delirium Chronic epididymitis Ibuprofen, heparin 25
Ciprofloxacin 57/F 500 mg bid 7 days Grand mal convulsion Metastatic breast
cancer
Theophylline, tamoxifen 73
Ciprofloxacin 74/F 500 mg bid 3 days Grand mal convulsion Anorexia nervosa,
gout, HTA
Theophylline 73
Ciprofloxacin 47/M NR NR Delirium NR Indomethacin 23
Ciprofloxacin 68/F 500 mg bid 1 week Polineuropathy Mastectomy,
collagenosis
Naproxen,chloroquine 58
Ciprofloxacin 46/M 500 mg NR Mania; aggression;
agitation; anxiety
NR Ibuprofen, lithium, amitriptyline 74
Ciprofloxacin 64/M 1000 mg NR Mania; psychotic disorder;
nervousness
NR Acetylsalicylic acid (aspirin) 74
Ciprofloxacin 39/M 750 mg q12h At first
administration
of foscarnet
Grand mal convulsion AIDS, PCP, candidiasis,
disseminated MAC
infection
Foscarnet, vancomycin, rifampin,
clarithromycin, fluconazole, cimetidine,
docusate sodium, morphine sulfate,
calcium carbonate, magnesium oxide
57
Ciprofloxacin 38/M 750 mg q12h 36 hours Grand mal convulsion PCP, candidiasis,
anaemia; hepatitis C,
wasting syndrome,
MAC infection
Foscarnet, ethambutol, pyrazinamide,
rifampin, clofazimine
57
Ciprofloxacin 61/M NR NR Serotonin syndrome Chronic, non-malignant
lower back pain, DM,
MDD
Venlafaxine,methadone, hydromorphone,
oxycodone
59
Continued next page
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Table IV. Contd
Suspected
quinolone
Age (y)/
sex
Daily dose Time to onset
of reaction
Adverse reaction(s)
[MedDRA
PT]
a
Clinical history Concomitant medication
b
Reference
Ciprofloxacin 42/F 750 mg bid 2 days Sedation
a
Ogilvie’s syndrome Methadone,venlafaxine
(only on the fourth occasion)
56
Ciprofloxacin 65/F 250 mg bid NR Epilepsy
a
Left hemiplegia, atrial
fibrillation; CCF, breast
cancer
Theophylline, digoxin, bumetanide, tamoxifen 54
Ciprofloxacin 79/F 500 mg bid 24 hours Anxiety disorder due to a
general medical condition;
agitation; confusional
state
a
COPD, CAD, MI Aminophylline, terbutaline, prednisone,
isosorbide dinitrate, meprobamate,
furosemide, hydroxyzine, diphenhydramine
55
Ciprofloxacin 74/M 500 mg bid 1 day Serotonin syndrome HTA, cerebrovascular
disease, depression,
PBH
Citalopram, enalapril, aspirin,
diazepam, reboxetine, sulpiride
66
Pefloxacin NR/F 800 mg 2 days Grand mal convulsion Parkinson’s disease,
broncho-emphysema
Theophyllline, levodopa/benserazide 67
Pefloxacin 77/F 2800 mg 7 days Grand mal convulsion DM Theophylline 33
Pefloxacin 31/F 2000 mg 4 days Delirium MMD Theophylline 33
Pefloxacin 37/M 400 mg bid 5 months Peripheral neuropathy Chronic vertebral
osteomyelitis
recurrence with
ofloxacin and
ciprofloxacin
Vincristine (past drug therapy) 22
Ofloxacin 84/F 400 mg q12h 3 days Convulsion CAD, DJD, CVA, MI Pentoxifylline,aspirin, furosemide,
isosorbide dinitrate, famotidine
65
Ofloxacin 62/F 400 mg NR Grand mal convulsion Asthma Theophyllline, phosphomycine, netilmicine 70
Ofloxacin 63/F NR NR Mania; paralysis NR Aminophylline, dihydrogesterone 74
a Only the ADRs belonging to the SOCs of interest are reported in this column. ADRs belonging to other SOCs are not mentioned.
b Italics represents the medicines that were responsible for the quinolone-drug interaction, leading to the neuropsychiatric ADR(s), being considered interacting agents.
ADRs =adverse drug reactions; bid =twice daily; CAD =coronary artery disease; CAP =community-acquired pneumonia; CCF =congestive cardiac failure; COPD =chronic
obstructive pulmonary disease; CVA =cerebrovascular accident (stroke); DJD =degenerative joint disease; DM =diabetes mellitus; F=female; HTA =hypertension; M=male;
MAC =Mycobacterium avium complex; MDD =major depressive disorder; MedDRA
=Medical Dictionary for Regulatory Activities; MI =myocardial infarction; MMD =myotonic
muscular dystrophy; NR =not reported; PBH =prostate benign hypertrophy; PCP =Pneumocystis carinii pneumonia; PT =Preferred Term; q12h =every 12 hours; SOCs =System
Organ Classes; TE =thromboembolism.
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agents (methadone and venlafaxine) was re-
ported, which manifested as serotonin syndrome
or sedation.
[56,59]
Two cases of neurological ADRs after the
concurrent administration of two quinolones
were reported: clonus after the administration of
alatrofloxacin and ciprofloxacin;
[35]
and myo-
clonus after the administration of ofloxacin and
pefloxacin.
[20]
4. Discussion
A slightly higher number of psychiatric ADRs
was reported among the overall individual case
reports.
The majority of CNS adverse reactions in-
duced by quinolones is related to their interaction
with neurotransmitters, and partially due to their
similarity in structure to GABA agonists. Quin-
olones may displace GABA from its receptors,
decreasing GABAergic inhibition and leading to
the stimulation of the CNS.
[34,36,37,41]
This stim-
ulation results in epileptogenic neurotoxicity
(e.g. seizures/convulsions). Binding to the GABA
receptor is strongly influenced by the side chain in
the 7-position of quinolones, as referred to in
section 1.
[1,6]
In vitro data have demonstrated that
the epileptogenic activity of quinolones is vari-
able, being the degree of excitatory effect as fol-
lows (from the highest to the smallest effect):
trovafloxacin >enoxacin >lomefloxacin >moxi-
floxacin >nalidixic acid >ciprofloxacin >oflox-
acin. No data were available for norfloxacin or
levofloxacin.
[6,41]
Trovafloxacin was rated as
having the highest epileptogenic activity, while
pefloxacin is associated with the fewest CNS ad-
verse reactions, despite the greatest CNS pene-
tration.
[40,41]
No individual case reports were
identified for trovafloxacin, which might be due
to its earlier withdrawal from the market. Levo-
floxacin has the lowest CNS penetration,
[14,16,38]
and therefore a lower rate of neurotoxicity. Cipro-
floxacin, ofloxacin and pefloxacin are known to
cross the BBB to a moderate extent in the pre-
sence of inflamed meninges,
[12,13,43]
which may be
one of the reasons for the increased number of
CNS adverse events identified in this review for
these three drugs (despite the seriousness of some
cases). However, none of the individual case
reports described the use of these quinolones for
the treatment of meningitis. CNS penetration of
quinolones plays an important role in determin-
ing the relative frequency and severity of CNS
toxicity,
[13]
but the relationship between the in-
cidence of these ADRs and the CNS pharmaco-
kinetics of quinolones remains unclear.
[12,13,43,45]
Additionally, ciprofloxacin has been extensively
used worldwide (marketed since 1987)
[12,13]
due
to its safety and tolerability profiles; therefore,
the frequency of exposure to this fluoroquinolone
may account for the number of ADRs reported in
the literature and identified in this review. As
cited by Heyd and Haverstock,
[116]
among a total
of 63 059 patients treated with oral ciprofloxacin
in clinical trials, adverse events occurred in 5.8%
of adult patients, with 1.1%being CNS-related
events. Ofloxacin and pefloxacin have not been
used to the same extent as ciprofloxacin and,
therefore, the number of CNS adverse reactions
identified for ofloxacin and pefloxacin may be
over-representative which is consistent with post-
marketing surveillance reports.
[26]
Moreover, oflox-
acin has been associated with sleep disturbances,
confusion, psychiatric disorders and convulsion
in the past,
[15]
which could have potentiated the
increased number of reports related to this drug,
as healthcare professionals may be more aware of
these events than of more common and familiar
complaints. Among the modern fluoroquinolones,
levofloxacin, the left optical isomer of ofloxacin,
has an overall incidence of CNS adverse effects of
0.2–1.1%(overall adverse effects 2–10%).
[15]
This
drug is associated with considerably fewer CNS
adverse reactions when compared with ofloxacin.
The underlying reason for this difference is the
influence of the R(+) isomer of ofloxacin, which
may contribute to the ADR profile of levo-
floxacin.
[13,117,118]
Contrary to expectations, no
individual case reports were identified for lome-
floxacin, yet it has been associated with a high
incidence of tremor, seizures and dizziness.
[15,117]
In a review by Bertino and Fish,
[117]
the rate of
reported seizures was approximately 45 per mil-
lion prescriptions of lomefloxacin, compared with
10 per million prescriptions with ciprofloxacin,
ofloxacin or norfloxacin together.
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Seizures and other neurological events have
been reported worldwide with nalidixic acid and
several fluoroquinolones. Seizures/convulsions
were one of the most common CNS adverse reac-
tions identified in this review for quinolones, de-
spite the rarity of overall CNS adverse reported in
the literature with this class of drugs. Seizures are a
rare ADR of ciprofloxacin,
[119]
while the Summary
of Product Characteristics (SPC) for ofloxacin re-
ports this event as very rare (<0.01%).
[120]
The
number of reports of seizures/convulsions may be
due to the seriousness or severity of such events,
as well as their clinical significance. They may be
precipitated by several factors, such as sleep de-
privation, malformations, head injuries, infec-
tions, metabolic disturbances, multiple sclerosis
and drugs.
[121]
The main mechanism underlying
this adverse event is the inhibition of GABA by
quinolones, as mentioned earlier. Other mech-
anisms have been proposed, such as the involve-
ment of the dopamine receptor
[60]
and the agonist
effect of fluoroquinolones on the glutamate re-
ceptor NMDA.
[61]
Fluoroquinolones are thought
to activate NMDA channels by chelating with
magnesium and removing its channel blocking
effect.
[60]
Possible contributing factors to the develop-
ment of several types of seizures and convul-
sions in patients taking quinolones may be a
history of seizures or epilepsy,
[35,36,62,63]
elec-
trolytic disturbances,
[35,41,64,65]
concomitant
medication,
[23,25,33-36,54-56,58-59,63,66-74]
history of re-
nal
[21,60,69,75,76]
and/or hepatic failure,
[53,75]
increased
age
[35,60,64,77]
and excessive dosages.
[35,52,53]
More-
over, these factors not only contribute to the de-
velopmentofseizures,butalsotosomepsychiatric
events induced by quinolones, which were men-
tioned in section 3.4.
Dosage is an important contributing factor to
the development of seizures because they have
been reported in children after the ingestion of
excessive doses of nalidixic acid.
[18,51]
Other cases
showed that fluoroquinolones were administered
at excessive dosages, indicating that no dose ad-
justments were made in patients with renal
[20,21,52]
or hepatic
[53]
disease. Caution is recommended
and required in patients with co-morbidities, as
well as dose adjustments to avoid the neurotoxi-
city of quinolones. Nevertheless, quinolones may
induce seizures even at therapeutic dosages be-
cause we have identified only seven cases of over-
dose and excessive dosage in this review.
The concomitant administration of theophyl-
line and NSAIDs is another contributing factor
to quinolone-induced seizures. In the presence of
a quinolone, the serum concentration of theo-
phylline increases about 20%and its clearance
decreases about 30%;
[34,67,70,73]
therefore, the dose
of theophylline should be reduced when a quin-
olone is started as the threshold for seizures is
lowered. In addition to seizures, visual hallu-
cinations have been reported in patients using
multiple drug therapy, including theophylline.
[30]
Ciprofloxacin, as well as theophylline is metabo-
lized by cytochrome P450 (CYP); therefore, the
interaction between these two drugs is likely to
occur in the liver via CYP.
[72]
This is not a class
effect as the affinity of each quinolone for CYP
varies. According to published data, fluoroquin-
olones are ranked as follows with regard to
interaction with theophylline (from the greatest
to the smallest effect): enoxacin (also inhibits
CYP)
[55]
>ciprofloxacin >norfloxacin >ofloxacin,
levofloxacin, trovafloxacin, gatifloxacin, moxi-
floxacin.
[13]
It has also been shown that position 1
influences theophylline interaction, the most
marked effects being with enoxacin, ciproflox-
acin and pefloxacin.
[78]
Indeed, several cases of
ADRs following interactions between theophyl-
line and ciprofloxacin or pefloxacin have been
reported (table IV). Contrary to expectation,
no individual case reports for an enoxacin-
theophylline interaction were identified in this
literature review.
The decrease in renal blood flow due to the
inhibition of prostaglandins, as a result of NSAID
activity, may increase the quinolone concentra-
tion, predisposing patients to ADRs. As cipro-
floxacin is mainly eliminated by renal excretion,
its elimination may be impaired by NSAID ac-
tivity.
[58]
Also, the potentiation by NSAIDs of the
competitive inhibition of neuronal GABA re-
ceptors by quinolones (by up to 30 000 times) may
induce these types of drug interactions and, con-
sequently, the development of neurotoxicity.
[13,79]
Shimada and Hori
[80]
demonstrated that fluoro-
Quinolones: Review of Adverse Reaction Reports 479
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quinolones may induce seizures at lower con-
centrations when administered concomitantly
with NSAIDs.
[80]
This is consistent with the re-
sults presented in this review. Additionally, the
structure at the 7-position of the quinolone in-
fluences the risk of NSAID-potentiated CNS
events. Fluoroquinolones with unsubstituted pi-
perazinyl rings (e.g. ciprofloxacin) have a stron-
ger interaction with NSAIDs.
[6]
The rank order
of inhibitory effects of the fluoroquinolones was
as follows (from the highest to the smallest effect)
prulifloxacin, norfloxacin >ciprofloxacin ‡en-
oxacin >gatifloxacin ‡ofloxacin, tosufloxacin,
lomefloxacin >levofloxacin ‡sparfloxacin ‡pa-
zufloxacin. No data were provided for pe-
floxacin. Fenbufen, flurbiprofen and ketoprofen,
among various NSAIDs, have been reported to
potently enhance the convulsive activity of
fluoroquinolones and, consequently, inhibition
of the GABA current by quinolones. A weaker
potentiation was seen with diclofenac, zaltopro-
fen and loxoprofen. Oxicam derivates, such as
tenoxicam and piroxicam, do not act as po-
tentiators of the convulsive activity of quino-
lones.
[81]
Quinolone-NSAID interactions dis-
cussed in this review did not occur with any of the
NSAIDs mentioned above.
The previous drug interactions are the most
common and the most reported in the literature,
as shown in table IV. In this literature review
we also described other fluoroquinolone drug
interactions, such as those with antivirals, anti-
histamines, vinca alkaloids, antidepressants, opiate
analgesics, and antimalarial and antineoplastic
drugs. The administration of chloroquine, an
antimalarial drug capable of inducing seizures, in
patients with a low seizure threshold precipitates
the development of seizures. The underlying me-
chanism for this pharmacokinetic interaction
may be the role of CYP, as both chloroquine and
ciprofloxacin are metabolized via CYP enzymes.
This interaction reported by Rollof and Vinge
[58]
did not result in seizures but in polyneuropathy.
The concurrent administration of ciprofloxacin
and two potent serotonergic agents (venlafaxineand
methadone) may also induce CNS adverse reac-
tions, identified in two individual case reports.
[56,59]
The concurrent administration of ciprofloxacin
and both methadone and venlafaxine led to the
development of serotonin syndrome in one case,
[59]
while in the other the patient became sedated
following the addition of ciprofloxacin to me-
thadone.
[56]
Ciprofloxacin was reintroduced
three times, and the patient became sedated on all
occasions. Additionally, on the last occasion,
venlafaxine had been replaced by fluoxetine.
[56]
Both methadone and venlafaxine are metabolized
by CYP isoenzymes (CYP1A2 for methadone
only, and CYP3A4 for methadone and venla-
faxine). Ciprofloxacin is a known potent in-
hibitor of CYP1A2 and depresses CYP3A4 in
human hepatic microsomes; therefore, a pharm-
acokinetic interaction involving ciprofloxacin,
methadone and/or venlafaxine may be responsi-
ble for the neurotoxicity of quinolones.
[56,59]
In-
terestingly, Montane
´et al.
[66]
reported a case of
serotonin syndrome induced by several drug in-
teractions, involving antidepressants and cipro-
floxacin. Serotonin syndrome first developed
when the patient added reboxetine to fluoxetine
and then when switched from fluoxetine to cita-
lopram. Despite the pharmacokinetic and phar-
macodynamic interactions involved in this case,
the addition of ciprofloxacin could have also
contributed to serotonin syndrome resulting in a
pharmacokinetic interaction between ciprofloxacin
and citalopram. CYP3A4, inhibited by ciproflox-
acin, is involved in the metabolism of citalopram,
leading to an increased plasma concentration of
this drug. The participation of ciprofloxacin in
serotonin syndrome is less likely,
[66]
but this drug
interaction should be considered when prescrib-
ing a quinolone to a patient receiving antidepre-
ssant treatment. Peripheral neuropathy following
administration of pefloxacin and subsequent ad-
ministrations of ofloxacin and ciprofloxacin was
reported. As the patient had been exposed in the
past to vinca alkaloids, known neurotoxic drugs,
Aoun et al.
[22]
suggested that vinca alkaloids might
potentiate fluoroquinolone-induced peripheral
neuropathy. Another drug interaction that may
enhance the risk of seizures is between foscarnet,
an antiviral drug, and epileptogenic agents (e.g.
fluoroquinolones). Foscarnet is known to induce
seizures; the concomitant administration of
ciprofloxacin may enhance the development of
480 Tome
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seizures by an unknown mechanism.
[57]
An ofloxa-
cin overdose potentiated the anticholinergic effect
of diphenhydramine and chlormezanone when
these three drugs were administered concurrently.
[19]
Although the convulsive potential of quino-
lones may also be related to their chemical
structures, there are no established data on their
cross-reactivity. Melvani and Speed
[35]
reported a
case of alatrofloxacin-induced clonus. Alatro-
floxacin, a pro-drug of trovafloxacin,
[7]
was ad-
ministered on the same day as the last two doses
of oral ciprofloxacin. On the other hand, Bagon
[20]
reported a case of myoclonus and muscle spasti-
city in an elderly patient with renal failure to
whom ofloxacin and pefloxacin were admin-
istered. Data on cross-reactivity of quinolones
are scarce, yet in both cases patients developed
neurological ADRs. The concurrent administra-
tion of two quinolones
[20,35]
might have increased
the risk of seizures because of a higher threshold
reduction. Further studies are required to investi-
gate the possibility of cross-reactivity between
quinolones.
An electrolyte disturbance may also contribute
to the epileptogenic activity of quinolones. Seizures
may occur with hypernatraemia,
[65]
hypomagne-
saemia
[41]
and hyponatraemia.
[35,41,64]
Hypomagne-
saemia is associated with neuronal irritability;
therefore, the administration of a quinolone trig-
gers seizures more easily.
[41]
Uraemic patients
may accumulate the quinolone or its metabolite,
precipitating convulsions, of which pefloxacin
[69]
was an example. Pefloxacin presents high serum
levels and undergoes biotransformation, leading
to the accumulation of the drug itself or its me-
tabolite in patients with renal or hepatic diseases,
and therefore increasing the risk of seizures.
[75]
In
the case of ofloxacin, its elimination is highly
dependent on renal excretion, requiring dosage
adjustments in patients with renal impairment.
[65]
Elderly patients are prone to develop seizures
and other neuropsychiatric adverse events (such
as delirium and psychosis) because of pharma-
codynamic changes that occur with increased
age. These changes include alterations in volume
of distribution, drug metabolism and elimination,
and protein binding.
[82]
Elderly patients should
be closely monitored when prescribing a quino-
lone, especially if they have CNS impairments,
multiple co-morbidities or are taking other med-
icines. There does not seem to be a high-risk
group for the development of neurotoxicity, at
least according to our results (31.7%of individual
case reports occurred in elderly patients) and
without other precipitating factors. These results
are consistent with the conclusions of Stahlmann
and Lode.
[83]
Alcohol dependence is a known risk factor for
seizures, which may occur until 2 days after
stopping drinking. Lahmek et al.
[84]
reported a
case of ofloxacin-induced seizures in a patient
undergoing detoxification for alcohol depend-
ence. Ofloxacin was considered the most prob-
able cause rather than alcohol dependence
because the patient stopped drinking 7 days prior
to seizures. Additionally, the patient was taking
venlafaxine but there are no reports of drug in-
teractions between ofloxacin and venlafaxine to
date. Patients treated with benzodiazepines have
a higher risk of seizures, due to a possible inter-
action of ofloxacin with the benzodiazepine-
binding sites located on the same complex as the
GABA receptor site. There might be a displace-
ment of GABA from its receptor, decreasing
GABAergic inhibition.
[84]
Akaike et al.
[122]
showed
contradictory findings: the inhibitory actions of
fluoroquinolones combined with biphenyl acetic
acid on GABA-mediated response were not in-
fluenced by the presence of flumazenil, a benzo-
diazepine antagonist.
Agbaht et al.
[85]
reported a case of grand mal
convulsion associated with ciprofloxacin in a pa-
tient with underlying thyrotoxicosis. This disease
lowers the threshold of epileptiform activity, and
may therefore cause seizures. Thyrotoxicosis may
be considered a risk factor for quinolone-induced
seizures.
Psychiatric adverse effects are rare, albeit ser-
ious. They seem to be dose-dependent and di-
rectly related to the quinolone concentration at
the receptor site. The underlying mechanism in-
volves GABA inhibition, as mentioned above;
[29,86]
however, the mechanism by which quinolone-
induced delirium remains unclear. Despite GABA
involvement, it is possible that the development
of quinolone-induced non-convulsive status
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epilepticus may potentiate some psychotic ADRs
(e.g. delirium). Isolated cases of abnormal EEG
have been reported, which may be a tool to ex-
clude quinolone-induced non-convulsive status
epilepticus.
[26]
Contrary to the majority of psy-
chiatric adverse effects, dizziness is not a rare event
in patients taking quinolones. However, it has only
been reported in two cases (ciprofloxacin and
ofloxacin),
[74]
probably because it is not a serious
and uncommon adverse event and does therefore
not require the attention of healthcare professionals
and thus reporting. Prescription Event Monitoring
in the UK
[123]
showed lower rates of dizziness with
ciprofloxacin, norfloxacin and ofloxacin. More-
over, the Swedish database (Sweweb)
[124]
had re-
ports of dizziness only with ciprofloxacin.
Several cases of psychosis,
[27-31,49,87-89]
delir-
ium,
[24-26,32,90,91]
mania
[74,92]
and hallucinations
[34,74]
have been reported, mainly with ciprofloxacin
and ofloxacin, despite their rarity. We believe
that these events were commonly reported in the
literature because of their seriousness (they can
progress to self-endangering, being life-threatening
or even fatal), severity and providing new in-
formation at the time of the report. Additionally,
as mentioned earlier, CNS adverse events may be
over-represented because the characteristics of
these events are well known by healthcare pro-
fessionals, as they are more frequently reported
than common gastrointestinal events or dizziness
and headache (the most common CNS adverse
effects listed in the SPCs of several quino-
lones).
[93,119,120,125-126]
A large, retrospective, 5-year
study showed that psychiatric adverse events
associated with fluoroquinolones occurred in
0.015%of inpatients.
[89]
Insomnia has been re-
ported in about 4.7%of patients treated with
ofloxacin, while psychosis occurs in <1%of
patients.
[13,93,119,120,125,126]
Therefore, reports of
insomnia are expected with quinolones, as well as
delirium and psychosis. Insomnia has also been
reported to the French database (2006) as a
common ADR (8%).
[93]
Delirium and psychosis
may also result from a quinolone-drug inter-
action (table IV); however, for the majority of
cases identified in this review, there was no pre-
cipitating factor for the development of such
CNS adverse events.
An isolated case of an acute psychotic reaction
following the use of topical ciprofloxacin (one
eyedrop every hour) in a young woman was re-
ported by Tripathi et al.
[49]
This ADR was sus-
pected to be idiosyncratic, aided by the increased
systemic absorption of ciprofloxacin secondary
to the severe eye inflammation. A second case of
neurotoxicity following topical administration of
ciprofloxacin was identified by Orr and Rowe.
[50]
In this case, several episodes of grand mal con-
vulsions following the intermittent prescription
of ciprofloxacin eardrops was reported.
[50]
No
other cases of ADRs following topical adminis-
tration of ciprofloxacin or any other quinolone
were identified. In fact, it is important to take
into consideration that topical medication, de-
spite being frequently omitted from medical his-
tories, can produce systemic effects, especially
where there are precipitating factors such as
concomitant drugs, previous psychiatric dis-
turbances, alcohol abuse and epileptogenic pre-
disposition.
A case of delusional parasitosis due to cipro-
floxacin, apparently the first such case report,
has been reported in the literature.
[94]
Hallu-
cinations, which can be a symptom of psychosis,
are rare among patients taking only fluoroquin-
olones, but are frequent in patients using multiple
drugs, with a quinolone being one of them. An
analysis of the Swedish database, Sweweb,
[124]
showed a small number of reports of hallu-
cinations after ciprofloxacin and levofloxacin
administrations.
Antibacterials are believed to be associated
with mania, despite being a rare event and af-
fecting individuals in an unpredictable way, as
cited by Abouesh et al.
[74]
In total, 40 cases of
fluoroquinolone-induced mania have been re-
ported worldwide,
[74,90]
and this is the most
common psychiatric ADR reported with fluoro-
quinolones (mainly with ciprofloxacin, ofloxacin
and norfloxacin), even though the SPCs of quin-
olones do not list this clinically significant ad-
verse event.
[119,120,125,126]
Mania symptoms in
some patients, as discussed by Abouesh et al.,
[74]
may be idiosyncratic, unless the patient has had
a history of personality disorders or psychosis,
which put them at a higher risk of developing
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mania.
[74,92]
Several mechanisms have been pro-
posed for antibacterial-induced mania, but with
reference to quinolones, GABA inhibition is the
agreed mechanism. James and Demian
[31]
sug-
gested that sepsis or brain injury/trauma may also
be contributing factors. Because of the char-
acteristics of mania reactions (seriousness and
consequences/outcome), these events are more
frequently reported by healthcare professionals
than other events. In addition, Abouesh et al.
[74]
presented an overview of spontaneous reports to
WHO and US FDA databases, which increases
the number of known reports.
A variety of hyperkinetic movement dis-
orders have been described after the administra-
tion of quinolones, especially ciprofloxacin. Among
them, tremor is a rare event,
[119,120]
which is
consistent with the number of reports published
(one case).
[95]
Other abnormal movements included
grimacing,
[96]
chorea,
[97]
dyskinesia,
[94,98]
Tourette-
like syndrome,
[99,100]
propriospinal myoclonus
[101]
and dystonia.
[60]
Of those, movement disorders
are listed in the US SPC for ciprofloxacin
[119]
and other quinolones.
[120,125,126]
These events
have been reported mainly in the elderly and
in patients with liver or renal diseases, which
is consistent with the predisposing factors for
neuropsychiatric ADRs induced by quinolones.
Dyskinesia was reported even in patients with
slight changes in liver metabolism.
[99]
Subclinical
hepatocerebral degeneration might also be a
precipitating factor for grimacing and dyskine-
sias.
[98]
The emergence of psychosis and Tourette-
like manifestations suggests that quinolones might
have some central dopaminergic action as dopa-
minergic mechanisms are involved in the genesis
of Tourette’s syndrome. GABA antagonism in
the basal ganglia may disinhibit dopaminergic
mechanisms.
[99,100]
This evidence was supported
in a mouse model where haloperidol protected
against quinolone-induced seizures.
[100]
Gait disturbances associated with gatifloxacin
have been reported
[102]
despite being a listed
event for some fluoroquinolones.
[93,119,120,125,126]
Hemiparesis, accompanied by dysarthria and
dysphonia following the administration of cipro-
floxacin was reported in an adolescent. The patient
was positively rechallenged, i.e. a new episode of
hemiparesis occurred. This case suggests a vas-
cular mechanism affecting the brain system.
[103]
Hemiparesis is not listed in the US SPC for
ciprofloxacin
[119]
or any other quinolone.
[120,125,126]
Sleep disorders, nightmares and insomnia were
identified in children aged 6 and 10 years.
[103]
Patients taking a recommended dose of ofloxacin
complained of sleep disturbances. In two case re-
ports, the symptoms resolved after ofloxacin sus-
pension and did not reoccur once a new quinolone
was introduced.
[104]
These reports are consistent
with the information collected from Sweweb,
[124]
despite being rare.
[126]
Although these events seem
to be common in children, no special warnings
are listed in the US SPC of ofloxacin.
[125]
Catatonic syndrome has been reported as a
complication of thyphoid fever, but the involve-
ment of ciprofloxacin in a patient being treated
for thyphoid fever remains uncertain and no clear
causal relationship can be made.
[105]
Recently,
catatonia was reported following the administra-
tion of levofloxacin.
[106]
The underlying hypotheses
suggest that catatonia is due to a dysregulation
of the dopaminergic neurotransmission or the
GABAergic neurotransmission, with the dysre-
gulation of the GABAergic neurotransmission
being the most consensual hypothesis.
[106]
The
administration of quinolones to patients where
neuromuscular transmission has already been
affected can aggravate or unmask myasthenia
gravis. Possible exacerbation of myasthenia gravis
has been reported with several quinolones. This
review identified two cases of exacerbation of myas-
thenia gravis after the administration of nor-
floxacin
[107]
and ciprofloxacin.
[108]
More recently,
the FDA warned that fluoroquinolones should
be avoided in patients already experiencing
myasthenia gravis because of their neuromus-
cular blocking activity and thus the exacerbata-
tion of muscle weakness.
[6,107,108,127]
Despite the majority of quinolones being
withdrawn from the market or their use being
restricted, no major differences in their CNS ad-
verse reaction profile were identified. Because of
a worldwide use of ciprofloxacin, we found more
individual case reports associated with this drug
than with other quinolones, which was expected.
Levofloxacin, also used worldwide, has fewer
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neuropsychiatric ADRs due to the lowest CNS
penetration. Levofloxacin also has a low poten-
tial for interaction with CYP, minimizing the risk
of drug interactions and allowing it to be an op-
tion in polypharmacy. Several CNS adverse re-
actions were also identified for ofloxacin and
pefloxacin, which may be over-representative as
these drugs are used in a less extent than cipro-
floxacin. In terms of the events themselves, the
types of events seen comparing different quino-
lones was consistent and similar from one quin-
olone to the other.
The results from the literature review showed
that about half of the individual case reports were
serious, with the majority of them being asso-
ciated with hospitalization or prolongation of the
existing hospitalization. The other half provided
no information on the seriousness of the case but
we consider that these case reports indicated an
event sufficiently serious and/or unexpected to be
reported in the worldwide literature and therefore
clinically relevant/significant. Moreover, the cases
occurred mainly in patients in ambulatory care
rather than inpatients and this is consistent with
the therapeutic uses/indications of quinolones.
This literature review has some limitations re-
garding how subjective the selection of articles
was. The limitations were mainly due to the
methodology used to conduct the review, which
excluded clinical trials and observational studies.
This was because the aim of the study was to
identify case reports and case series from the lit-
erature and to characterize the CNS adverse re-
action profile of quinolones based on case reports
and case series. Because of the information that
can be retrieved from clinical trials, an important
bias was introduced in this review. Additionally,
the quality of the case reports, the lack of com-
pleteness and detailed information of the in-
dividual case reports may also introduce bias.
The bias was minimized by using the guidelines
for submitting adverse events reports for pub-
lication,
[48]
which helped us to collect the most
appropriate information from each identified
case report/case series, increasing the quality of
the information retrieved. Several reports were
published prior to those guidelines (prior to
2007), which decreased the amount of informa-
tion available, clarity and quality of the earlier
case reports. The information retrieved from the
literature may be an important pharmaco-
vigilance tool, especially in the evaluation of the
safety profile of a drug and the benefit-risk ana-
lysis. The lack of information on the reported
ADRs at the time of publication of the articles
included in our review meant we could not eval-
uate the impact of such publications in the SPCs
of the marketed quinolones. As we could not re-
trieve the history of the SPCs, especially those at
the time of publication of the articles, we do not
have accurate information as to whether the
event was labelled or not at that time or if it was
included in the SPCs after publication. Due to the
absence of information on patient exposure, it
was not possible to evaluate/estimate the fre-
quency of these ADRs.
5. Conclusions
The results of our review showed that the
majority of CNS adverse reactions was expected
for quinolones, in particular for ciprofloxacin.
Ciprofloxacin, ofloxacin and pefloxacin were the
quinolones with more neurological and psychia-
tric ADRs reported in the literature. Ciproflox-
acin has been extensively used worldwide, which
may explain the observed pattern of ADRs, while
for ofloxacin and pefloxacin, the number of re-
ports may be over-represented.
Mania, the most reported event, is not in-
cluded in the SPC of quinolones; however, due to
the high number of reports, the need for its in-
clusion in the SPCs should be evaluated by the
manufacturers, and the underlying mechanism
clarified. Literature searches such as this are a
known pharmacovigilance tool, which can be
used in updating SPCs.
Patients with underlying medical conditions or
receiving concomitant medication may be at
higher risk of developing neuropsychiatric ADRs;
however, these events may also occur in ‘healthy’
patients. One factor that should be further
investigated is a possible cross-reactivity between
quinolones.
Several factors should be taken into account
when explaining CNS adverse effects, such as CNS
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penetration, chemical structure of the quinolone
and the convulsive activity of each quinolone.
Although these factors have been identified, the
propensity of individual quinolones to cause
convulsions is unclear and further research is
warranted.
Acknowledgements
The authors would like to thank Liliana Coelho, assistant
at the Medical Department, Grupo Tecnimede, for her sup-
port and assistance with retrieving full-text articles.
Both authors are full-time employees of Grupo Tecni-
mede, which markets some fluoroquinolones (ciprofloxacin,
levofloxacin, lomefloxacin and ofloxacin) in some European
and non-European countries. No sources of funding were
used to assist in the preparation of this review.
References
1. Mehlhorn AJ, Brown DA. Safety concerns with fluoro-
quinolones. Ann Pharmacother 2007; 41: 1859-66
2. Zhanel GH, Noreddin AM. Pharmacokinetics and pharmaco-
dynamics of the new fluoroquinolones: focus on respiratory
infections. Curr Opin Pharmacol 2001; 1 (5): 459-63
3. Blondeau JM. Fluoroquinolones: mechanism of action,
classification, and development of resistance. Surv Oph-
thalmol 2004; 49 Suppl. 2: S73-8
4. Melhus A. Fluoroquinolones and tendon disorders. Expert
Opin Drug Saf 2005; 4 (2): 299-309
5. Lewis RJ, Mohr III JF. Dysglycaemias and fluoroquino-
lones. Drug Saf 2008; 31 (4): 283-92
6. Dukes MNG, editor. Meyler’s side effects of drugs: the
international encyclopedia of adverse drug reactions and
interactions: fluoroquinolones. 15th ed. Amsterdam:
Elsevier Science, 2006: 1396-407
7. Sprandel KA, Rodvold KA. Safety and tolerability of
fluoroquinolones. Clin Cornerstone 2003; 5 Suppl. 3: S29-36
8. Smith DA, Schmid EF. Drugs withdrawals and the lessons
within. Curr Opin Drug Discov Devel 2006; 9 (1): 38-46
9. Rubinstein E. History of quinolones and their side effects.
Chemotherapy 2001; 47 Suppl. 3: 3-8
10. European Medicines Agency. EMEA restricts use of oral
norfloxacin drugs in UTIs. London: European Medicines
Agency, 2008 Jul 24
11. European Medicines Agency (EMEA), Danish Medicines
Agency. EMEA recommends restricting the use of oral
moxifloxacin-containing medicines. London: European
Medicines Agency, 2008 Jul 24
12. Owens Jr RC, Ambrose PG. Antimicrobial safety: focus
on fluoroquinolones. Clin Infect Dis 2005; 41 Suppl. 2:
S144-57
13. Fish DN. Fluoroquinolone adverse effects and drug inter-
actions. Pharmacotherapy 2001; 21 (10 Pt 2): 253-72S
14. Sweetman SC, editor. Martindale: the complete drug ref-
erence. 33rd ed. London: Pharmaceutical Press; 2002: 113,
182-6, 201, 209, 219-20, 232; 248, 266-7
15. Ball P. Adverse drug reactions: implications for the devel-
opment of fluoroquinolones. J Antimicrob Chemother
2003; 51 Suppl. 1: 21-7
16. Rodvold KA, Neuhauser M. Pharmacokinetics and pharm-
acodynamics of fluoroquinolones. Pharmacotherapy 2001;
21 (10 Pt 2): 233-52S
17. Perry CM, Barman Balfour JA, Lamb HM. Gatifloxacin.
Drugs 1999 Oct; 58 (4): 683-96; discussion 697-8
18. Jo M, Tachi N, Shinoda M. Convulsions from excessive
dosage of nalidixic acid: a case report. Brain Dev 1979; 1:
327-9
19. Koppel C, Hopfe T, Menzel J. Central anticholinergic
syndrome after ofloxacin overdose and therapeutic doses
of diphenhydramine and chlormezanone. J Toxicol Clin
Toxicol 1990; 28: 249-53
20. Bagon JA. Neuropsychiatric complications following
quinolone overdose in renal failure [letter]. Nephrol Dial
Transpl 1999; 14: 1337
21. Tattevin P, Messiaen T, Pras V, et al. Confusion and gen-
eral seizures following ciprofloxacin administration. Ne-
phrol Dial Transplant 1998; 13: 2712-3
22. Aoun M, Jacquy C, Debusscher L, et al. Peripheral neu-
ropathy associated with fluoroquinolones [letter]. Lancet
1992; 340: 127
23. Oro
´n JD, Ivorra J, Portilla J, et al. Reaccio
´n psico
´tica tras
la administracio
´n de indometacina y ciprofloxacino [let-
ter]. Rev Clin Esp 1992; 191: 401
24. Alte
´s J, Gasco
´J, Antonio J, et al. Ciprofloxacin and delir-
ium. Ann Intern Med 1989; 110: 170-1
25. McDermott JL, Gideonse N, Campbell JW. Acute delir-
ium associated with ciprofloxacin administration in a
hospitalized elderly patient. J Am Geriatr Soc 1991; 39:
909-10
26. Kiangkitiwan B. Levofloxacin-induced delirium with psy-
chotic features. Gen Hosp Psychiatry 2008; 30 (4): 381-3
27. Reeves RR. Ciprofloxacin-induced psychosis. Ann Pharm-
acother 1992; 26: 930-1
28. Meher LK, Tripathy D, Acharya S. Ciprofloxacin induced
psychosis. J Assoc Physicians India 1992; 40: 418-9
29. Mulhall JP, Bergmann LS. Ciprofloxacin-induced acute
psychosis. Urology 1995; 46 (1): 102-3
30. Zaudig M, von Bose M, Weber MM, et al. Psychotoxic
effects of ofloxacin. Pharmacopsychiatry 1989; 22: 11-5
31. James E, Demian A. Acute psychosis in a trauma patient
due to ciprofloxacin. Postgrad Med J 1998; 74: 189-90
32. Hakko E, Mete B, Ozaras R, et al. Levofloxacin-induced
delirium [letter]. Clin Neurol Neurosurg 2005; 107 (2):
158-9
33. Andrejak M, Schmit JL, Tondriaux A, et al. Neurological
side effects of fluoroquinolones: apropos of 9 cases
concerning pefloxacin [in French]. Therapie 1992; 47 (5):
415-8
34. Asensio-Sa
´nchez VM, Rodrı
´guez-Delgado B, Garcı
´a-
Herrero E, et al. Visual hallucinations secondary to
ciprofloxacin treatment. Arch Soc Esp Oftalmol 2007; 82
(5): 299-301
35. Melvani S, Speed BR. Alatrofloxacin-induced seizures
during slow intravenous infusion. Ann Pharmacother
2000; 34: 1017-9
Quinolones: Review of Adverse Reaction Reports 485
ª2011 Adis Data Information BV. All rights reserved. Drug Saf 2011; 34 (6)
This material is
the copyright of the
original publisher.
Unauthorised copying
and distribution
is prohibited.
36. Quigley CA, Lederman JR. Possible gatifloxacin-induced
seizure. Ann Pharmacother 2004; 38: 235-7
37. Isaacson SH, Carr J, Rowan AJ. Ciprofloxacin-induced
complex partial status epilepticus manifesting as an acute
confusional state. Neurology 1993; 43: 1619-21
38. Wimer SM, Schoonover L, Garrison MW. Levofloxacin:
a therapeutic review. Clin Ther 1998; 20 (6): 1049-70
39. Balfour JA, Wiseman LR. Moxifloxacin. Drugs 1999 Mar;
57 (3): 363-73; discussion 374
40. De Sarro A, De Sarro G. Adverse reactions to fluoro-
quinolones: an overview on mechanistic aspects. Curr
Med Chem 2001; 8 (4): 371-84
41. Kushner JM, Peckman HJ, Snyder CR. Seizures associated
with fluoroquinolones. Ann Pharmacother 2001; 35 (10):
1194-8
42. Oliphant CM, Green GM. Quinolones: a comprehensive
review. Am Fam Physician 2002; 65 (3): 455-64
43. Turnidge J. Pharmacokinetics and pharmacodynamics of
fluoroquinolones. Drugs 1999; 58 Suppl. 2: 29-36
44. Tamai I, Yamashita J, Kido Y, et al. Limited distribution
of new quinolone antibacterial agents into brain caused by
multiple efflux transporters at the blood-brain barrier.
J Pharmacol Exp Ther 2000; 295 (1): 146-52
45. Mandell L, Tillotson G. Safety of fluoroquinolones: an
update. Can J Infect Dis 2002; 13 (1): 54-61
46. Case report [online]. Available from URL: http://en.wiki
pedia.org/wiki/Case_report [Accessed 2010 Sep 8]
47. ICH E2E: pharmacovigilance planning. CPMP/ICH/
5716/03 [online]. Available from URL: http://www.ich.
org/products/guidelines/efficacy/article/efficacy-guidelines.
html [Accessed 2010 Sep 8]
48. Kelly WN, Arellano FM, Barnes J, et al. Guidelines for
submitting adverse event reports for publication. Drug
Saf 2007; 30 (5): 367-73
49. Tripathi A, Chen SI, O’Sullivan S. Acute psychosis fol-
lowing the use of topical ciprofloxacin. Arch Ophthalmol
2002; 120: 665-6
50. Orr CF, Rowe DB. Eardrops attacks: seizures triggered by
ciprofloxacin eardrops. Med J Aust 2003; 178: 343
51. Islam MA, Sreedharan T. Convulsions, hyperglycemia and
glycosuria from overdose of nalidixic acid. JAMA 1965;
192: 1100-1
52. Schwartz MT, Calvert JF. Potential neurological toxicity
related to ciprofloxacin. DICP 1990; 24 (2): 138-40
53. Kim SH, Jeong SH, Kim JW, et al. A case of hemiballism as
a rare side effect of ciprofloxacin in a patient with liver
cirrhosis. Chemotherapy 2009; 55: 207-10
54. Holden R. Probable fatal interaction between ciprofloxacin
and theophylline [letter]. BMJ 1988; 297: 1339
55. Spivey JM, Laughlin PH, Goss TF, et al. Theophylline
toxicity secondary to ciprofloxacin administration. Ann
Emerg Med 1991; 20: 1131-4
56. Herrlin K, Segerdahl M, Gustafsson LL, et al. Methadone,
ciprofloxacin, and adverse drug reactions. Lancet 2000;
356: 2069-70
57. Fan-Havard P, Sanchorawala V, Oh J, et al. Concurrent
use of foscarnet and ciprofloxacin may increase the pro-
pensity for seizures. Ann Pharmacother 1994; 28: 869-72
58. Rollof J, Vinge E. Neurological adverse effects during
concomitant treatment with ciprofloxacin, NSAIDs, and
chloroquine: possible drug interaction. Ann Pharma-
cother 1993; 27: 1058-9
59. Lee J, Franz L, Goforth HW. Serotonin syndrome in a
chronic-pain patient receiving concurrent methadone,
ciprofloxacin, and venlafaxine [letter]. Psychosomatics
2009; 50 (6): 638-9
60. Sharma DD, Aggarwal A, Sharma RC, et al. A probable
association of acute dystonia with gemifloxacin adminis-
tration. Indian J Med Sci 2009; 63 (12): 557-60
61. Christie MJ, Wong K, Ting RH, et al. Generalized seizure
and toxic epidermal necrolysis following levofloxacin ex-
posure. Ann Pharmacother 2005; 39 (5): 953-5
62. Simpson KJ, Brodie JR. Convulsions related to enoxacin
[letter]. Lancet 1985; II: 161
63. Poe TE, Marion GS, Jackson DS. Seizures due to nalidixic
acid therapy. South Med J 1984; 77: 539-40
64. Anastasio GD, Menscer D, Little JM. Norfloxacin and
seizures [letter]. Ann Intern Med 1988; 109: 169-70
65. Traeger SM, Nonfiglio MF, Wilson JA, et al. Seizures
associated with ofloxacin therapy. Clin Infect Dis 1995; 21
(6): 1504-6
66. Montane
´E, Barriocanal A, Isern I, et al. Multiple drug
interactions –induced serotonin syndrome: a case report.
J Clin Pharm Ther 2009; 34: 485-7
67. Conri C, Lartigue MC, Abs L, et al. Convulsions chez une
malade traite
´e par pe
´floxacine et the
´ophylline [letter].
The
´rapie 1990; 45: 358
68. Bader MB. Role of ciprofloxacin in fatal seizures. Chest
1992; 101: 883-4
69. Romano C, Cristina T, Daniela C, et al. Epileptic attacks
associated with pefloxacin treatment in a patient on
CAPD [letter]. Clin Nephrol 1989; 32: 48-9
70. Bercault N, DeMasure M, Benhamou CL, et al. Seizures in
the course of prolonged treatment with ofloxacin. Rev
Med Interne 1993; 14: 194
71. Slavich IL, Gleffe RF, Haas EJ. Grand mal epileptic
seizures during ciprofloxacin therapy. JAMA 1989; 261:
558-9
72. Karki SD, Bentley DW, Raghavan M. Seizure with cipro-
floxacin and theophylline combined therapy. DICP 1990;
24 (6): 595-6
73. Semel JD, Allen N. Seizures in patients simultaneously re-
ceiving theophylline and imipenem or ciprofloxacin or
metronidazole. South Med J 1991; 84: 465-8
74. Abouesh A, Stone C, Hobbs WR. Antimicrobial-induced
mania (antibiomania): a review of spontaneous reports.
J Clin Psychopharmacol 2002; 22: 71-81
75. Lucet JC, Tilly J, Lerebours G, et al. Neurological toxicity
related to pefloxacin [letter]. J Antimicrob Chemother
1988; 21: 811-2
76. Walton GD, Hon JK, Mulpur TG. Ofloxacin-induced sei-
zures. Ann Pharmacother 1997; 31 (12): 1475-7
77. Jeandel C, Laurain MC, Jouanny P, et al. E
´tat de mal
e
´pileptique sous ofloxacine. Rev Med Interne 1994; 15:
218-9
78. Leone R, Venegoni M, Motola D, et al. Adverse drug
reactions related to the use of fluoroquinolone anti-
486 Tome
´& Filipe
ª2011 Adis Data Information BV. All rights reserved. Drug Saf 2011; 34 (6)
This material is
the copyright of the
original publisher.
Unauthorised copying
and distribution
is prohibited.
microbials: an analysis of spontaneous reports and fluor-
oquinolone consumption data from three Italian regions.
Drug Saf 2003; 26 (2): 109-20
79. Halliwell RF, Su J, Demuro A, et al. Characterization of
the interaction between a novel convulsant agent, norbi-
phen, and GABAA and other ligand-gated ion channels.
Neuropharmacology 2002; 43: 778-87
80. Shimada J, Hori S. Adverse effects of fluoroquinolones.
Prog Drug Res 1992; 38: 133-43
81. Kim J, Ohtani H, Tsujimoto M, et al. Quantitative compar-
ison of the convulsive activity of combinations of twelve
fluoroquinolones with five nonsteroidal anti-inflammatory
agents. Drug Metab Pharmacokinet 2009; 24 (2): 167-74
82. Marinella MA. Myoclonus and generalized seizures asso-
ciated with gatifloxacin treatment. Arch Intern Med 2001;
161: 2261-2
83. Stahlmann R, Lode H. Fluoroquinolones in the elderly:
safety considerations. Drugs Aging 2003; 20 (4): 289-302
84. Lahmek P, Michel L, Meunier N, et al. A seizure attributed
to ofloxacine in a woman undergoing detoxification for
alcohol dependence. Case Report Med. Epub 2010 Jan 24
85. Agbaht K, Bitik B, Piskinpasa S, et al. Ciprofloxacin-
associated seizures in a patient with underlying thyrotox-
icosis: case report and literature review. Int J Clin
Pharmacol Ther 2009; 47 (5): 303-10
86. Hall CE, Keegan H, Rogstad KE. Psychiatric side effects of
ofloxacin used in the treatment of pelvic inflammatory
disease. Int J STD AIDS 2003; 14 (9): 636-7
87. McCue JD, Zandt JR. Acute psychoses associated with the
use of ciprofloxacin and trimethoprim-sulfamethoxazole.
Am J Med 1991; 90 (4): 528-9
88. Grimm O, Alm B, Fur Seelische Z. A case of ciprofloxacin-
induced acute polymorphic psychosis with a distinct def-
icit in executive functions [letter]. Psychosomatics 2007;
48 (3): 269
89. Norra C, Skobel E, Breuer C, et al. Ciprofloxacin-induced
acute psychosis in a patient with multidrug-resistant
tuberculosis. Eur Psychiatry 2003; 18 (5): 262-3
90. Farrington J, Stoudemire A, Tierney J. The role of cipro-
floxacin in a patient with delirium due to multiple etiolo-
gies. Gen Hosp Psychiatry 1995; 17: 47-53
91. Fennig S, Mauas L. Ofloxacin-induced delirium [letter].
J Clin Psychiatry 1992; 53 (4): 137-8
92. Ahuja N, Lloyd AJ. Antibiomania and ciprofloxacin-
induced mania [letter]. Psychosomatics 2007; 48 (4): 36
93. de Bazignan AD, Thiessard F, Miremont-Salame
´G, et al.
Psychiatric adverse effects of fluoroquinolones: review of
cases from the French pharmacologic surveillance data-
base. Rev Med Interne 2006; 27 (6): 448-52
94. Steinert T, Studemund H. Acute delusional parasitosis
under treatment with ciprofloxacin. Pharmacopsychiatry
2006; 39 (4): 159-60
95. Cheung YF, Wong WW, Tang KW, et al. Ciprofloxacin-
induced palatal tremor. Mov Disord 2007; 22 (7): 1038-43
96. Lee CH, Cheung RTF, Chan TM. Ciprofloxacin-induced
oral facial dyskinesia in a patient with normal liver and
renal function. Hosp Med 2000; 61: 142-3
97. Azar S, Ramjiani A, Van Gerpen JA. Ciprofloxacin-
induced chorea. Mov Disord 2005; 20: 513-4
98. Pastor P, Moitinho E, Elizalde I, et al. Reversible oral-
facial dyskinesia in a patient receiving ciprofloxacin hy-
drochloride. J Neurol 1996; 243: 616-7
99. MacLeod W. Case report: severe neurological reaction to
ciprofloxacin. Can Fam Physician 2001; 47: 553-5
100. Thomas RJ, Reagan DR. Association of a Tourette-like syn-
drome with ofloxacin. Ann Pharmacother 1996; 30: 138-41
101. Post B, Koelman JHTM, Tijssen MAJ. Propriospinal
myoclonus after treatment with ciprofloxacin. Mov Dis-
ord 2004; 19: 595-7
102. Mohan N, Menon K, Rao PG. Oral gatifloxacin-induced
ataxia [letter]. Am J Health Syst Pharm 2002; 59 (19): 1894
103. Rosolen A, Drigo P, Zanesco L. Acute hemiparesis asso-
ciated with ciprofloxacin [letter]. BMJ 1994; 309: 1411
104. Upton C. Sleep disturbance in children treated with oflox-
acin [letter]. BMJ 1994; 309: 141
105. Akhtar S, Ahmad H. Ciprofloxacin-induced catatonia
[letter]. J Clin Psychiatry 1993; 54: 115-6
106. Youssef NA, Benazzi F, Desan PH. Levofloxacin-induced
catatonia. Prog Neuropsychopharmacol Biol Psychiatry
2009; 33 (4): 741-2
107. Rauser EH, Ariano ER, Anderson AD. Exacerbation of
myasthenia gravis by norfloxacin. DCIP Ann Pharma-
cother 1990; 240: 207-8
108. Mumford CJ, Ginsberg L. Ciprofloxacin and myasthenia
gravis [letter]. BMJ 1990; 301: 818
109. Fraser AG, Harrower ADB. Convulsions and hypergly-
caemia associated with nalidixic acid [letter]. BMJ 1977;
2 (6101): 1578
110. Striano P, Zara F, Coppola A, et al. Epileptic myoclonus as
ciprofloxacin-associated adverse effect. Mov Disord 2007;
22 (11): 1675-6
111. Bellon A, Perez-Garcia G, Coverdale JH, et al. Seizures
associated with levofloxacin: case presentation and lit-
erature review. Eur J Clin Pharmacol 2009; 65 (10): 959-62
112. Kisa C, Yildirim SG, Aydemir C, et al. Prolonged electro-
convulsive therapy seizure in a patient taking ciproflox-
acin. J ECT 2005; 21 (1): 43-4
113. LaSalvia EA, Domek GJ, Gitlin DF. Fluoroquinolone-
induced suicidal ideation. Gen Hosp Psychiatry 2010
Jan-Feb; 32 (1): 108-10
114. Sire S, Staub-Schmidt T, Ragnaud JM, et al. A
`prpos d’une
crise comitiale sous ofloxacine. Rev Med Interne 1996; 17:
601-2
115. Barrett MJ, Login IS. Gemifloxacin-associated neurotoxi-
city presenting as encephalopathy. Ann Pharmacother
2009; 43 (4): 782-4
116. Heyd A, Haverstock D. Retrospective analysis of the safety
profile of oral and intravenous ciprofloxacin in a geriatric
population. Clin Ther 2000; 22 (10): 1239-50
117. Bertino Jr J, Fish D. The safety profile of the fluoroquin-
olones. Clin Ther 2000; 22 (7): 798-817
118. Stahlmann R, Lode H. Toxicity of quinolones. Drugs 1999;
58 Suppl. 2: 37-42
119. Cipro
: summary of product characteristics. Wayne (NJ):
Bayer Healthcare Pharmaceuticals Inc., 2009
120. Tavanic
500 mg tablets: summary of product character-
istics. Guildford: Sanofi-Aventis, 2009
Quinolones: Review of Adverse Reaction Reports 487
ª2011 Adis Data Information BV. All rights reserved. Drug Saf 2011; 34 (6)
This material is
the copyright of the
original publisher.
Unauthorised copying
and distribution
is prohibited.
121. Seizure: causes [online]. Available from URL: http://en.
wikipedia.org/wiki/Seizure#Causes [Accessed 2010 Feb 15]
122. Akaike N, Shirasaki T, Yakushiji T. Quinoloneand fenbufen
interact with GABA(A) receptor in dissociated hippo-
campal cells of rat. J Neuropsychol 1991; 66 (2): 497-504
123. Wilton LV, Pearce GL, Mann RD. A comparison of
ciprofloxacin, norfloxacin, ofloxacin, azithromycin and
cefixime examined by observational cohort studies. Br J
Clin Pharmacol 1996; 41 (4): 277-84
124. Sweweb [online]. Available from: URL: http://sweweb.
mpa.se/swedisii/ [Accessed 2010 Feb 15]
125. Utinor
tablets 400 mg: summary of product character-
istics. Whitehouse Station (NJ): Merck Sharp &Dohme
Limited, 2009
126. Tarivid
200 mg and 400 mg tablets: summary of product
characteristics. Guildford: Sanofi-Aventis, 2009
127. US FDA. Risk of fluoroquinolone-associated myasthenia
gravis exacerbation February 2011 label changes for
fluoroquinolones [online]. Available from URL: http://
www.fda.gov/Safety/MedWatch/SafetyInformation/ucm
247115.htm2011 [Accessed 2011 Apr 18]
Correspondence: Dr Ana Maria Tome
´, Medical Department,
Grupo Tecnimede, Zona Industrial da Abrunheira, Rua da
Tapada Grande, n.2–Abrunheira, 2710-089 Sintra,
Portugal.
E-mail: dmed.fv@tecnimede.pt
488 Tome
´& Filipe
ª2011 Adis Data Information BV. All rights reserved. Drug Saf 2011; 34 (6)
