REVIEW
Ophthalmic adverse drug reactions to systemic drugs: a systematic review
Ana Miguel
1,2*, Filipe Henriques
2, Luís Filipe Azevedo
1and Altamiro Costa Pereira
11
Center for Research in Health Technologies and Information Systems (CINTESIS) and Department of Health Information and Decision
Sciences, Faculty of Medicine, University of Porto, Portugal
2
Department of Ophthalmology, Central University Hospital of Coimbra, Coimbra, Portugal
ABSTRACT
Purpose
To perform a comprehensive and systematic review regarding ophthalmic adverse drug reactions (ADRs) to systemic drugs to: (i)
systematically summarize existing evidence, (ii) identify areas, ophthalmic ADRs or drugs that lacked systematization or assessment (namely
drugs with original studies characterizing speci
fic ophthalmic ADRs but without causality assessment nor without meta-analysis).
Methods
Systematic review of several electronic databases (last search 1/7/2012): Medline, SCOPUS, ISI web of knowledge, ISI
Confer-ence Proceedings, International Pharmaceutical Abstracts and Google scholar. Search query included: eye, ocular, ophthalmic,
ophthalmol-ogy, adverse and reaction. Inclusion criteria were: (i) Primary purpose was to assess an ophthalmic ADR to a systemic medication; (ii) Patient
evaluation performed by an ophthalmologist; (iii) Studies that speci
fied diagnostic criteria for an ocular ADR. Different types of studies were
included and analyzed separately. Two independent reviewers assessed eligibility criteria, extracted data and evaluated risk of bias.
Results
From 562 studies found, 32 were included (1 systematic review to sildena
fil, 11 narrative reviews, 1 trial, 1 prospective study, 6
transversal studies, 6 spontaneous reports and 6 case series). Drugs frequently involved included amiodarone, sildena
fil, hydroxychloroquine
and biphosphonates. Frequent ophthalmic ADRs included: keratopathy, dry eye and retinopathy.
Conclusions
To increase evidence about ophthalmic ADRs, there is a need for performing speci
fic systematic reviews, applying strictly the
World Health Organization
’s (WHO) definition of ADR and WHO causality assessment of ADRs.
Some ophthalmic ADRs may be frequent, but require ophthalmological examination; therefore, ophthalmologists
’ education and protocols
of collaboration between other specialties whenever they prescribe high-risk drugs are suggestions for the future. Copyright © 2014 John
Wiley & Sons, Ltd.
key words
—adverse drug reactions; clinical pharmacology; pharmacoepidemiology; ophthalmology
Received 13 March 2013; Revised 10 November 2013; Accepted 9 December 2013
INTRODUCTION
Ophthalmology is perhaps one of the medical specialties
in which there are the fewest assessed adverse drug
reactions (ADRs), representing a particular challenge
in Pharmacovigilance.
1However, the eye is a complex
organ in which minimal impairment can produce a
sub-stantial functional effect.
2Ophthalmic ADRs are
usually not continuously detected, although they might
be either frequent or specific of a drug or drug group,
such as acute angle-closure glaucoma and myopic
shift caused by topiramate,
3cataracts provoked by
corticosteroids,
4floppy iris syndrome caused by
tamsulosine
5and uveitis caused by rifabutin.
6Some ADRs are rare but can cause irreversible
blindness (such as in optic atrophy provoked by
eth-ambutol),
7while others are extremely frequent but
usually harmful (namely cornea verticillata caused
by amiodarone).
8There are reports that suggest ophthalmic ADRs
provoked by a systemic drug, but remain unsupported
because no systematic review has been performed.
Many ophthalmic ADRs have been identi
fied solely
due to spontaneous reports, namely blurred vision
caused by leuprolide,
9or other ophthalmic ADRs
caused by different drugs such as biphosphonates,
cetirizine or isotretinoin.
2Therefore, on the one hand,
prospective studies or trials should be performed to
study the causality of each drug to each ophthalmic
ADR; on the other hand, a systematic review should
*Correspondence to: A. Miguel, Department of Health Information andDeci-sion Science, Faculty of Medicine of Oporto. Rua Quinta do Sardoal, VE3, nº10, 4430–182 V.N.Gaia, Portugal. Email: myworld_ana@hotmail.com
2014; 23: 221–233
be performed to clarify and assess what ophthalmic
ADRs can occur after the correct prescription of each
drug. A systematic review would be useful not only
to identify drugs in which ophthalmic ADRs are
frequent or serious, but also to increase knowledge of
physicians (prescribing physicians and
ophthalmolo-gists), enabling a greater detection of ophthalmic
ADRs after an ophthalmic examination and enabling
the construction of multi-disciplinary protocols
when-ever a high-risk drug is prescribed.
General ADRs are estimated to cause of 2.7% to
15.7% hospital admissions and to occur in 16.9% of
hospitalized
patients
(con
fidence interval 95%:
13.6%, 20.2%).
11In a study performed in the United
States (US), it was estimated that more than 100 000
people die every year as a consequence of fatal ADRs,
placing fatal ADRs between the fourth and sixth
lead-ing causes of death in the US.
12However, the speci
fic
frequency of ophthalmic ADRs is not known.
Although there are several studies about ophthalmic
ADRs, this theme presents with speci
fic
difficul-ties,
13,14and the methods of identi
fication and
reporting ADRs vary greatly.
15,16Some studies have
established recommendations,
17,18and others offer
guidelines to performing systematic reviews of studies
of ophthalmic ADRs.
19,20We intended to perform a general systematic review
about ophthalmic ADRs to systemic drugs in order to,
on the one hand, systematically summarize existing
evidence, and on the other hand, identify areas of
spe-ci
fic ophthalmic ADRs or drugs that lacked
systemati-zation or assessment. This includes the identi
fication
of drugs that cause speci
fic ophthalmic ADRs which
are well described in original studies but without
systematic review nor meta-analysis (therefore,
oppor-tunities for speci
fic systematic reviews with
meta-analysis in the future are also identi
fied).
METHODS
We performed a systematic review of studies that
assessed ophthalmic ADRs to systemic drugs according
to the guidelines of the Cochrane Collaboration
19and
PRISMA Statement,
21adapted to this theme.
Definitions
We used the following de
finition for adverse drug
reaction:
“any noxious, unintended and undesired effect
of a drug, which occurs at doses used in humans for
pro-phylaxis, diagnosis, or therapy
”, according to the World
Health Organization (WHO) de
finition
22of 1972.
An adverse event is:
“an injury related to medical
management,
in
contrast
to
complications
of
disease
”.
23Medical management includes all aspects
of care, including diagnosis and treatment, failure to
diagnose or treat and the systems and equipment used
to deliver care.
23Therefore, to increase speci
ficity, we
wanted to assess only adverse drug reactions.
Search methods
We searched through several electronic databases
(last date of search was 1/7/2012): Medline, SCOPUS,
ISI web of knowledge, ISI Conference Proceedings,
International Pharmaceutical Abstracts and Google
scholar. We used a search query created after a pilot
study to add speci
ficity (full search query available if
requested to the corresponding author) that included
the terms: eye, ocular, ophthalmic, ophthalmology,
adverse and reaction. We searched for grey literature
and unpublished data and hand-searched all references
of included studies and relevant reviews.
Selection criteria
Studies were included if they followed all inclusion
criteria
listed below:
(1) Studies in which the primary purpose was to assess
an ophthalmic ADR to a systemic medication.
Since there is a wide misuse of the terms ADR,
ad-verse event (AE) and adad-verse drug event (ADE), we
obtained also the full text of studies who claimed to
assess AEs or ADEs, to verify their methodology,
and to include the studies that actually assessed
ADRs, although they called it AEs or ADEs.
(2) Studies with patient evaluation performed by an
ophthalmologist.
(3) Studies that specified diagnostic criteria for an
ocular ADR.
We also included studies with different languages
(we hired a translator), any country and experimental
studies (if any). We did so to have a more thorough
and complete literature search. We did not exclude
systematic nor narrative reviews if they added useful
information about ocular ADRs, as we intended to
have a general overview that summarized and added
further systematization to existing evidence, and to
identify areas or speci
fic ophthalmic ADRs that lacked
systematization or assessment.
Exclusion criteria:
(1) Studies assessing adverse events that did not
correspond to ADRs (for example, we excluded
a. miguel
et al.
reports of capsular rupture in phacoemulsi
fication
surgery, but we did not exclude reports of capsular
rupture due to intra-operatory
floppy iris
syn-drome, a syndrome that is an ADR provoked by
tamsulosine or other drugs).
(2) Systemic ADRs to topical ophthalmic drugs, or
ophthalmic ADRs to topical ophthalmic drugs
(they were not the purpose of our study and would
increase heterogeneity and reduce clarity of our
study).
(3) Studies that were comments or letters, if they
would not add new scienti
fic evidence to our
re-view. However, letters or comments that included
case reports not published elsewhere about
spe-ci
fic ocular ADRs were not excluded, in order to
identify rare ophthalmic ADRs.
(4) Studies assessing drugs already removed from the
market.
Data collection and extraction
Two independent reviewers, AM and FH,
first
exam-ined each title and abstract to exclude obviously
irrel-evant reports and then independently examined each
full text report, to determine eligibility according to
in-clusion criteria. Disagreements were solved by
con-sensus, recorded and analyzed using kappa statistics.
Primary outcome was the presence and type of
ocu-lar ADR and the respective causative systemic drug.
Secondary outcomes included: ocular structure
af-fected, diagnosis, serious or vision-threatening ADR.
All symptoms, visual acuity (VA), signals and results
of complementary examination performed at
presenta-tion were recorded, as well as after a follow-up.
Atti-tude or treatment performed for each ADR was also
registered (suspension of the causative drug, speci
fic
treatment, administration of an antidote, no treatment
necessary). If VA was not recorded in the logMAR
scale,
24it was converted.
We always assessed the drug name, identi
fied the
therapeutic drug class according to Anatomical
Thera-peutic Chemical Classi
fication System of WHO
25and
reported the number of days during which the drug
was used and the administration route (if that
informa-tion was available). We veri
fied if causality was
assessed in the original studies (and according to what
classi
fication, preferably WHO’s
23or Naranjo
’s,
26and
respective results) as well as predictability of ADRs
(using Hartwig
’s predictability scale, for example),
27preventability (e.g. Schumok & Thornton
’s
preventabil-ity criteria)
28and types of ADRs (Rawlins and
Thompson
’s classification
29). We did not intend to
iden-tify all of the ophthalmic ADRs, but to systematize the
most important and the most frequent ADRs according
to the results of our systematic search.
Risk of bias assessment
We performed risk of bias assessment for each
in-cluded study and recorded it in a standardized form
created to assess ADR studies (in a previous work
10)
and adapted to Ophthalmology after a pilot study.
We did not use scales (discouraged by the Cochrane
approach
20) but criteria from Cochrane, STROBE,
30QUOROM
31and PRISMA
21adapted to the particular
scope of ophthalmic ADR evaluation, which included:
complete description of study design, description of
study type (case report, case series, prospective
observa-tional study, trial,…), adequate diagnostic criteria for
ophthalmic ADR, complete ophthalmologic evaluation
at presentation, quantified visual acuity at presentation
and follow-up, results of complementary testing
described at presentation and follow-up, definition of
ADR presented, rationale for study size, causality
as-sessment of ADR, preventability asas-sessment of ADR,
description of all statistical methods, characterization
of study participants, description of methods to prevent
bias (information bias, selection bias and other bias) and
presentation of complete summary measures. The two
reviewers independently assessed study quality and risk
of bias; disagreements were solved by consensus.
Studies were divided in low risk of bias (5 or less
parameters with medium, unclear or high risk of bias),
medium risk (6 to 9) and high risk (10 or more
parame-ters evaluated as medium, unclear or high risk of bias).
RESULTS
Literature search
Pubmed search yielded 124 results; SCOPUS yielded
72 results; Google Scholar 60; ISI Web of Knowledge
yielded 154; others yielded 152. From these 562
stud-ies (corresponding to 300 distinct studstud-ies), 163 were
selected to obtain full text and then 32 studies were
included
9,17,32–61(Fig. 1): 1 systematic review of
ADRs to a specific drug, 11 narrative reviews, 1 trial,
1 prospective study, 6 case–control or cohort or
cross-sectional studies, 6 spontaneous reports and 6 case
reports or case series. Kappa agreement for study
in-clusion was 0.80 during the
first phase and 0.82 during
the full text review (good agreement).
Characteristics of included studies
Table 1 summarizes the characteristics of included
ADRs, most of them narrative reviews without
sys-tematic criteria nor bibliographic search.
Ophthalmic ADRs
Many different ophthalmic ADRs exist to many
sys-temic drugs. In Table 2, we represent a summary of
the main ophthalmic ADRs found in this systematic
review, according to each speci
fic drug, dose, risk
fac-tors and tried to characterize the ophthalmic ADR (if
reported) and to evaluate the level of evidence of each
of the studies reporting each ADR (according to the
Oxford Levels of Evidence
62). Keratitis, retinopathy,
glaucoma, dry eye and blurred vision were the most
frequent ADRs identi
fied.
We identi
fied many ophthalmic ADRs to drugs that
have original studies but are currently lacking a
sys-tematic review (therefore representing an opportunity
for further studies, as described in the Discussion
Section, below). Many studies were found but only
one systematic review (of ophthalmic ADRs to
sildena
fil
56) and few narrative reviews with systematic
search were performed. Therefore, examples of drugs
that cause ophthalmic ADRs that would bene
fit from
a recent and speci
fic systematic review are:
tamoxi-fen,
amiodarone,
antidepressants,
phenotiazines,
hydroxychloroquine, oral contraceptives, etc.
Risk of bias assessment
In Fig. 2, we present the summary of our quality
eval-uation of included studies, according to each
parame-ter assessed - risk of bias graph. Few studies had low
risk of bias. Only one study performed rationale for
study size. Most studies (25) performed a complete
initial evaluation by an ophthalmologist, but only 11
performed a follow-up of at least 1 month. Only 13
studies performed causality assessment for ADR and
only 7 applied or presented WHO
’s definition of an
ADR. Risk of bias summary, which contains detailed
risk of bias assessment for each included study, is
available if requested to contact author.
DISCUSSION
What this study adds
There is an increasing number of studies of ophthalmic
ADRs. In spite of the common belief that ADRs in
Ophthalmology are rare, some ADRs might be
ex-tremely frequent (such as cornea verticillata caused
by amiodarone
8), but require speci
fic
ophthalmologi-cal examination for its detection. Every ocular
struc-ture might be affected by an ADR. There is a need
for performing speci
fic systematic reviews of
ophthal-mic ADRs, because the majority of included studies
were narrative non-systematic reviews, most of which
without the strict application of WHO
’s definition of
ADR nor causality assessment of ADRs.
Several drugs that may provoke different
ophthal-mic ADRs were identi
fied, namely amiodarone,
sildena
fil, psychotropic drugs, alpha-blockers,
cortico-steroids and topiramate. Although cornea verticillata
is found very frequently in patients medicated with
amiodarone (authors report a rate of 100%
46), this
finding rarely reduces visual function; on the other
hand, amiodarone may provoke a rare optic
neuropa-thy that may provoke marked visual loss.
18Sildena
fil
and tadala
fil have been recently studied, but while
some authors report no difference between ERG
pat-terns of placebo versus these drugs,
53others found
several ADRs associated with sildena
fil,
58namely:
ischemic optic neuropathy, central retinal vein
occlu-sion, cilio-retinal artery occluocclu-sion, acute angle closure
glaucoma and optic atrophy.
Strengths
of our systematic review lie in the
com-prehensive search performed, the general increase in
systematization and characterization of ophthalmic
ADRs, the summary of existing evidence according
to WHO
’s causality criteria for ADR and WHO’s
def-inition of ADR and
finally the identification of specific
ophthalmic ADRs that could bene
fit from future
spe-ci
fic systematic reviews with possible meta-analysis.
Limitations
of our systematic review include not
only heterogeneity found in different types of ADRs
but also the extreme variability in the methodologies
of studies of ophthalmic ADRs (from isolated case
re-ports to retrospective series of spontaneous rere-ports,
Figure 1. Flowchart of search strategya. miguel
et al.
Table 1. Includ ed studies in this systematic revi ew. *Ophtha lmic ADRs will be describe d with furthe r detail in Table 2 Ye ar, auth or Study type Drug studied Oph thalmic ADR( s) report ed * Sum mary of study 19 86 Davidso n 32 Narr ative review Sev eral Man y ocul ar ADRs cau sed by: cort icosteroids, chlo roquin e, amio darone, phenot hiazines, tamoxifen … Narrative revi ew without de fi niti on of ADR no r causality as sessme nt 19 89 Curran 33 Cas e series Dox orrubicin Iritis, conj unct ivitis, peri orbital ed ema, ke ratitis, op tic neuropa thy Case series of 4 cases of ocular ADRs to doxo rrubi cin 19 91 Hobley 34 Cas e report Dig oxin Scin tillating visual fi eld loss (central scotom a) + dischroma topsia Case repo rt: visual fi eld defect due to digoxin (therapeutic level) 19 92 Malek 35 Narr ative review Oral cont raceptiv es • Retinal hemor rhage or emb oli, macular or pa pillary ede ma, op tic ne uropat hy Narrative revi ew of ocular ADRs by oral contraceptives. 19 93 Goldma n 36 Narr ative review Ant icon vulsiva nts • Carba mazep ine : diplo pia, pare sis of extraocular musc les, nis tagmus , visua l alluc inations Narrative revi ew of ocular ADRs of co mmon anticonvulsiv ants • Phenyto in : nis tagmus with out oscillop sia, my driasis • Others: pa resis of extraocular musc les 19 94 Macaro l 37 Spo ntaneo us report s Pam idrona te Scler itis, conj unctivitis, anterior uveitis Retrospective se ries of spon taneous case report s 19 95 Oshika 38 Narr ative review Ne uropsy chiatric dr ugs • Phenothiazin e: corneal et lens deposi ts A narra tive revi ew of ophth almic ADRs of neuropsy chiatric drugs • Thiorida zine : retinop athy • Tricyclic antidepr essants : glauco ma, dec reased acc ommod ation • Lithium : papille dema, exop hthalmia • Chlorpr omazi ne : kerato pathy 19 95 Fraun-Fe lder 9 Lette r with spon taneou s report s Leup rolid e Blur red vision A retrospect ive stu dy of series of spon taneou s repo rts of oc ular ADRs of leup rolid e 19 95 b Fraun -Felde r 39 Ret rospectiv e case –cont rol stu dy Nia cin Dryn ess, blurred vision, diplo pia, cysto id maculopat hy ADRs of patients takin g niac in were com pared to other dy slipid emia drugs 19 97 Sweene y 40 Pro spectiv e study R isperid one Eye movem ents affe cted: prolon ged laten cy afte r and alt eration of sacca dic mo vemen ts Prospectiv e study of patie nts with risperidone (4 weeks) 19 99 Dulley 41 Narr ative review Tamo xife n • Retinopath y with de posits Narrative revi ew about ocular ADRs of tamoxifen • Keratopa thy with deposi ts • Colour vision defec ts • Foveal disfunction and ERG ch ange 19 99 Solom on 42 Lette r with case report s In fl uenza vac cine • Case 1: ante rior uv eitis Letter with case repo rts not previo usly pu blished • Case 2: rea ctivatio n o f herpe tic keratitis • Case 3: left kerato plasty rejection 19 99 Doughty 43 Narr ative review Mi graine drug s Cyp rohept adine, pizo tyline , amitriptiline, p ropranolo l, tim olol, clon idine ,fl un arizine: dry eye A narra tive revi ew of med ication s o f hea daches and their ocular ADRs 20 01 Ikaheimo 44 Obse rvat ional cros s-sectional study Fl ecainide • Cornea l depo sits Observ ational stu dy in which 38 fl ecaini de med icated patients were exa mined. • Dry eye 20 01 Fraunfeld er 45 Cas e series of spon taneou s report s Isotr etinoin • Many ADRs : abnorma l meib omia n glan ds, blep haroc onjunc tivitis, corn eal opacities, decreased vis ion, keratitis, … Analysis o f 1 7 4 1 sponta neous reports with possi ble ocular ADRs to isotretinoin 20 02 Ikaheimo 46 Obse rvat ional cros s-sectional study Am ioda rone • Cornea l depo sits (in 10 0% of the patients) Observ ational stu dy in which 22 patients with long-term amiodarone we re studied • Anterio r subcap sular lens depo sit (22.2%) • Dry eye s (9 .1%) 20 03 Fraun-Felder 18 Narr ative review Sev eral • Amiod arone : corne a verticillata, periocular staining , o p tic neur opathy A narra tive revi ew was perform ed of ocular ADRs , without systematic stu dy search but with systematic WHO causality assessmen t when eve r p o ssible. Offe rs good guidelines and clinica l imp lications for eac h drug. • Cetirizine : m y driasis, ocul ogyr ic crisis … • Hydrox ychloro qui ne : corne al deposi ts, epip hora, extrao cular paresi s, pto sis
(Continues
)
Table 1. (Conti nued) Ye ar, auth or Study type Drug studied Oph thalmic ADR( s) report ed * Sum mary of study • Isotretinoin : conjun ctitivis, corneal de posits, acute my opia, op tic ne uritis • Biphos phonat es : episcleritis, conjun ctivitis, nerve palsy ,… • Sildena fi l: dis chrom atopsia, blurre d vision • Topira mate : acu te glau coma, acu te myopia , ocul ar pain, uv eitis, … 20 04 Fraun-Felder 47 Ret rospectiv e series of report s Sev eral • B iphospho nat es : co njunctivitis, uv eitis, blurre d vis ion, sc leritis A larg e retrospect ive series of spon taneous report s o f ocular ADRs to differen t syste mic dr ugs. WHO ’s de fi nition of ADR and W H O ’s cau sality as sessment were perform ed. • Ce tirizine : blurr ed vis ion, kerato conj unctivitis sicca, ocul ogyr ic crisis •Isotretinoin : blurred vision • Topira mat e: acute glauco ma, acu te myop ia, peri orbital edema, scle ritis 20 06 Fraun-Felder 48 Lette r with retrospect ive report s o f spon taneou s report s o f ocul ar ADRs C ycloox ygena se-2 In hibitors Blur ry vis ion and conj unct ivitis we re the most report ed ADRs Letter with large series of sponta neous repo rts (100 6) of oc ular ADRs to cyclooxy genase-2 Inhib itors (238 reports of blurry vision and 71 of conj unct ivitis from celecox ib). 20 07 Santaella 49 Narr ative review Sev eral Sev eral drugs were assessed, such as: pamidron ate, alen dronat e, rised ronate, topir amate Narrative revi ew of several retrospective case series and report s o f ocul ar ADRs to spec ifi c syste mic drugs. 20 07 Sowka 50 Cas e report Si ldena fi l Opt ic atroph y after the use of silde na fi l in a 68-y ear old man. Case repo rt with a follo w-up of 4 mont hs. No causality as sessme nt of ADR no r WHO ’sd efi niti on of ADR was used . 20 08 Mandal 51 Two case repo rts Top iramate, > 6 mo nths, 10 0– 150 mg/day De fects in visual fi eld (case 1-qu adran tic defects, case 2-arc uate defec ts) Two case report s o f vis ual fi eld alterations induce d b y topirama te, (Naranjo ’s C A was pe rformed). 20 09 Bell 52 Ret rospectiv e study Tams ulosin Intra-opera tory fl oppy iris (IFIS) an d related surg ical outc omes Retrospective coho rt study of 96 128 patients: tamsulosine was associated with IFI S and intraoperatory com plicatio ns 20 09 Cordel 53 Tri al Si ldena fi l and tada la fi l Ele ctroretinography (ERG ) respon ses were the same for placebo , silde na fi l and tada la fi l. Subjects we re rand omized to use of a plac ebo (n = 82), tada la fi l (n = 85 ) o r sildena fi l (n = 77) daily for 6 m o nths. 20 09 El-Domyati 54 Cas e report Si ldena fi l A 48-year -old no nsmoker patient suff ered from nonart eritic ischem ic optic neur opathy . "Sev eral weeks later", the visual acu ity gradually improv ed Case repo rt. C ausality asse ssment of W H O was not perform ed. Follo w-up of "sev eral weeks later", not speci fi ed. 20 10 Richa 55 Narr ative review Psyc hotrop ics • Phenoth iazine s, lithium : kerato conj unctivitis A narra tive revi ew was perform ed with several psychotr opic dr ugs • Chlorpromazine: periocular pigmenta tion • Tricyclic antidepressants, topir amate : u v eitis • TCAs, typic al antipsy chotics, sele ctive serotonin reuptake inhib itors: my driasis 20 10 Al-Hu ssaini 56 Com prehens ive narra tive revi ew Alp ha-blo ckers Intra-opera tive Fl oppy Iris Syn drom e (IFIS). Review about IFIS and drugs. "Th ere is no evid enc e to supp ort alpha-blocker dis continu ation prior to surgery. " 20 11 Lebreton 57 Narr ative review with syste matic searc h C orticos teroids • Ocular hype rtensio n A narra tive revi ew was perform ed of ophtha lmic ADRs of cort icosteroids • Cataract (posterior subc apsula r) • Central Ser ous Chorioretinopa thy • Ptosis • Exophth almia 20 11 Azzou ni 58 Syst ematic revi ew Si ldena fi l Systema tic review of ocul ar ADRs by silde na fi l. WHO ’s cau sality as sessment was perform ed an d o f
(Continues
)
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Table 1. (Conti nued) Ye ar, auth or Study type Drug studied Oph thalmic ADR( s) report ed * Sum mary of study Ant erior and posterior nonart eritic ischem ic optic neurop athy, cen tral re tinal vein occlus ion, cilio-retinal artery occ lusion, acu te angl e closu re glau com a and op tic atro phy after sild ena fi l use. National Regist ry of Drug -Induce d Ocular Side Effects. 20 12 Seitz 59 Cas e-crosso ver study Ant idep ressants Ac ute angl e-clos ure glau com a (AACG) (o dds ratio for any antid epress ant expo sure in the period imme diately preceding AACG was 1.62, 95% con fi denc e interval of 1.16 –2.26) . Authors searched acute angle -closure glaucom a, and investigated whethe r they had an exposure to antidepressants p revious ly, using adm inistrative databases. 20 12 Saint-Je an 60 Cas e series In hibitor of epid ermal gr owth fa ctor receptor (EG FR) Multi ple epith elial defects, corne al melting , ectropion and corne al perfor ation (requi ring a p enetrating ke ratoplasty). Retrospective case series of 10 patients with ocul ar ADRs. De fi nition of ADR was no t used . 20 12 Neudor fer 61 Ret rospectiv e study of ou tcomes Isotr etinoin An association was foun d betwee n iso tretinoin and conjun ctivitis, ho rdeolum, chalazio n, blepha ritis, eye pain , and dry eye. Retrospective stu dy with medical database s to identify ADRs in patients using iso tretinoin. Table 2. Summ ary of op hthalmic adver se drug reactions Ther apeu tic group Dru g(s) respo nsible(s ) De scriptio n o f ocular ADR Classi fi cati on of ADR -Re porting studie s -Pati ent (P), ocular segme nt/complain ts (O) -Rawlin ’s type A/B -Stu dy ’s level of eviden ce (Oxf ord classi fi cation 62) -Com plementary examination (C) -Sev erity assessmen t (SA) ; causality as sessme nt (CA ) -Rev ersibility of ADR (R) , fo llow-up time (F) Ac ne trea ting age nts Isotretinoin Certai n ADRs : pseudotum our cerebri, mei bomian gla nd alte rations, blepha roc onjunct ivitis, kerat itis, m yopia, cor neal opacitie s, ocular discomf ort, dry eye , photo phobia , dec reased vis ion and terat ogenic ocular abnorm alities . (Ma ny othe r ADRs we re re ported). -Type A and B Narrative revi ew 18 and case series 45 (lev el 4) A recen t stu dy 61 iden tifi ed a haz ard ratio of 1.70 (p < 0.05) for oc ular ADRs afte r isotretinoin. -With CA (WHO ’s) Retro spective study using med ical data bases 61 (level 2c ) Ant i-allergic Anti-histamine s: cetirizine Pup illary chan ges, anis ocoria , decr eased acc ommod ation and blu rred vision. Dry ey e 47 -Type B: all except ocul ogyric crisis (A). Narrative revi ews 18,47 (level 4) Oculo gyri c crisis 18 :“ eye s and lids are tonic ally elevat ed and the neck is hypere xtended, usually withou t visual com plaints ”.I ti sa cert ain ADR . 18 -WHO ’s cau sality as sessment (CA) was perf ormed. 18 Ant i-arrhyth mics Flecainide Corne al depo sits : 1 4 .5% -Type A - Cross-sectional stu dy 44 Dry eye : 10.5% -N o C A nor SA -Leve l 2 c
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Table 2. (Conti nued) Ther apeu tic group Dru g(s) respo nsible(s ) De scriptio n o f ocular ADR Classi fi cati on of ADR -Re porting studie s -Pati ent (P), ocular segme nt/complain ts (O) -Rawlin ’s type A/B -Stu dy ’s level of eviden ce (Oxf ord classi fi cation 62) -Com plementary examination (C) -Sev erity assessmen t (SA) ; causality as sessme nt (CA ) -Rev ersibility of ADR (R) , fo llow-up time (F) -1 3 to 1 3 2 mont hs of follo w-up Amioda rone Corne al depo sits : 1 0 0 % o f the patients 32,46 -Type A: dr y eye , corne al and lens deposi ts. Res t: type B. - Cross-sectional stu dy 46 (lev el 2c) and narrative revi ews 18,32,46 (lev el 4) Anterio r subc apsula r lens depo sits 46 : 22% -WHO cau sality 18 Dry eye 46 :9 % Amio darone -optic neuropa thy 18 :m o re insidi ous in onset and reso lution , more bilateral, less involvem ent in visual acu ity compa red to non-arteritic ischa emic neuropa thy. Other 47 : Pho tosensitivity, pe riocular ski n pigm entatio n, blep harocon junctivitis, thyroid eye dis ease, los s o f eye lashes, pseu dotumo r cereb ri. -3 to 131 mo nths of fo llow-up in a pros pective study 46 Certai n ADRs 18 : photose nsitivity, co rneal deposi ts, vis ual cha nges , skin pigm entation, blep harocon junctivitis, thyroid eye disease. Ant iconvu lsivants -Carbam azepine (CB ) Diplo pia : cau sed by CB in 0.2 –4% of patients 36 (if CB + othe r anticonvuls ivants, frequen cy can rise to 88%). Dip lopia can be rever sible with dose redu ction. 36 -All Rawlin ’s type B (alth ough diplo pia may reso lve with do se reduc tion 38 ), exc ept: -Narr ative review base d o n case report s 36 -Pheny toin (PH) Nysta gmus : in 75% of patients with CB + PH. 36 Typ e A : dec rease d ocul ar move ments, mydr iasis, cha nges in conv ergence -All stu dies Leve l 4 -Pheno barbital (PB) and othe r barbitu rates Als o report ed after prim idone and PH . -No study with SA nor CA Decre ased oc ular m ovement s: b y C B and PB 36 Opht halmo plegia : b y P B and PH Oculo gyri c crisis : b y C B (in an 8-y., rever sible 36 ) Blurre d vision :C B 36 ; Mydr iasis :P H 36 Dis orders of con vergen ce, mios is : barbitu rates 36 Papil ledema :C B 36 (C, F: not speci fi ed in any study ) Ant idepressants and antipsicotics -Pheno tiazine (PT) Corne al and lens depo sits : b y PT, C P , 38 levo proma zine; these deposi ts usua lly do not interfere with vis ual acu ity -Usually typ e B (decreased accom modation is type A) -Narr ative review s o f case series of se veral psychi atric drugs 38,55 -Thior idazine Kerat opathy : Cornea l ede ma by PT (r eversible if sto pped), epite lial ke ratopathy b y C P 38 (visu al acu ity remains good, may be rever sible if C P is stopp ed) -N a C A n o r SA was perform ed -Pro spective study of risperidone 40 -Tricyclic antidepressants (TA ) Pig mentary retinopa thy 55 : b y thio ridazine (more fr equen t in hig h dose, may be irreve rsible); rarely also by CP and tri fl uoperaz ine 38 -Case crosso ver study 59 -Lithium Papil ledema , exoph thalm ia : lithium 38 -Chlorproma zine (CP)
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Table 2. (Conti nued) Ther apeu tic group Dru g(s) respo nsible(s ) De scriptio n o f ocular ADR Classi fi cati on of ADR -Re porting studie s -Pati ent (P), ocular segme nt/complain ts (O) -Rawlin ’s type A/B -Stu dy ’s level of eviden ce (Oxf ord classi fi cation 62) -Com plementary examination (C) -Sev erity assessmen t (SA) ; causality as sessme nt (CA ) -Rev ersibility of ADR (R) , fo llow-up time (F) -Leve l 4 (low evid enc e) for the na rrative review s, 38,55 leve l 2 c for case cros sover 59 and 2b for the pros pective study 40 Altera tion of saccadi c ey e movem ents : risperidone 38,40 -Mon oamine oxidas e inhibitors (MAO Is) Angl e-clos ure glaucoma : b y TA, in sus ceptible patients with shall ow ante rior cha mbe r 59,63 -Risperid one Decre ased accommo dat ion : TA, MA OIs (C, F, freque ncy: not speci fi ed ) Ant i-erectile dis function age nts Sildena fi l Certai n ADRs 18,47 : dyschr omatop sia (objec ts appea r more blue /green), bl urred vis ion , chan ges in light per ception , electro rretino gram changes, conjunc tival hype remia and photop hobia . -T ype A and B Narrative revi ews, 18,47 systematic revi ew of case reports 58 and case repo rt 50 (lev el 4) Case report 50 : o p tic atrophy (without CA). Trial 53 : n o chang es in electroretinogr aphy respon ses for plac ebo, sild ena fi l and tada la fi l (no ADR) . -W ith CA: W H O ’s 18,47 an d Naranjo ’s 58 Trial 53 (level 1b ) Others 58 : Ant erior an d posterior nonart eritic ischem ic optic neurop athy, cen tral retin al vein occ lusion, cilio-retinal artery occlus ion, acute angl e closure glau coma. -W ithout CA nor SA 50 Ant i-in fl amm atory drug s Cycloox ygena se-2 Inhibitors Blurry vision and conjunc tivitis by rofec oxib, celec oxib and valdeco xib (pos itive dec hallenge and rec hallenge tests) -T ype B Retro spective series of spon taneou s repo rts 48 (level 4) -W ith CA Corticos teroids Ocula r hype rtension : Odds ratio 1.41 (CI 95% 1.2 –1.6) 64 Glauco ma report edly in up to 30% of patients 32 -T ype A: cata ract Narrative revi ews 32,57 (level 4) Cata ract (posterior subc apsula r): 4.7% – 15.3% 65,32 -T ype B: other ADRs Case –cont rol studies 64,65 (level 3b ) Cen tral serou s cho rioretinopat hy :O R 3 7 (CI95 % 6– 222) 57 -W ithout CA nor SA Others: ptosis, exop hthalm ia (6 –8% 57 ), vira l retin itis, dela y in cor neal cicatrization Ben ign prostatic hy perplasia drug s Alpha-blocke rs (e.g. tamsulosin) Mor e post-op eratory complications (in 14 days ) in patie nts with tamsulo sine 52 : intra -operato ry fl op py iris -W ithout CA Retro spective study 52 of 96 128 patients (lev el 2b) Intra-opera tive Flop py Iris Syn drome (IFI S ). IFIS se verity is related with numb er of the follo wing cr iteria: -W ith SA Narrative revi ew with syste matic search 56 • iris billow s with intraocular irr igation curr ents • iris prolap se tend ency • intra opera tory pupil lary cons triction Biph osphon ates Pamidro nate Risedronate Alendronic acid Zolendron ate Risedronate sodiu m Etidronate dis sodium Anter ior uveiti s: uni or bilate ral, 24 h to 1 7 days after medication, 37 mild to severe (2 hosp italizations) -T ype B -Ret rospectiv e series of spon tane ous case report s 37 and narra tive revi ews 18,47 Scler itis, epis cleritis : unilate ral, in 1– 6 days . -No C A , 37 bu t recha llenge wa s perform ed in 5 patie nts with uveitis (4 positive rec hallenge tests) Conju nctivi tis : mil d, in 1– 48 h. -W ith CA 18 perform ed in a narra tive revi ew -Leve l 4
(Continues
)
Table 2. (Conti nued) Ther apeu tic group Dru g(s) respo nsible(s ) De scriptio n o f ocular ADR Classi fi cati on of ADR -Re porting studie s -Pati ent (P), ocular segme nt/complain ts (O) -Rawlin ’s type A/B -Stu dy ’s level of eviden ce (Oxf ord classi fi cation 62) -Com plementary examination (C) -Sev erity assessmen t (SA) ; causality as sessme nt (CA ) -Rev ersibility of ADR (R) , fo llow-up time (F) Nerve palsy, ret robu lbar neuritis , yello w vision, blurre d vision C, F, frequen cy: no t spec ifi ed. C ausality assessmen t 18,47 : Certai n ADR : blurre d vision , ocul ar irrita tion, conj unctivitis, pain , epip hora, photoph obia, anterior uvei tis, anterior scleritis, episcleritis, orbit al edema. Possib le : retrob ulbar ne uritis, yellow vision , diplo pia, cra nial ne rve palsy, ptosis , visua l hallu cinatio ns. Drug s used in hea rt failure Digoxin -3 6 -year-o ld female -Rawlin ’s: B /idios yncratic ADR -Case report 34 Dis chrom atopsi a + sc intillating visu al fi eld (VF) alterations, 3 mont hs after adm inistration of digox in -N o S A -Leve l 4 (low evid enc e). Man y othe r studies not included because tox ic digoxin leve ls Colour test FM-10 0: defec t o n blue colour. -N o C A -Rev ersibility, follow-up: not speci fi ed Drug s used in neop lastic dis orders Imatinib Perior bital edema (after CA, certain ADR) . -Type A: pe riorbital edema. Rest: type B. Narrative revi ew 18 (lev el 4) Epip hora (prob able ADR) -With CA (WHO ’s) Other possi ble ADRs: extra ocular mu scle pares is, ptosis and blepha roconj unct ivitis . Inhibitor of epidermal growth factor recep tor (EGFR ) Multi ple epith elial def ects (in 10 ey es of all cases), cornea l melting (in 3 eyes of 2 patients), lower lid ect ropion (2 eyes of 1 patient) and cor neal perfor ation requ iring a penetr ating kerato plasty (in 2 eyes of 2 patie nts). Variab le follo w-ups (all > 1 month) . -Type B Retro spective series of spon taneou s repo rts 60 (level 4) -N o C A nor SA Drug s used in Rhe umatology Chloroq uine Corne al depo sits, epiph ora, ophtha lmoplegia , pto sis -Type A: mac ulopath y (related to cum ulative do se), corne al deposi ts Narrative revi ews 18,32 (level 4) Hydrox ychlor oquine Macu lopathy : d ramatic retinop athy with macular atroph y in a bu ll’ s-ey e pattern. No frequen cy is repo rted but: “approx imately on e million peop le have used hydrox ychlor oquine , with only 20 cases of retin al toxicity in the low dose rang e (< 6.5 mg /kg/day )” 18 -Type B: ophtha lmop legia, ptosis Basel ine an d anual ophtha lmic exa minatio ns are recom mende d with: visual acuity, amsl er ’s grid, colo ur test, and ideally fund us photogr aph and visual fi eld. -With CA (WHO) 18 and withou t 32 Horm one-rela ted ther apy Oral cont raceptiv es Retina l hemo rrhag e o r emboli, Macula r edema , Papillary edema , R etrobulba r opt ic neur opathy -Rawlin ’s type B -Narr ative review 35 ba sed on few case reports (low ev idence) -Pati ent: no t spec ifi ed -N o S A -Leve l 4 -O cular segme nt: posterior (retinal alterations and pa pillary ede ma, va scular cha nges) -N oC A -Compl ementary exa minatio n: an giogra phy, CT scan
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Table 2. (Conti nued) Ther apeu tic group Dru g(s) respo nsible(s ) De scriptio n o f ocular ADR Classi fi cati on of ADR -Re porting studie s -Pati ent (P), ocular segme nt/complain ts (O) -Rawlin ’s type A/B -Stu dy ’s level of eviden ce (Oxf ord classi fi cation 62) -Com plementary examination (C) -Sev erity assessmen t (SA) ; causality as sessme nt (CA ) -Rev ersibility of ADR (R) , fo llow-up time (F) -Follo w-up: vari able (case repo rts) Leupro lide Blurre d vision : duration betwee n 1 h and 15 days , may be asso ciated with he adache s o r dizziness. -Type B -Serie s o f spon taneou s case report s 9 Other : papi lledem a, ocular pain ,“ ocular vascul ar acciden ts ” -N o C A nor SA -Leve l 4 Tamoxi fen Crys tallin retinopa thy : in the mac ula, may be asso ciated with mac ular ede ma -Usually typ e B -Narr ative review 41,47 Kerat opathy with whorl-like opacities -N o C A nor SA 41 -Leve l 4 Colour vision de fects -C A (WH O cau sality ) 47 Fove al disf unction with ERG chang es Doxorr ubicin Case 1: iritis, conjun ctivitis -Type B -Case series of 4 case s 33 (lev el 4) Case 2: perio rbital edem a -N o C A nor SA Case 3: keratit is Case 4: optic neu ropath y (F, C , follo w-up : not report ed) Lip id low ering age nts Niacin Dry eye (Fis her exact tes t p = 0.011) , -Type B -Case –contro l study 39 Blurre d vision (p = 0.0011 ) -No CA nor SA -Leve l 3 b Diplo pia (p = 0.5 , non statistically sig ni fi cant) Cysto id m aculopa thy (2 cases) Mi graine drug s Cyprohep tadin e,
pizotyline, amitriptiline, propran
olol, tim olol, clonidine, fl unarizine Dry eye : all -Type A -Narr ative review s 43,18 Diplo pia : cypr oheptadi ne, pizotyline, amy triptiline -N o S A nor CA -Leve l 4 Mydr iasis : cypr oheptadi ne, pizotyline, amy triptiline Decre ase in acc ommo dation : propran olol, timolo l Chang es in intraoc ular press ure : all Topirama te Certai n ADRs by top irama te : ac ute angle closur e glaucom a (usu ally bilate ral, in 1– 14 days , supr achor oidal effusion), decr eased vision, head aches, hype remia, mydria sis, uveiti s, visu al fi eld defect s, myop ia . -C A perf ormed by Fra unfelder 18 -Narr ative review s 18,51 Proba ble ADRs by topirama te : blepha rospa sm and oc ulogyric cris is . -Leve l 4 Case reports of others ADR s, as visual fi eld defec ts 51 Va ccines In fl uenza va ccine Case1 : 4 1 y , man , reve rsible anterio r uveiti s -Type B -Lette r with case report s 42 Case 2: 72 y, woma n, reactiva tion of her petic keratit is -N o C A nor SA were perfor med -Leve l 4 Case 3: 74 y, man , left ker atoplast y rej ection
prospective observational studies and trials). These
limitations were expected, because this was a
system-atic review with a very general scope and because
the detection of ophthalmic ADRs depends on the
de-gree of suspicion and an adequately performed
oph-thalmologic examination. Many ophthalmic ADRs
are only detected by case reports or spontaneous
re-ports, representing a limitation but simultaneously an
opportunity to improve. Consequently, there are many
ophthalmic ADRs that are based on a low level of
evidence. We believe this is an additional reason for
applying systematically the WHO de
finition for
ADR and a causality assessment (whether WHO
’s or
Naranjo
’s), in order to decrease doubts. High-risk drugs
such as the ones identi
fied in Table 2 should be
associ-ated with protocols of evaluation (especially in
suscepti-ble individuals or in high doses) by an ophthalmologist,
in order to detect sooner and with higher sensitivity and
speci
ficity the respective ophthalmic ADRs.
CONCLUSION
Ophthalmologists
’ education (to increase recognition of
ophthalmic ADRs) and the dissemination of protocols
of collaboration between Ophthalmology and other
Medicine specialties whenever they prescribe high-risk
drugs (such as sildena
fil, biphosphonates, psychiatric
medication, tamoxifen, hydroxichloroquine) are strong
suggestions for the future.
CONFLICT OF INTEREST
The authors declare no con
flict of interest.
KEY POINTS
•
Ophthalmology is perhaps one of the medical
specialties in which there are the few assessed
ADRs, but the eye is a complex organ in which
minimal impairment can produce a substantial
functional effect.
•
We performed a systematic review regarding
oph-thalmic ADRs to systemic drugs, to systematically
summarize evidence and to identify speci
fic areas
that lacked systematization or assessment.
•
From 562 studies initially found, only 32 were
in-cluded, and few studies had low risk of bias. Drugs
frequently involved included amiodarone,
sildena-fil, hydroxychloroquine and biphosphonates.
•
Many ophthalmic ADRs are frequent but remain
unnoticed; therefore, the systematization of
spe-ci
fic ophthalmic ADRs, the increase of knowledge
and the dissemination of protocols of collaboration
are suggested.
ETHICS STATEMENT
Authors confirm to have adhered to Ethics principles
and Helsinqui Declaration during all phases of this
study.
ACKNOWLEDGEMENTS
The authors would like to thank MSD for obtaining the
full text of 8 articles and Théa for obtaining the full text
of 7 articles.
Figure 2. Risk of bias graph
a. miguel
et al.
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